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Update in Endocrine Autoimmunity

Diabetes Center, Department of Medicine, University of California-San Francisco, San Francisco, California 94143-0540

Address all correspondence and requests for reprints to: Mark S. Anderson, M.D., Ph.D., University of California-San Francisco Diabetes Center, Box 0540, 513 Parnassus Avenue, San Francisco, California 94143-0540. E-mail: manderson{at}diabetes.ucsf.edu.

	Abstract

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Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

Synthesis: Rapid progress has recently been made in our understanding of the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and confirmed many new genes outside of the established role of the human leukocyte antigen locus with these diseases, and indicate an essential role of immune response pathways in these diseases. Progress has also been made in identifying new autoantigens and the development of new animal models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for potentially treating and reversing the underlying autoimmune process.

Conclusion: Although autoimmune endocrine disorders are complex in etiology, these recent advances should help contribute to improved outcomes for patients with, or at risk for, these disorders.

	Introduction

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Autoimmune diseases represent a significant health burden in the developed world afflicting 5–10% of the population (1), and a sizable percentage of these diseases involve an untoward immune response against an endocrine organ. Virtually any endocrine organ can be targeted by the immune system as part of an autoimmune response, and frequently responses to multiple organs can occur in the same patient as part of a polyglandular autoimmune syndrome. More common endocrine autoimmune syndromes include Hashimoto’s thyroiditis, Graves’ disease, and type 1 diabetes, whereas more rare syndromes include Addison’s disease, oophoritis, lymphocytic hypophysitis, and hypoparathyroidism. For years, the etiology and pathogenesis of these disorders have remained obscure, but the diseases are generally thought to involve a cellular and humoral immune response that pathologically targets the affected organ(s). This is evidenced by a wide number of observations, including the presence of autoantibodies in affected patients, improvement of some diseases by immunosuppressive drugs, and the demonstration of lymphocytic infiltrates in the targeted organs. Over the last few years, rapid progress in our understanding of these diseases has come through a number of efforts, particularly in genetics. In this review, I will highlight some of the recent advances in our understanding, diagnosis, and treatment of endocrine autoimmune diseases.

	Genetics

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There is good evidence that most autoimmune endocrine diseases have a genetic component to their etiology. Some of the best evidence comes from familial inheritance studies on type 1 diabetes and thyroiditis (2, 3). In the case of type 1 diabetes, the lifetime concordance rate for disease in monogenic twins is around 50% and for siblings is around 3–4%. This shows significant risk when compared with the general population risk of around 0.3%. These data also show that there is a significant genetic contribution to disease risk and that other factors (i.e. environmental) are also involved in disease pathogenesis. For several decades, the major genetic association of autoimmune endocrine diseases with polymorphisms in the human leukocyte antigen (HLA) region has been recognized. The HLA is a genetic region on chromosome 6 that encodes a large number of immune response genes, and in most cases disease risk maps to polymorphisms in the major histocompatibility complex (MHC) class II genes DR and DQ. The MHC class II gene products along with antigenic peptides are part of the ligand complex for CD4+ T-cell receptors, and the association likely highlights the importance of T cells in these diseases (4). Interestingly, it remains to be determined how these risk polymorphisms lead to increased susceptibility to autoimmunity. Some investigators have proposed promiscuous peptide binding by MHC risk alleles as a potential mechanism, but more definitive data are needed (5). It is also important to note that in most cases, subjects harboring a MHC risk allele are more likely not to develop autoimmunity except in rare isolated incidents (6), thus, these risk alleles should be thought of as being necessary but not sufficient for the development of disease. Recently, significant progress has been made in expanding our understanding of genetic disease risk beyond the MHC, particularly with informative monogenic forms of endocrine autoimmunity and in highly powered genetic studies that include genome-wide association (GWA) efforts.

