- Email: [email protected]
Editorial overview
661
Autoimmunity Editorial overview Christophe Benoist* and Maureen Howard† Addresses *Immunology Section, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA; e-mail: [email protected] †Division of Autoimmune Diseases, Corixa, 301 Penobscot Drive, Redwood City, CA 94063, USA; e-mail: [email protected] Current Opinion in Immunology 2000, 12:661–663 0952-7915/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved.
Introduction Autoimmune deviation and disease remains one of the more obscure areas of immunology. Although we have detailed knowledge of immune receptors and co-stimulatory molecules, we are still unable to frame a coherent explanation of autoimmunity or to explain why a particular individual presents with, for example, diabetes or myasthenia gravis. Similarly, although these are exciting times for the development of therapeutic approaches directly downstream from gene discoveries and animal models of the past decade, no immunological therapy can make the claim today of having solved an autoimmune condition. The reviews in this section illustrate several important areas of progress in the past few years.
Identifying antigens Identifying the target autoantigen in an autoimmune situation is a key element in approaching the particular disease. As illustrated by Elson and Barker (pp 664–669), this has been accomplished far more effectively in the area of immunglobulin-mediated diseases than for those diseases where T cells are thought to play the dominant effector role. As discussed by Mocci, Lafferty and Howard (pp 725–730), it is still unclear for several T cell mediated diseases whether ‘The Antigen’ exists: is there one selfstructure that represents the dominant target throughout the course of autoimmune progression? There have been several provocative reports in the past year that identified key autoantigens in such diseases. Two such culprits, insulin and GAD, have been highlighted for Type I diabetes in the NOD mouse model. These were not newcomers, as they had been previously shown to be autoimmune targets, but the surprise was in the dominance of the anti-insulin response and in the completeness of the protection afforded by GAD-antisense transgenes. The two observations are not necessarily contradictory, as the two targets could conceivably be involved at different stages and stimulate different populations. They do, however, need confirmation in independent approaches. The generality of these observations, particularly to human disease, also needs to be addressed. In any case, the concept
of multiple, distinct autoantigens for a particular autoimmune disease playing critical pathogenic roles in individual or different patients does not necessarily jeopardize antigen-specific therapeutic strategies if, as hypothesized by Mocci, Howard and Lafferty, the strategies operate via mechanisms of bystander suppression and/or modulation of events that regulate tolerance. Equally important, and directly linked to the issue of autoantigen identification, is the necessity to be able to quantitate and trace autoaggressive T cells in affected individuals. Such a capability would be highly desirable in basic studies of autoimmune pathogenesis in order to understand the biology of autoimmune T cells in a normal context, free of the over-representations that are induced by transgenic TCR expression. More importantly, such a tool is needed to monitor protocols for tolerogenic or immunomodulatory protocols that are currently being tested in clinical trials. Present assays are cumbersome and finicky, have dismal signal : noise ratios even in the best of hands and are thus maladapted in practice to monitor therapeutic protocols for tolerance/transplantation. A seductive solution lies in the use of multimerized MHC–peptide compounds, which have demonstrated informativeness in following infectious or antitumor responses. The cogent review by Ferlin, Glaichenhaus and Mougneau (pp 670–675) describes the current attempts that are being made to use such reagents in autoimmune contexts (findings have included an important negative result from the Denver group, i.e. the absence of T cells specific for an immunodominant peptide from collagen in joints of rheumatoid arthritis patients). Although all technical problems have not been fully resolved (particularly for MHC class II multimers), the technique appears to hold much promise. Elson and Barker present a comprehensive analysis of diseases in which the effector mechanisms have been resolutely ascribed to autoantibodies. In these cases, the target antigens have been identified and the pathogenic nature of the antibodies well established. Yet investigations must now move one step back — to identify the self-peptides that stimulate the T helper populations that underlie the production of these antibodies. In most instances, the hurdles are the same as those encountered with T cell mediated diseases but carry the same hope that T cell directed immunointervention may block autoantibody production.
