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Autoimmunity A bias from tolerance to immunity
815
Autoimmunity A bias from tolerance to immunity Editorial overview Pamela S Ohashi* and Nora Sarvetnickt Addresses
*Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, ON M5G 2M9, Canada tDepartment of Immunology, IMM23, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA Current Opinion in Immunology 1997, 9:815-817
http://biomednet.com/elecref/0952791500900815 © Current Biology 0952-7915 Abbreviations EAE experimental autoimmune encephalomyelitis insulin dependent diabetes mellitis IDDM LCMV lymphocytic choriomeningitis virus T cell receptor TCR transforming growth factor TGF TNF tumor necrosis factor tumor necrosis factor receptor TNFR
Autoimmune disease is a result of the breakdown of self tolerance to a level where a clinically detectable alteration in tissue function or metabolism occurs. To begin to understand the processes that lead to this state, it is important to dissect the mechanisms of lymphocyte tolerance to self antigens as well as processes that govern full T cell activation. It is this balance between tolerance and immunity that is disrupted in susceptible individuals leading to autoimmune disease. Self reactive lymphocytes may be tolerized to peripheral self ligands through mechanisms that include deletion and unresponsiveness. Studies collectively suggest that abundant self antigens may induce tolerance through peripheral T cell deletion. Recent experiments by Kurts et al. [1,2] have clearly shown that pancreatic self antigens may find their way to the local lymph nodes and induce tolerance by cross-priming after presentation on bone marrow derived cells. However, the properties of the bone marrow derived cells that bias the induction of deletion versus activation and autoimmunity are not known. A multitude of studies have begun to identify cell surface receptor/ligand complexes along with intracellular substrates that may be important in the induction of lymphocyte apoptosis (as reviewed by Wang and Lenardo (pp818-821). T h e tumor necrosis factor ( T N F ) / T N F R family of molecules have been shown to be involved in the induction and maintanence of peripheral T cell tolerance. Systemic autoimmunity has been associated with deficiencies in the CD95 pathway that lead to elimination of self reactive T and B cells as well as 'unchecked activation' (as reviewed by Hunig and Schimpl
pp826-830). Further breeding experiments in mice have demonstrated that the absence of both family members fas and T N F R 1 accentuate a similar disease [3]. However, the phenotype of having predominant CD4- CD8- B220 ÷ T C R ÷ lymphocytes and lymphadenopathy in this autoimmune model is peculiar and the underlying mechanisms of how this population arises and the significance for, or relevance to, 'normal' mechanisms of peripheral T cell tolerance is not clear. In addition, alternative pathways involving fas/fas ligand interactions may contribute to autoimmunity [4-6] . Other models have shown that IL-2 appears to be an extremely critical molecule for the control and maintenance of balanced T cell responses, without which conditions leading to autoimmune disease, including proliferation and activation of B cells, are favored (as reviewed by Hunig and Schimpl). Experiments have shown that apoptosis via the fas/fas ligand or IL-2/IL-2R pathways are potentially related, emphasizing the myriad mechanisms and checkpoints controlling peripheral T cell tolerance. Many other studies have demonstrated that a population of potentially autoreactive cells exists and remains unaware or 'ignorant' towards self ligands. Although it is not clear what percentage of the repertoire may potentially be autoreactive, recent reports in the literature have suggested that an 'unpredicted' flexibility exists between the T C R and potential ligands [7]. In many cases, the induction of autoimmunity may involve the full activation of these potentially autoreactive cells. This may occur through several mechanisms that have been discussed in the reviews in this issue. One favoured model for the induction of autoimmunity is through molecular mimicry. Environmental pathogens are predicted to carry distinct epitopes that induce pathogen-specific lymphocytes which have the misfortune of cross reacting with self ligands. T h e evidence for molecular mimicry has been outlined for human diseases (Hausmann and Wucherfennig pp831-838) and animal models (Tung et al. pp839-845). T h e importance of environmental pathogens and the induction of B cell-dominant autoimmune diseases have been discussed by Murakami and Honjo (pp846-850). Emerging data suggest that related cross-reactive T C R ligands that provide the basis for autoimmunity by molecular mimicry, may actually possess little sequence homology with the antigenic ligand. Hausmann and Wucherpfennig predict that the mature T cell repertoire