Monogenic diseases

Autoimmune polyglandular syndrome type 1 (APS1) is a rare monogenic autosomal recessive disorder characterized by a panoply of autoimmune syndromes in the same patient, many of which are directed against endocrine organs. Prominent clinical features are hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis (7). More variable endocrine features also include Hashimoto’s thyroiditis, oophoritis, type 1 diabetes, and lymphocytic hypophysitis. Through a positional cloning effort, the defective gene was identified in 1997 by two independent groups and termed autoimmune regulator (Aire) (8, 9). Since its identification, much has been learned about the function of Aire in promoting immune tolerance and has been accelerated by the generation of a mouse model by knocking out the murine orthologue of the gene (10, 11). Aire appears to function as a transcription factor and is mainly expressed in a specialized subset of cells in the thymus called medullary epithelial cells (mTECs). Within mTECs, Aire helps promote the transcription of many self-antigen genes, including the insulin gene (a known endocrine autoantigen) (11). A consequence of this self-antigen expression within the thymus is that it promotes the negative selection (or deletion) of autoreactive thymocytes that naturally develop in the thymus (12, 13, 14). Thus, in the absence of Aire, there is a failure to delete autoreactive T cells within the thymus, which then leads to a predisposition to widespread multi-organ autoimmunity (Fig. 1). Mouse studies have confirmed that the thymic defect is sufficient to induce the autoimmune syndrome associated with disease (11), and recent studies in humans have suggested that the long-known association of thymomas with the autoimmune syndrome myasthenia gravis may be attributable to the loss of AIRE expression in this thymic tumor (15). In addition, there is a developing picture that similar mechanisms are in play for more common endocrine autoimmune syndromes, like type 1 diabetes, in which a polymorphism in the insulin gene has been demonstrated to control thymic expression levels and correlates with disease risk (i.e. high thymic expression alleles have lower disease risk) (16, 17, 18). Recent associations with variation in the thyroglobulin gene and thyroiditis (3, 19) could involve a similar mechanism, but this has yet to be tested. An autosomal dominant allele of AIRE has also been recently associated with Hashimoto’s thyroiditis (20), and recently the susceptibility has been shown to be due to a quantitative effect on self-antigen expression within the thymus (21). Together, these recent advances on Aire have helped establish a critical relationship between thymic expression of self-antigens and the prevention of autoimmune endocrine syndromes.

View larger version (26K): [in this window] [in a new window]   FIG. 1. Model of the function of Aire in the thymus. A, Aire appears to help mediate the transcription of many self-antigens in mTECs in the thymus. B, Impact of Aire on T-cell selection. These self-antigens are then presented in the thymus to developing thymocytes (blue-colored cells) in the medulla, and this results in the deletion of self-antigen specific thymocytes in this compartment. In the absence of Aire, the self-antigens fail to be generated by these mTECs, and self-antigen specific T cells mature and escape the thymus and migrate into the periphery and promote autoimmune responses.

View larger version (27K): [in this window] [in a new window]   FIG. 2. Model of Treg function. Tregs expressing the FoxP3 gene play a key role in dampening responses by effector T cells (Teff), including autoreactive T cells specific for organ-specific antigens. This suppression is essential because the loss of Treg function has been demonstrated to lead to catastrophic autoimmunity like that in patients with the IPEX syndrome. The suppression by these cells in vivo also appears to be antigen specific and raises the possibility that these cells could be harnessed to induce antigen-specific immune tolerance in the future.