Regulatory cells The importance (or rather the failure) of immunoregulatory cells in autoimmune diseases is an emerging theme that has gathered much attention in the past few years. As reviewed in depth by Roncarolo and Levings (pp 676–683),
662
Autoimmunity
a number of reports have described cell populations that are capable, in cell transfer systems, of dampening or preventing the actions of autoimmune T cells. The impact of regulatory cells also constitutes an important element of Sakaguchi’s presentation (pp 684–690) of recent results on animal models of autoimmunity. This is a loaded subject, however. Immunology carries the weight of an ‘original sin’ — the exuberant descriptions of suppressor cell circuits circa 1980. The phenomenology that was thought to be due to specific suppression was later shown to reflect either a deviation and a switch to other response modes that were missed in the original assays or, in other cases, insufficiently rigorous interpretation of borderline data. The present line of research must thus overcome the taboo that covers ‘suppression’ but also avoid repeating past errors. For example, interpretation of results may be strongly influenced by the recently recognized behavior of naïve T cells that are transferred into lymphopenic environments — a frequent situation in such assays — in which they acquire enhanced response characteristics similar to those of memory cells (recently reviewed by Surh and Sprent [1]). Thus, the aggressive or the regulatory populations (or both) may acquire unusual phenotypic properties as a consequence of homeostatic expansion. In some studies, the experimental readouts (disease/no-disease) are too simplistic for such complex biological systems. Finally, some experimental results may not reflect ‘regulatory’ cells proper — the term carries a strong teleological element of implied function — but merely nonspecific deviation or response dampening (alteration of homeostatic cues, exhaustion of cytokine supplies, etc.). The brief history of ‘suppressorology’ should inspire caution: “Les peuples qui oublient l’Histoire sont condamnés à la répéter”. Regulatory populations have been described in a variety of experimental contexts using different reagents or markers. Roncarolo and Levings take a gallant stab at sorting the data to bring out consistent findings that might allow the definition of unique populations but the authors stress that it is an arduous task. Surface markers on these cells lack specificity, in that they are shared with activated or memory cells. Likewise, the expression of particular cytokines (IL-10 and TGF-β) is not specific and its importance may depend on the experimental context. Some lines of convergence do come out, though; for example, the CD45RBlo subset described in some systems is likely to be the same population as the CD25+ cells described in others. Aside from their basic identification, many tantalizing questions remain about these cells. For example, what is their origin, their receptor specificity and their relationship with anergized or deviated byproducts of tolerance induction? Is their sole mode of action via immunodepressing cytokines?
Genetics Genetic components have a major role in the determinism of autoimmune diseases although they are by no means
the only cause. Encinas and Kuchroo (pp 691–697) describe the present status of the linkage analyses of genetic polymorphisms with human and rodent diseases. This is very much still ‘work in progress’, with few or no genes yet formally identified. Encinas and Kuchroo do bring out dominant concepts that have come from these studies. One is that a number of the regions identified are shared between different autoimmune diseases. Although some may be ‘fortuitous’ (many assignments are still at a low level of resolution), it appears that some loci confer a generic propensity to autoimmunity. It is fairly logical that alleles conferring broad lymphocyte over-responsiveness could have such an effect (akin to the phenotypes of mice with knockouts for some regulatory cytokines, e.g. CTLA-4 or TGF-β). The second concept is that of complexity. It has long been recognized that the majority of autoimmune diseases are polygenic (with APECED as a noted exception), requiring additive contributions from a constellation of loci. This complexity may have been over-estimated (many reported loci do not reach full statistical significance or contribute only minimally to genetic variance, or may reflect epigenetic effects that we have not fathomed). Yet, as analyses reach finer resolution, a frequent observation is that of an additional layer of complexity: in several instances, the genetic regions identified in the first screens turn out to harbor two or three susceptibility/resistance loci. These observations bring back the notion of haplotypes, or the concerted action of tightly linked and co-inherited gene groups, a concept that was first applied to the function and evolution of the MHC. Overall, this work has been hard slogging but the persistent efforts of some groups have now brought several of these loci into the range of resolution that allows them to be approached by high-throughput sequencing. Undoubtedly, the existing or forthcoming complete sequences of the human and mouse genomes will provide a major boost to these studies. The inability to assess directly the contribution of specific genes and cell populations has always been a major roadblock for investigators working with human diseases (and these scientists have sat longingly through meeting sessions devoted to transgenic mice). Germline manipulation, cell transfers and even simple, directed immunisations are forbidden tools for studies in humans. The new developments reviewed by Fugger (pp 698–703) may bring this unfair advantage to a close: transgenic mice now exist in which human MHC or TCR genes, or combinations thereof, function in lieu of their murine counterparts. The suitable choice of alleles means that it should be possible to test the link between allelic variation and disease susceptibility in these chimeric mice or to map the dominant epitopes of human autoantigens. These are early days, of course, as it may prove important to ‘humanize’ several coreceptor or co-stimulatory genes as well and perhaps to aim for more faithful expression by gene knockins rather than
Editorial overview Benoist and Howard
by classical transgenesis. Yet the first results are exciting and indicate this will be a productive strategy. Ultimately, one might dream of massive parallel transgenesis, yielding a mouse in which all CD genes and assorted MHC, TCR and immunoglobulin loci have been switched to their human counterpart.