816
Autoimmunity
includes a spectrum of reactive T cells. At one extreme, T cells may be highly specific for their cognate ligand. However, these T cells are rarely engaged because of the extreme specificity requirements. At the other end of the spectrum, T C R interactions are relatively degenerate and may be frequently engaged and activated. It is speculated that these T cells would be potentially cross-reactive with self ligands and initiate autoimmune disease. Recent studies have identified a cross-reactive self ligand for a T C R that is specific for lymphocytic choriomeningitis virus (LCMV) (T Ohteki et al., personal communication). This related self ligand is derived from an enzyme, dopamine beta monoxogenase, and is expressed in the adrenal medulla. Noteably, LCMV infection of T C R transgenic mice fully activates virus specific cytolytic T cells and leads to inflammation of the adrenal medulla and alterations in dopamine metabolism. Thus a direct correlation has been shown between a pathogen, LCMV, and a related cross-reactive self ligand in vivo. Once self-reactive lymphocytes have been activated, the progression to autoimmune disease often involves further events that enhance disease progression in vivo. Studies with autoimmune ovarian disease in mice have highlighted the relevance of T - B epitope spreading (the recognition of minor epitopes that are not normally included in a primary response to a given antigen) and the requirement for the tissue specific antigens in disease progression, These studies have also emphasized the importance of T helper cell tolerance in maintaining B cell tolerance (see Tung et aL pp839-845).
the priming of autoreactive T cells prior to autoimmunity may lead to the effective blocking of such molecules in therapeutic strategies. King and Sarvemick have reviewed recent studies on the dependency of autoimmunity on specific CD40mediated costimulatory signals that have underscored the importance of these processes in autoimmunity in diabetes, myasthenia gravis and EAE. However, once immune responses are initiated a variety of factors, some genetic, influence the course and the pathogenicity of the autoreactive response. The participation of antigen presenting cells in the development of, and alteration in, the immune response to target antigens, with the potential for regulatory responses to arise, will be an interesting area for further study. T h e ability of soluble mediators to alter the course of immune and autoimmune responses has been the subject of much recent investigation. While the ability of Th2 type mediators (IL-4, ILl0) to inhibit initiating or ongoing autoimmunity has been clearly shown in some circumstances, these antagonistic relationships between the T cell subsets are far from straightforward or easily manageable. Additionally, there appears to be increasing evidence for the presence of other categories of regulatory cells from recent studies on NKI.1 T cells and TGF-13-producing regulatory cells. T h e ability of these factors to have diverse effects on T cell subtypes that collaborate or act temporally during autoimmune disease remains to be studied in greater detail.
Another important factor that contributes to the activation of self reactive cells is the induction of cytokines (Murakami and Honjo, Sacca et al. pp851-857) and appropriate costimulation (Lu et al. pp858-862, King and Sarvetnick pp863-871). Recent studies on the role of inflammatory mediators have elegantly demonstrated that the lymphotoxin/TNF family of molecules are integrally involved in lymphoid organ development. Furthermore, the notion that inflammation and lymphoid organ development are processes with similar features has emerged during the past year. These concepts are discussed in the review by Sacca et al. (pp851-857).
Accumulating evidence has evoked novel mechanisms that may regulate self tolerance in vivo. Hayday and Geng (pp884-889) have outlined compelling evidence that y8 T cells may be involved in the regulation of autoimmune disease. Studies have shown that 78 T cells do not recognize the conventional peptide/MHC ligand normally recognized by T cells expressing the ~ TCR. Instead, T cells expressing a y8 receptor may interact with natural self ligands induced by cellular stress, thereby potentially defining "1(8 T cells as self-reactive. In vivo evidence suggests that y8 T cells may regulate a variety of autoimmune diseases, possibly through interactions with 'stress'-associated ligands.