Rapid advances in human genetics have afforded the opportunity to identify new risk alleles associated with common diseases, like type 1 diabetes and thyroiditis, that have previously been elusive. This has been due to a number of factors, including the completion of the human genome sequence, the development of a catalog of common genetic variation (i.e. the haplotype map), affordable technologies for high-density/high-throughput genotyping, and adequately powered sample sizes of cases and controls (32, 33). In this regard, the most progress has been made with studies on type 1 diabetes and thyroiditis, in which adequately powered sample collections have been amassed to detect common variants using GWA and confirm previously established associations. Studies with type 1 diabetes samples have established a large number of genes associated with risk outside of the HLA region. Before the advent of GWA, the insulin (17, 34), PTPN22 (35), CTLA4 (36), and interleukin-2 receptor -chain (also known as CD25) (37) genes were established to be associated with disease, and have also been confirmed with GWA. With the advent of large GWA studies on type 1 diabetes, MDA5 (38), KIAA0350 (a C-type lectin of unknown function) (39, 40, 41), and several loci harboring other genes have been associated with disease (41). Although Hashimoto’s thyroiditis and Graves’ disease are distinct in their clinical presentations, they likely share many commonalities in their pathogenesis. Most large genetic studies on autoimmune thyroid disease have used large Graves’ collections, and there has been difficulty in detecting loci when Graves’ and Hashimoto’s patients are pooled together (42). In fact, a very recent study on Hashimoto’s thyroiditis patients has demonstrated different HLA class II associations when compared with Graves’ (43). To date, established genes outside of HLA for Graves’ include the TSH receptor (44, 45), PTPN22 (46, 47), CTLA4 (36), and FCRL3 (a Fc receptor family member) (45). Beyond these recent findings, it should be noted that there is an extensive body of literature examining candidate gene associations with thyroiditis, type 1 diabetes, and Addison’s disease. These reported associations may hold true associations but have yet to be replicated in these large collection studies for thyroiditis and type 1 diabetes. This may be due to many factors, but caution is warranted given the likely bias for reporting false-positive results in such studies, especially those that may be underpowered or may have unrecognized population stratification (48). The NALP1 gene, a likely regulator in the innate immune system, was also recently shown to have an association with multiple autoimmune diseases in families with vitiligo (49). In this study, families with two or more members with vitiligo and at least one with an autoimmune condition that included but was not limited to type 1 diabetes, Addison’s disease, and thyroiditis were collected, and convincing linkage was demonstrated to this gene.

In terms of the non-HLA genes outlined previously, the risk conferred by them, with few exceptions, is relatively small, with most having an odds ratio less than 1.5. In addition, the biological mechanisms by which these common alleles confer genetic risk still remain to be completely elucidated (Table 1). Despite this, when these findings are put into the context of what we know about autoimmunity and immune tolerance mechanisms, a picture is starting to emerge. First, there appears to be at least a set of genes that generally increase autoimmune disease risk, like PTPN22, CTLA4, NALP1, and FCRL3, which have established risk for many autoimmune diseases. For example, PTPN22 has been established as a risk gene for rheumatoid arthritis, systemic lupus erythematosus, juvenile rheumatoid arthritis, and myasthenia gravis, in addition to its established association with thyroiditis and type 1 diabetes. Second, some disease risk genes fit into context with established pathways related to immune tolerance. For example, CTLA4 (which is highly expressed in T cells) is known to play a critical role in dampening and suppressing T-cell responses in biological studies (50), and its association with multiple autoimmune diseases makes good sense. PTPN22 encodes a signaling phosphatase expressed in T cells that likely controls T-cell signaling, and the risk variant encodes an amino acid change that likely confers biological activity in T-cell activation pathways. Third, there are associations with emerging immune tolerance pathways. For instance, the association with CD25 may have a relationship with the function and activity of CD4+CD25+Tregs. The association of innate immune response genes like MDA5 and NALP1 may help explain the bridge between environmental triggers and activation of autoimmune responses. The association of the TSH receptor with Graves’ may also have a relationship with thymic expression of self-antigens, but making these links will need more study. Finally, there are some associations that are not completely clear, like KIAA0350, which may help identify unexpected pathways associated with disease.