Novel therapeutic approaches Together, the reviews by Harrison and Hafler (pp 704–711), and Illei and Lipsky (pp 712–718) present a panorama of present attempts at, and successes with, immunomodulatory therapies in patients. Antigen-specific tolerance induction represents, of course, the ‘Holy Grail’ of immune manipulation, selectively targeting disease-causing lymphocytes. It has precedent in animal models, many of which have demonstrated sensitivity to a variety of tolerance induction regimens. As shown by Harrison and Hafler, we are witnessing an explosion in the approaches that are currently being followed. Some trials deal with the more classical routes of tolerogen administration: mucosal (oral or nasal) routes, which may be complicated by the fact that antigen thus presented can also induce responses and cytotoxic T lymphocyte activity; or systemic modes of administration, in particular with the large DPT-1 trial of systemic insulin administration for the prevention of insulin-dependent diabetes mellitus. Altered peptide ligands (APLs) and the anergy that they can induce in autoantigen-reactive T cells may be worthwhile agents in some cases. Yet what is an antagonist APL for a given T cell may well be a stimulatory agonist for another, making the therapy problematic on a population basis. More exotic approaches (e.g. transduction of antigen-reactive T cells with vectors expressing immumoregulatory cytokines or tolerance induction by plasmid-DNA immunization) require a better analysis of their potential in animal-model systems. Finally, early results with the use of various types of soluble MHC–peptide chimeric molecules are looking promising in both mouse models and early human clinical trials. Cop-1 (glatimer acetate) is an intriguing compound that probably bridges antigen-specific and -nonspecific approaches. Originally thought to be an analog of myelin basic protein, this synthetic copolymer seems to have some efficacy for multiple sclerosis patients. It is now believed to act more by multivalent low-affinity triggering of T cells, perhaps thus nonspecifically deviating ongoing
663
responses to self-antigens. Cytokines and their receptors are the main targets of non-specific therapeutic approaches, reviewed in depth by Illei and Lipsky. Agents that block TNF signalling are the big success story, with their marked activity in rheumatoid arthritis. It will be important to see whether the disease manifestations that persist in many anti-TNF-treated patients are susceptible to IL-1-directed intervention, as some of the animal models might suggest. Among therapies that target costimulatory molecules, CTLA4–Ig seems perhaps the most promising in early trials, in keeping with striking data that had previously been obtained in mice. On the other hand, the blockade of other key costimulatory molecules (CD40L/CD154 in particular) has been more disappointing in practise.
Apoptosis And in the end, of course, there must be death. Vaux and Flavell (pp 719–724) present today’s view of this key biological process, which underlies both the ability to tolerize autoreactive lymphocytes and the final effector mechanisms that lead to destruction of the target tissues. Complexity, here, is also the order of the day. Charts of intracellular apoptosis pathways linking death receptors, caspases and pro- or anti-apoptotic regulators grow more complex every year, in particular with the realisation that what had initially appeared to be simple linear pathways are really multibranched, redundant and interconnected. As Vaux and Flavell point out, major autoimmune diseases are not due to mutations in single death-controlling loci, as could in theory have been expected, probably because of multilevel redundancy and control pathways. At the same time, the effect of mutations or transgenic overexpression of single molecules can have obvious autoimmune consequences, in particular for members of the TNF-receptor family. Ultimately, reaching an understanding and managing autoimmunity may mean coming to terms with complexity, at the inter- and intra-cellular levels, and realising that the simplistic schemas the human mind can encompass are insufficient to deal with the full extent of biological complexity.
Reference 1.
Surh CD, Sprent J: Homeostatic T cell proliferation. How far can T cells be activated to self-ligands? J Exp Med 2000, 192:F9-F14.