T h e role of specific costimulatory molecules and their contribution to the disease process is an important issue. As reviewed by Lu et al. (pp858--862), the CD80/CD86 molecules play critical roles in the immune response. However, blocking either one of these molecules during autoimmune disease results in entirely contrasting outcomes, which even vary in different diseases (EAE and IDDM) in the N O D mouse. Thus, the precise cellular players and their temporal role in the disease process may govern these responses. A greater understanding of
Overall it has been an exciting year with many advances in the tolerance and autoimmunity research area. T h e increased knowledge of initiating mechanisms combined with a further understanding of regulatory circuits involved in disease progression allow a more complete understanding of the pathways to disease. Conversely, the rather controversial area of counter-regulation by factors and T cells hints at the counter-balance that acts to keep peace in normal individuals, which could be heightened to prevent disease.
Editorial overview Ohashi and Sarvetnick
References and recommended reading 1.
Kurts C, Heath WR, Carbone FR, Allison J, Miller JFAP, Kosaka H: Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med 1996, 184:923-930.
2.
Kurts C, Kosaka H, Carbone FR, Miller JFAP, Heath WR: Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8 + T cells. J Exp Med 1997, 186:239-245.
3.
Zhou T, Edwards CK III, Yang P, Wang Z, Bluethmann H, Mountz JD: Greatly accelerated lymphadenopathy and autoimmune disease in Ipr mice lacking tumor necrosis factor receptor I. J Immuno/1996, 156:2661-2665.
817
4.
Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A: Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 1997, 275:960-963.
5,
Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA(?) Jr, Matis LA: The role of Fas in autoimmune diabetes. Ceil 1997, 89:17-24. Kang S, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, Baekkeskov S: Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 1997, 3:738-743.
6.
Kersh G J, Allen PM: Essential flexibility in the T-cell recognition of antigen. Nature 1996, 380:495-498.
Autoimmunity A bias from tolerance to immunity Editorial overview Pamela S Ohashi* and Nora Sarvetnickt Addresses
*Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, ON M5G 2M9, Canada tDepartment of Immunology, IMM23, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA Current Opinion in Immunology 1997, 9:815-817
http://biomednet.com/elecref/0952791500900815 © Current Biology 0952-7915 Abbreviations EAE experimental autoimmune encephalomyelitis insulin dependent diabetes mellitis IDDM LCMV lymphocytic choriomeningitis virus T cell receptor TCR transforming growth factor TGF TNF tumor necrosis factor tumor necrosis factor receptor TNFR
Autoimmune disease is a result of the breakdown of self tolerance to a level where a clinically detectable alteration in tissue function or metabolism occurs. To begin to understand the processes that lead to this state, it is important to dissect the mechanisms of lymphocyte tolerance to self antigens as well as processes that govern full T cell activation. It is this balance between tolerance and immunity that is disrupted in susceptible individuals leading to autoimmune disease. Self reactive lymphocytes may be tolerized to peripheral self ligands through mechanisms that include deletion and unresponsiveness. Studies collectively suggest that abundant self antigens may induce tolerance through peripheral T cell deletion. Recent experiments by Kurts et al. [1,2] have clearly shown that pancreatic self antigens may find their way to the local lymph nodes and induce tolerance by cross-priming after presentation on bone marrow derived cells. However, the properties of the bone marrow derived cells that bias the induction of deletion versus activation and autoimmunity are not known. A multitude of studies have begun to identify cell surface receptor/ligand complexes along with intracellular substrates that may be important in the induction of lymphocyte apoptosis (as reviewed by Wang and Lenardo (pp818-821). T h e tumor necrosis factor ( T N F ) / T N F R family of molecules have been shown to be involved in the induction and maintanence of peripheral T cell tolerance. Systemic autoimmunity has been associated with deficiencies in the CD95 pathway that lead to elimination of self reactive T and B cells as well as 'unchecked activation' (as reviewed by Hunig and Schimpl