	Diagnostics

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Autoantibodies

Autoantibodies are a key tool in the diagnosis of patients with autoimmune endocrine diseases and those at risk for these diseases. As outlined earlier, a major clinical phenotype of patients with the APS1 disorder is the presence of hypoparathyroidism, which is presumably autoimmune in origin, and a recent study has identified a parathyroid autoantigen called NACHT leucine-rich-repeat protein 5 (NALP5) (54). Interestingly, NALP5 is highly expressed in both the parathyroid and ovary, and autoreactivity to NALP5 may explain both the hypoparathyroidism and oophoritis associated with the APS1 disorder. However, it still remains to be determined if NALP5 is expressed in the thymus under the control of AIRE. A similar set of studies searching for pituitary autoantibodies has revealed tudor domain containing protein 6 as a pituitary autoantigen in APS1 subjects (55). The autoantigen is quite prevalent in APS1 subjects, but its direct correlation with pituitary autoimmunity in APS1 or in isolated lymphocytic hypophysitis remains to be established. Another set of recent studies has found that autoantibodies to type 1 interferons are generally predictive of the APS1 disorder (56, 57, 58). The clinical meaning of these autoantibodies currently remains unclear but may have some relationship to the candidiasis commonly observed in APS1 subjects. The specificity of this test for APS1 also appears to be on par with gene sequencing of AIRE in the initial studies, and raises the possibility that this assay may be of utility in patients and those at risk for the disorder. Recently, a new autoantigen has also been established for subjects with type 1 diabetes (59). ZnT8 is an islet-specific zinc transporter for which a large number of subjects with type 1 diabetes have reactive autoantibodies. The marker may prove particularly useful in subjects who test negative for other established autoantibodies to glutamate decarboxylase, insulin, and I-A2.

	Animal Models

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Animal models have proven to be invaluable in furthering our understanding of autoimmunity, given the inherit complexity of these diseases. Both the Aire knockout and FoxP3 knockout lines of mice have been valuable in unraveling the function of Aire and FoxP3 as outlined previously, but there have also been other recent advances with other animal models. A broad concept worth mentioning with animal models is segregating these models into those that have spontaneous development of autoimmune disease vs. those that are induced (i.e. immunizing with organ extract or antigen in the context of a strong adjuvant). Although induced models may be of some value, they are also hampered in identifying precipitating factors for disease because this is likely bypassed by the immunization process. Certainly, one of the most widely used spontaneous models in autoimmune endocrine disease research is the nonobese diabetic mouse strain model of autoimmune diabetes, which shows defects in multiple pathways of immune tolerance (60). This mouse strain has proven to be valuable in dissecting out the role of various immune cell populations and immune pathways in their contribution to the autoimmune diabetes process. In addition, it should also be noted that this strain has been shown to have an increased susceptibility to spontaneous autoimmune thyroiditis when its MHC locus is replaced in a congenic fashion (61) or when crossed to a dominant point mutation in Aire (21). A spontaneous thyroiditis model was also recently described using a T-cell receptor transgenic approach and emphasizes the importance again of T cells in driving this autoimmune disease (62). Another interesting development in animal models is the recent demonstration of genetic susceptibility loci in Portuguese water dogs for Addison’s disease (63). This dog breed shows a relatively high predisposition to acquired adrenal insufficiency with estimates around 1.5% of these dogs being affected [compared with approximately 0.01% in the human population (64)]. With recent advances in the genetic study of dogs and excellent pedigree records for this breed, Chase et al. (63) were able to demonstrate significant linkage for Addison’s disease to two loci in the dog genome. One locus was in the region of the dog MHC, and the second was in a genetic region rich for immune response-related genes, which includes CTLA4. Further work will be needed in this system to unravel the exact genes and polymorphisms responsible for the Addison’s disease risk, but this unique animal model may bring new mechanistic insights for this disorder. These recent findings also suggest that further work in nonrodent models of autoimmune endocrine conditions may be genetically tractable given the rapid advances in whole genome sequencing.