Autoimmunity Editorial overview Christophe Benoist* and Maureen Howard† Addresses *Immunology Section, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA; e-mail: [email protected] †Division of Autoimmune Diseases, Corixa, 301 Penobscot Drive, Redwood City, CA 94063, USA; e-mail: [email protected] Current Opinion in Immunology 2000, 12:661–663 0952-7915/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved.
Introduction Autoimmune deviation and disease remains one of the more obscure areas of immunology. Although we have detailed knowledge of immune receptors and co-stimulatory molecules, we are still unable to frame a coherent explanation of autoimmunity or to explain why a particular individual presents with, for example, diabetes or myasthenia gravis. Similarly, although these are exciting times for the development of therapeutic approaches directly downstream from gene discoveries and animal models of the past decade, no immunological therapy can make the claim today of having solved an autoimmune condition. The reviews in this section illustrate several important areas of progress in the past few years.
Identifying antigens Identifying the target autoantigen in an autoimmune situation is a key element in approaching the particular disease. As illustrated by Elson and Barker (pp 664–669), this has been accomplished far more effectively in the area of immunglobulin-mediated diseases than for those diseases where T cells are thought to play the dominant effector role. As discussed by Mocci, Lafferty and Howard (pp 725–730), it is still unclear for several T cell mediated diseases whether ‘The Antigen’ exists: is there one selfstructure that represents the dominant target throughout the course of autoimmune progression? There have been several provocative reports in the past year that identified key autoantigens in such diseases. Two such culprits, insulin and GAD, have been highlighted for Type I diabetes in the NOD mouse model. These were not newcomers, as they had been previously shown to be autoimmune targets, but the surprise was in the dominance of the anti-insulin response and in the completeness of the protection afforded by GAD-antisense transgenes. The two observations are not necessarily contradictory, as the two targets could conceivably be involved at different stages and stimulate different populations. They do, however, need confirmation in independent approaches. The generality of these observations, particularly to human disease, also needs to be addressed. In any case, the concept
of multiple, distinct autoantigens for a particular autoimmune disease playing critical pathogenic roles in individual or different patients does not necessarily jeopardize antigen-specific therapeutic strategies if, as hypothesized by Mocci, Howard and Lafferty, the strategies operate via mechanisms of bystander suppression and/or modulation of events that regulate tolerance. Equally important, and directly linked to the issue of autoantigen identification, is the necessity to be able to quantitate and trace autoaggressive T cells in affected individuals. Such a capability would be highly desirable in basic studies of autoimmune pathogenesis in order to understand the biology of autoimmune T cells in a normal context, free of the over-representations that are induced by transgenic TCR expression. More importantly, such a tool is needed to monitor protocols for tolerogenic or immunomodulatory protocols that are currently being tested in clinical trials. Present assays are cumbersome and finicky, have dismal signal : noise ratios even in the best of hands and are thus maladapted in practice to monitor therapeutic protocols for tolerance/transplantation. A seductive solution lies in the use of multimerized MHC–peptide compounds, which have demonstrated informativeness in following infectious or antitumor responses. The cogent review by Ferlin, Glaichenhaus and Mougneau (pp 670–675) describes the current attempts that are being made to use such reagents in autoimmune contexts (findings have included an important negative result from the Denver group, i.e. the absence of T cells specific for an immunodominant peptide from collagen in joints of rheumatoid arthritis patients). Although all technical problems have not been fully resolved (particularly for MHC class II multimers), the technique appears to hold much promise. Elson and Barker present a comprehensive analysis of diseases in which the effector mechanisms have been resolutely ascribed to autoantibodies. In these cases, the target antigens have been identified and the pathogenic nature of the antibodies well established. Yet investigations must now move one step back — to identify the self-peptides that stimulate the T helper populations that underlie the production of these antibodies. In most instances, the hurdles are the same as those encountered with T cell mediated diseases but carry the same hope that T cell directed immunointervention may block autoantibody production.
