AUTOIMMUNITY - Human & Disease

AUTOIMMUNITY

 AUTOIMMUNITY

What is tolerance?

Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.










Is tolerance innate or acquired?

The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.”

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.










What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens?

Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are:

• Central tolerance.

• Thymic selection of T cells 

during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.


• Receptor-editing of BCRs:

this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing.

• Peripheral tolerance.

• Clonal anergy :

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.








self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.









• Immunologic ignorance:

self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection.

• Tregs and Bregs: 

some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10.

• Idiotype network theory: 

a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.









What is autoimmunity?
The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.









However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories:

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.













• Organ-specific autoimmunity: 

defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]).

• Systemic autoimmunity:
 
defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]).

What are the stages of an autoimmune disease?

Autoimmune diseases generally follow three stages:
1. Genetic risk: 

some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition.

2. Autoimmunity:

 the development of autoimmune phenomena such as autoantibodies produced by B cells that
have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.










3. Disease:

 the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.













AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.









The mechanisms that may be involved in the pathogenesis of autoimmune disease.

Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . 

More than one of the following possible mechanisms may contribute to the development of autoimmunity:

• Superantigens:

 these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help.

• T-B cell discordance with abnormal receptor-mediated feedback and suppression: 

T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process.

• Molecular mimicry: 

an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response.

• Cytokine dysregulation:

 innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells.

• Defective apoptosis:

 accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.









• Epitope spreading:

 occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes.

• Cryptic epitope exposure:

 the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue.

What is the difference between autoinflammatory disease and an autoimmune disease?

Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.

AUTOIMMUNITY What is tolerance? Tolerance is the term used to describe the phenomenon of antigen-specific unresponsiveness. In other words, the immune system encounters certain antigens to which it is programmed specifically to not respond and therefore, not eradicate. Is tolerance innate or acquired? The phenomenon of tolerance is present in both innate and adaptive immune systems. We are protected from the innate immune system by specific mechanisms that block its activities, such as membrane complement regulatory proteins that protect self-tissues from the alternative complement pathway. The adaptive immune system “learns” to be tolerant of some specific antigens, such as self-tissues, just as it learns to be “intolerant” of many foreign antigens. When discussing autoimmune disorders, we often narrow our perspective to the tolerance of autoantigens, such as an individual’s own nucleoproteins or cell-surface molecules, by the adaptive immune system. However, the phenomenon of tolerance is not limited to autoantigens. In fact, tolerance to exogenous antigens, such as dietary proteins, is just as crucial for the survival of an individual as “self-tolerance.” What are the main pathogenetic mechanisms used to develop and maintain tolerance to self-antigens? Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are: • Central tolerance. • Thymic selection of T cells : during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery. • Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing. • Peripheral tolerance. • Clonal anergy : self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system. • Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/ peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection. • Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL- 10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10. • Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies. What is autoimmunity? The term autoimmunity is commonly employed to describe conditions in which self-tolerance is broken and an individual becomes the victim of his or her own immune response. Just like immunity to foreign antigens, autoimmune disorders are antigen-driven processes that are characterized by specificity, high affinity, and memory. However, an autoimmune process involves the immune system’s recognition of an antigen, either foreign or self, that is then followed by an assault on its own self-antigens (i.e., autoantigens). Typically, these processes develop in an individual who previously displayed tolerance to the same antigens that are now targeted by the immune response. Therefore, most autoimmune processes are better described not simply as an absence of tolerance but as a loss of previously established tolerance. Clinically, autoimmunity can be divided into two categories: • Organ-specific autoimmunity: defined as an immune response against a single autoantigen or a restricted group of autoantigens within a given organ (e.g., myasthenia gravis [antibodies to acetylcholine receptor]). • Systemic autoimmunity: defined as an immune response against multiple autoantigens resulting in clinical manifestations in multiple organs (e.g., systemic lupus erythematosus [SLE]). What are the stages of an autoimmune disease? Autoimmune diseases generally follow three stages: 1. Genetic risk: some genes contribute significant risk (e.g., HLA), whereas most genes (e.g., PTPN22, STAT4) confer a modest risk (usually 2–3 fold), but in aggregate, the risk is quite high in the setting of a combination of disease-promoting polymorphisms, which are usually (90%) in regulatory proteins and the “right” environmental exposure. Epigenetics (DNA methylation, histone modifications, microRNAs) also contribute to the genetic predisposition. 2. Autoimmunity: the development of autoimmune phenomena such as autoantibodies produced by B cells that have lost self-tolerance (and presumably driven by autoimmune T cells) but in a state wherein the individual still does not exhibit symptoms because the target organs have not yet become damaged to a sufficient level. 3. Disease: the third stage is the development of clinical symptoms that impair quality of life and require treatment. Although most autoimmune diseases are detected and treated only in the third phase, ongoing work in several diseases is expected to allow the detection of a “preclinical” disease state in which specific preventive therapies could be used. The mechanisms that may be involved in the pathogenesis of autoimmune disease. Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops . More than one of the following possible mechanisms may contribute to the development of autoimmunity: • Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help. • T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process. • Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response. • Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells. • Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells. • Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. • Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue. What is the difference between autoinflammatory disease and an autoimmune disease? Autoinflammatory diseases (e.g., Familial Mediterranean fever, Familial Autoinflammatory Syndromes) are diseases that have a chronic inflammatory response due to a defect in a component or regulation of the innate immune system. Autoimmune diseases (e.g., SLE) typically involve self-reactive CD4+ T lymphocytes and abnormalities in regulation of the adaptive immune system.
Next Post Previous Post