	Environmental Effects

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Recent epidemiological evidence has suggested that there is an increasing incidence of many autoimmune conditions, including type 1 diabetes (65, 66). A prevailing hypothesis for the increase in these recent trends is the "hygiene hypothesis," whereby the relative decrease in childhood infections from improved living conditions and increased immunizations may be a factor (67). Along these lines, Kondrashova et al. (68) recently examined the prevalence of thyroid autoimmunity in two geographically adjacent regions in Russia and Finland that share similar genetic ancestry. In this study an increased prevalence of antithyroid peroxidase and antithyroglobulin antibodies was observed in Finnish children over Russian children. The authors go on to suggest that the increased rate in Finland could be due to socioeconomic factors that include a lower rate of childhood infections.

	Treatment

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The mainstay of treatment for most autoimmune endocrine disorders is of course replacement therapy with the exception of Graves’ disease. To date, the main area for which some progress has been made in reversing or treating the underlying autoimmune process has been in type 1 diabetes, and this was recently reviewed in this series (69). One developing area of immunotherapy outside of type 1 diabetes worth mentioning involves the B-cell depleting agent rituximab (anti-CD20). This drug has been demonstrated to have efficacy in the treatment of several autoimmune diseases (70) with a relatively good side effect profile, and initial case reports suggested that it may have some efficacy in the treatment of Graves’ disease (71, 72). Because a pathogenic autoantibody is responsible for this disorder, this is a rational treatment, however, it should be noted that plasma cells do not express CD20, and depletion of mature anti-TSH receptor antibody producing cells may be intractable to this approach. Recently, two controlled pilot studies for the treatment of Graves’ with anti-CD20 showed less encouraging results but some efficacy in patients with low anti-TSH receptor antibody levels (73, 74). There has also been a case report of ulcerative colitis being associated with the treatment of a Graves’ patient in a similar trial (75) and brings into question the need for this therapy over established treatments. Despite this, rituximab may prove to be worthwhile in unique circumstances such as in the prevention of severe ophthalmopathy in those patients receiving thyroid ablation.

Conclusion

The endocrine system is commonly pathologically targeted by the immune system and can often lead to clinical disease through complete destruction of the organ. For years, our main genetic understanding of these disorders has been that the MHC genetic region encodes a significant degree of risk. Recent, rapid advances in genetics have shed new light on immune pathways and mechanisms that are involved in the pathogenesis of these diseases. These pathways include those revealed by monogenic autoimmune diseases, like APS1 and IPEX, which reveal the importance of thymic selection and Tregs in maintaining tolerance. In addition, rigorously powered genetic studies have reinforced the notion that T-cell response genes are involved in disease pathogenesis and that many autoimmune endocrine diseases share similar genetic risk. In addition, to our advancing knowledge in genetics, there have also been recent strides in identifying new diagnostic markers and new treatments for these diseases. Despite these advances, much work remains to be done, including addressing the fundamental question of why the endocrine system is so commonly targeted by autoimmune responses.

	Acknowledgments

 
I thank Jason DeVoss for help with the figures.

	Footnotes

 
M.S.A. is supported by the National Institutes of Health, The Pew Scholars, The Burroughs Wellcome Fund, the Juvenile Diabetes Research Foundation, and the Sandler Foundation.

Disclosure Statement: The author has nothing to disclose.

Abbreviations: Aire, Autoimmune regulator; APS1, autoimmune polyglandular syndrome type 1; GWA, genome-wide association; HLA, human leukocyte antigen; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; MHC, major histocompatibility complex; mTEC, medullary epithelial cell; NALP5, NACHT leucine-rich-repeat protein 5; Treg, regulatory T cell.

Received June 9, 2008.

Accepted July 31, 2008.