Regulatory cells The importance (or rather the failure) of immunoregulatory cells in autoimmune diseases is an emerging theme that has gathered much attention in the past few years. As reviewed in depth by Roncarolo and Levings (pp 676–683),
662
Autoimmunity
a number of reports have described cell populations that are capable, in cell transfer systems, of dampening or preventing the actions of autoimmune T cells. The impact of regulatory cells also constitutes an important element of Sakaguchi’s presentation (pp 684–690) of recent results on animal models of autoimmunity. This is a loaded subject, however. Immunology carries the weight of an ‘original sin’ — the exuberant descriptions of suppressor cell circuits circa 1980. The phenomenology that was thought to be due to specific suppression was later shown to reflect either a deviation and a switch to other response modes that were missed in the original assays or, in other cases, insufficiently rigorous interpretation of borderline data. The present line of research must thus overcome the taboo that covers ‘suppression’ but also avoid repeating past errors. For example, interpretation of results may be strongly influenced by the recently recognized behavior of naïve T cells that are transferred into lymphopenic environments — a frequent situation in such assays — in which they acquire enhanced response characteristics similar to those of memory cells (recently reviewed by Surh and Sprent [1]). Thus, the aggressive or the regulatory populations (or both) may acquire unusual phenotypic properties as a consequence of homeostatic expansion. In some studies, the experimental readouts (disease/no-disease) are too simplistic for such complex biological systems. Finally, some experimental results may not reflect ‘regulatory’ cells proper — the term carries a strong teleological element of implied function — but merely nonspecific deviation or response dampening (alteration of homeostatic cues, exhaustion of cytokine supplies, etc.). The brief history of ‘suppressorology’ should inspire caution: “Les peuples qui oublient l’Histoire sont condamnés à la répéter”. Regulatory populations have been described in a variety of experimental contexts using different reagents or markers. Roncarolo and Levings take a gallant stab at sorting the data to bring out consistent findings that might allow the definition of unique populations but the authors stress that it is an arduous task. Surface markers on these cells lack specificity, in that they are shared with activated or memory cells. Likewise, the expression of particular cytokines (IL-10 and TGF-β) is not specific and its importance may depend on the experimental context. Some lines of convergence do come out, though; for example, the CD45RBlo subset described in some systems is likely to be the same population as the CD25+ cells described in others. Aside from their basic identification, many tantalizing questions remain about these cells. For example, what is their origin, their receptor specificity and their relationship with anergized or deviated byproducts of tolerance induction? Is their sole mode of action via immunodepressing cytokines?
Genetics Genetic components have a major role in the determinism of autoimmune diseases although they are by no means
the only cause. Encinas and Kuchroo (pp 691–697) describe the present status of the linkage analyses of genetic polymorphisms with human and rodent diseases. This is very much still ‘work in progress’, with few or no genes yet formally identified. Encinas and Kuchroo do bring out dominant concepts that have come from these studies. One is that a number of the regions identified are shared between different autoimmune diseases. Although some may be ‘fortuitous’ (many assignments are still at a low level of resolution), it appears that some loci confer a generic propensity to autoimmunity. It is fairly logical that alleles conferring broad lymphocyte over-responsiveness could have such an effect (akin to the phenotypes of mice with knockouts for some regulatory cytokines, e.g. CTLA-4 or TGF-β). The second concept is that of complexity. It has long been recognized that the majority of autoimmune diseases are polygenic (with APECED as a noted exception), requiring additive contributions from a constellation of loci. This complexity may have been over-estimated (many reported loci do not reach full statistical significance or contribute only minimally to genetic variance, or may reflect epigenetic effects that we have not fathomed). Yet, as analyses reach finer resolution, a frequent observation is that of an additional layer of complexity: in several instances, the genetic regions identified in the first screens turn out to harbor two or three susceptibility/resistance loci. These observations bring back the notion of haplotypes, or the concerted action of tightly linked and co-inherited gene groups, a concept that was first applied to the function and evolution of the MHC. Overall, this work has been hard slogging but the persistent efforts of some groups have now brought several of these loci into the range of resolution that allows them to be approached by high-throughput sequencing. Undoubtedly, the existing or forthcoming complete sequences of the human and mouse genomes will provide a major boost to these studies. The inability to assess directly the contribution of specific genes and cell populations has always been a major roadblock for investigators working with human diseases (and these scientists have sat longingly through meeting sessions devoted to transgenic mice). Germline manipulation, cell transfers and even simple, directed immunisations are forbidden tools for studies in humans. The new developments reviewed by Fugger (pp 698–703) may bring this unfair advantage to a close: transgenic mice now exist in which human MHC or TCR genes, or combinations thereof, function in lieu of their murine counterparts. The suitable choice of alleles means that it should be possible to test the link between allelic variation and disease susceptibility in these chimeric mice or to map the dominant epitopes of human autoantigens. These are early days, of course, as it may prove important to ‘humanize’ several coreceptor or co-stimulatory genes as well and perhaps to aim for more faithful expression by gene knockins rather than
Editorial overview Benoist and Howard
by classical transgenesis. Yet the first results are exciting and indicate this will be a productive strategy. Ultimately, one might dream of massive parallel transgenesis, yielding a mouse in which all CD genes and assorted MHC, TCR and immunoglobulin loci have been switched to their human counterpart.