pp826-830). Further breeding experiments in mice have demonstrated that the absence of both family members fas and T N F R 1 accentuate a similar disease [3]. However, the phenotype of having predominant CD4- CD8- B220 ÷ T C R ÷ lymphocytes and lymphadenopathy in this autoimmune model is peculiar and the underlying mechanisms of how this population arises and the significance for, or relevance to, 'normal' mechanisms of peripheral T cell tolerance is not clear. In addition, alternative pathways involving fas/fas ligand interactions may contribute to autoimmunity [4-6] . Other models have shown that IL-2 appears to be an extremely critical molecule for the control and maintenance of balanced T cell responses, without which conditions leading to autoimmune disease, including proliferation and activation of B cells, are favored (as reviewed by Hunig and Schimpl). Experiments have shown that apoptosis via the fas/fas ligand or IL-2/IL-2R pathways are potentially related, emphasizing the myriad mechanisms and checkpoints controlling peripheral T cell tolerance. Many other studies have demonstrated that a population of potentially autoreactive cells exists and remains unaware or 'ignorant' towards self ligands. Although it is not clear what percentage of the repertoire may potentially be autoreactive, recent reports in the literature have suggested that an 'unpredicted' flexibility exists between the T C R and potential ligands [7]. In many cases, the induction of autoimmunity may involve the full activation of these potentially autoreactive cells. This may occur through several mechanisms that have been discussed in the reviews in this issue. One favoured model for the induction of autoimmunity is through molecular mimicry. Environmental pathogens are predicted to carry distinct epitopes that induce pathogen-specific lymphocytes which have the misfortune of cross reacting with self ligands. T h e evidence for molecular mimicry has been outlined for human diseases (Hausmann and Wucherfennig pp831-838) and animal models (Tung et al. pp839-845). T h e importance of environmental pathogens and the induction of B cell-dominant autoimmune diseases have been discussed by Murakami and Honjo (pp846-850). Emerging data suggest that related cross-reactive T C R ligands that provide the basis for autoimmunity by molecular mimicry, may actually possess little sequence homology with the antigenic ligand. Hausmann and Wucherpfennig predict that the mature T cell repertoire
816
Autoimmunity
includes a spectrum of reactive T cells. At one extreme, T cells may be highly specific for their cognate ligand. However, these T cells are rarely engaged because of the extreme specificity requirements. At the other end of the spectrum, T C R interactions are relatively degenerate and may be frequently engaged and activated. It is speculated that these T cells would be potentially cross-reactive with self ligands and initiate autoimmune disease. Recent studies have identified a cross-reactive self ligand for a T C R that is specific for lymphocytic choriomeningitis virus (LCMV) (T Ohteki et al., personal communication). This related self ligand is derived from an enzyme, dopamine beta monoxogenase, and is expressed in the adrenal medulla. Noteably, LCMV infection of T C R transgenic mice fully activates virus specific cytolytic T cells and leads to inflammation of the adrenal medulla and alterations in dopamine metabolism. Thus a direct correlation has been shown between a pathogen, LCMV, and a related cross-reactive self ligand in vivo. Once self-reactive lymphocytes have been activated, the progression to autoimmune disease often involves further events that enhance disease progression in vivo. Studies with autoimmune ovarian disease in mice have highlighted the relevance of T - B epitope spreading (the recognition of minor epitopes that are not normally included in a primary response to a given antigen) and the requirement for the tissue specific antigens in disease progression, These studies have also emphasized the importance of T helper cell tolerance in maintaining B cell tolerance (see Tung et aL pp839-845).