Novel therapeutic approaches Together, the reviews by Harrison and Hafler (pp 704–711), and Illei and Lipsky (pp 712–718) present a panorama of present attempts at, and successes with, immunomodulatory therapies in patients. Antigen-specific tolerance induction represents, of course, the ‘Holy Grail’ of immune manipulation, selectively targeting disease-causing lymphocytes. It has precedent in animal models, many of which have demonstrated sensitivity to a variety of tolerance induction regimens. As shown by Harrison and Hafler, we are witnessing an explosion in the approaches that are currently being followed. Some trials deal with the more classical routes of tolerogen administration: mucosal (oral or nasal) routes, which may be complicated by the fact that antigen thus presented can also induce responses and cytotoxic T lymphocyte activity; or systemic modes of administration, in particular with the large DPT-1 trial of systemic insulin administration for the prevention of insulin-dependent diabetes mellitus. Altered peptide ligands (APLs) and the anergy that they can induce in autoantigen-reactive T cells may be worthwhile agents in some cases. Yet what is an antagonist APL for a given T cell may well be a stimulatory agonist for another, making the therapy problematic on a population basis. More exotic approaches (e.g. transduction of antigen-reactive T cells with vectors expressing immumoregulatory cytokines or tolerance induction by plasmid-DNA immunization) require a better analysis of their potential in animal-model systems. Finally, early results with the use of various types of soluble MHC–peptide chimeric molecules are looking promising in both mouse models and early human clinical trials. Cop-1 (glatimer acetate) is an intriguing compound that probably bridges antigen-specific and -nonspecific approaches. Originally thought to be an analog of myelin basic protein, this synthetic copolymer seems to have some efficacy for multiple sclerosis patients. It is now believed to act more by multivalent low-affinity triggering of T cells, perhaps thus nonspecifically deviating ongoing
663
responses to self-antigens. Cytokines and their receptors are the main targets of non-specific therapeutic approaches, reviewed in depth by Illei and Lipsky. Agents that block TNF signalling are the big success story, with their marked activity in rheumatoid arthritis. It will be important to see whether the disease manifestations that persist in many anti-TNF-treated patients are susceptible to IL-1-directed intervention, as some of the animal models might suggest. Among therapies that target costimulatory molecules, CTLA4–Ig seems perhaps the most promising in early trials, in keeping with striking data that had previously been obtained in mice. On the other hand, the blockade of other key costimulatory molecules (CD40L/CD154 in particular) has been more disappointing in practise.
Apoptosis And in the end, of course, there must be death. Vaux and Flavell (pp 719–724) present today’s view of this key biological process, which underlies both the ability to tolerize autoreactive lymphocytes and the final effector mechanisms that lead to destruction of the target tissues. Complexity, here, is also the order of the day. Charts of intracellular apoptosis pathways linking death receptors, caspases and pro- or anti-apoptotic regulators grow more complex every year, in particular with the realisation that what had initially appeared to be simple linear pathways are really multibranched, redundant and interconnected. As Vaux and Flavell point out, major autoimmune diseases are not due to mutations in single death-controlling loci, as could in theory have been expected, probably because of multilevel redundancy and control pathways. At the same time, the effect of mutations or transgenic overexpression of single molecules can have obvious autoimmune consequences, in particular for members of the TNF-receptor family. Ultimately, reaching an understanding and managing autoimmunity may mean coming to terms with complexity, at the inter- and intra-cellular levels, and realising that the simplistic schemas the human mind can encompass are insufficient to deal with the full extent of biological complexity.
Reference 1.
Surh CD, Sprent J: Homeostatic T cell proliferation. How far can T cells be activated to self-ligands? J Exp Med 2000, 192:F9-F14.