the priming of autoreactive T cells prior to autoimmunity may lead to the effective blocking of such molecules in therapeutic strategies. King and Sarvemick have reviewed recent studies on the dependency of autoimmunity on specific CD40mediated costimulatory signals that have underscored the importance of these processes in autoimmunity in diabetes, myasthenia gravis and EAE. However, once immune responses are initiated a variety of factors, some genetic, influence the course and the pathogenicity of the autoreactive response. The participation of antigen presenting cells in the development of, and alteration in, the immune response to target antigens, with the potential for regulatory responses to arise, will be an interesting area for further study. T h e ability of soluble mediators to alter the course of immune and autoimmune responses has been the subject of much recent investigation. While the ability of Th2 type mediators (IL-4, ILl0) to inhibit initiating or ongoing autoimmunity has been clearly shown in some circumstances, these antagonistic relationships between the T cell subsets are far from straightforward or easily manageable. Additionally, there appears to be increasing evidence for the presence of other categories of regulatory cells from recent studies on NKI.1 T cells and TGF-13-producing regulatory cells. T h e ability of these factors to have diverse effects on T cell subtypes that collaborate or act temporally during autoimmune disease remains to be studied in greater detail.
Another important factor that contributes to the activation of self reactive cells is the induction of cytokines (Murakami and Honjo, Sacca et al. pp851-857) and appropriate costimulation (Lu et al. pp858-862, King and Sarvetnick pp863-871). Recent studies on the role of inflammatory mediators have elegantly demonstrated that the lymphotoxin/TNF family of molecules are integrally involved in lymphoid organ development. Furthermore, the notion that inflammation and lymphoid organ development are processes with similar features has emerged during the past year. These concepts are discussed in the review by Sacca et al. (pp851-857).
Accumulating evidence has evoked novel mechanisms that may regulate self tolerance in vivo. Hayday and Geng (pp884-889) have outlined compelling evidence that y8 T cells may be involved in the regulation of autoimmune disease. Studies have shown that 78 T cells do not recognize the conventional peptide/MHC ligand normally recognized by T cells expressing the ~ TCR. Instead, T cells expressing a y8 receptor may interact with natural self ligands induced by cellular stress, thereby potentially defining "1(8 T cells as self-reactive. In vivo evidence suggests that y8 T cells may regulate a variety of autoimmune diseases, possibly through interactions with 'stress'-associated ligands.
T h e role of specific costimulatory molecules and their contribution to the disease process is an important issue. As reviewed by Lu et al. (pp858--862), the CD80/CD86 molecules play critical roles in the immune response. However, blocking either one of these molecules during autoimmune disease results in entirely contrasting outcomes, which even vary in different diseases (EAE and IDDM) in the N O D mouse. Thus, the precise cellular players and their temporal role in the disease process may govern these responses. A greater understanding of
Overall it has been an exciting year with many advances in the tolerance and autoimmunity research area. T h e increased knowledge of initiating mechanisms combined with a further understanding of regulatory circuits involved in disease progression allow a more complete understanding of the pathways to disease. Conversely, the rather controversial area of counter-regulation by factors and T cells hints at the counter-balance that acts to keep peace in normal individuals, which could be heightened to prevent disease.
Editorial overview Ohashi and Sarvetnick
References and recommended reading 1.
Kurts C, Heath WR, Carbone FR, Allison J, Miller JFAP, Kosaka H: Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med 1996, 184:923-930.
2.
Kurts C, Kosaka H, Carbone FR, Miller JFAP, Heath WR: Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8 + T cells. J Exp Med 1997, 186:239-245.
3.
Zhou T, Edwards CK III, Yang P, Wang Z, Bluethmann H, Mountz JD: Greatly accelerated lymphadenopathy and autoimmune disease in Ipr mice lacking tumor necrosis factor receptor I. J Immuno/1996, 156:2661-2665.
817
4.
Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A: Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 1997, 275:960-963.
5,
Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA(?) Jr, Matis LA: The role of Fas in autoimmune diabetes. Ceil 1997, 89:17-24. Kang S, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, Baekkeskov S: Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 1997, 3:738-743.
6.
Kersh G J, Allen PM: Essential flexibility in the T-cell recognition of antigen. Nature 1996, 380:495-498.