	References

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1. Jacobson DL, Gange SJ, Rose NR, Graham NM 1997 Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84:223–243[CrossRef][Medline]
2. Redondo MJ, Yu L, Hawa M, Mackenzie T, Pyke DA, Eisenbarth GS, Leslie RD 2001 Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44:354–362[CrossRef][Medline]
3. Jacobson EM, Tomer Y 2007 The genetic basis of thyroid autoimmunity. Thyroid 17:949–961[CrossRef][Medline]
4. Anderson MS 2002 Autoimmune endocrine disease. Curr Opin Immunol 14:760–764[CrossRef][Medline]
5. Suri A, Levisetti MG, Unanue ER 2008 Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity? Curr Opin Immunol 20:105–110[CrossRef][Medline]
6. Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS, Babu SR, Yu L, Miao D, Erlich HA, Fain PR, Barriga KJ, Norris JM, Rewers MJ, Eisenbarth GS 2006 Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci USA 103:14074–14079[Abstract/Free Full Text]
7. Perheentupa J 2006 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 91:2843–2850[Abstract/Free Full Text]
8. Finnish-German APECED Consortium 1997 An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 17:399–403[CrossRef][Medline]
9. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N 1997 Positional cloning of the APECED gene. Nat Genet 17:393–398[CrossRef][Medline]
10. Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kampe O, Eskelin P, Pelto-Huikko M, Peltonen L 2002 Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 11:397–409[Abstract/Free Full Text]
11. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D 2002 Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401[Abstract/Free Full Text]
12. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC 2003 Aire regulates negative selection of organ-specific T cells. Nat Immunol 4:350–354[CrossRef][Medline]
13. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D 2005 The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–239[CrossRef][Medline]
14. DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi R, Fong L, Anderson MS 2006 Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med [Erratum (2007) 204:203] 203:2727–2735[CrossRef]
15. Strobel P, Murumagi A, Klein R, Luster M, Lahti M, Krohn K, Schalke B, Nix W, Gold R, Rieckmann P, Toyka K, Burek C, Rosenwald A, Muller-Hermelink HK, Pujoll-Borrell R, Meager A, Willcox N, Peterson P, Marx A 2007 Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J Pathol 211:563–571[CrossRef][Medline]
16. Chentoufi AA, Polychronakos C 2002 Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes [Erratum (2002) 51:2665] 51:1383–1390[CrossRef]
17. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C 1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15:289–292[CrossRef][Medline]
18. Pugliese A, Zeller M, Fernandez Jr A, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD 1997 The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297[CrossRef][Medline]
19. Tomer Y, Greenberg DA, Concepcion E, Ban Y, Davies TF 2002 Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases. J Clin Endocrinol Metab 87:404–407[Abstract/Free Full Text]
20. Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, Marcocci C 2001 A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab 86:4747–4752[Abstract/Free Full Text]
21. Su MA, Giang K, Zumer K, Jiang H, Oven I, Rinn JL, Devoss JJ, Johannes KP, Lu W, Gardner J, Chang A, Bubulya P, Chang HY, Peterlin BM, Anderson MS 2008 Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J Clin Invest 118:1712–1726[CrossRef][Medline]
22. Ochs HD, Gambineri E, Torgerson TR 2007 IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res 38:112–121[CrossRef][Medline]
23. Hori S, Nomura T, Sakaguchi S 2003 Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061[Abstract/Free Full Text]
24. Fontenot JD, Gavin MA, Rudensky AY 2003 Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336[CrossRef][Medline]
25. Ramsdell F 2003 Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19:165–168[CrossRef][Medline]
26. Sakaguchi S, Yamaguchi T, Nomura T, Ono M 2008 Regulatory T cells and immune tolerance. Cell 133:775–787[CrossRef][Medline]
27. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L 2007 Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8:351–358[CrossRef][Medline]
28. Kim JM, Rasmussen JP, Rudensky AY 2007 Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–17[CrossRef][Medline]
29. Tanchot C, Vasseur F, Pontoux C, Garcia C, Sarukhan A 2004 Immune regulation by self-reactive T cells is antigen specific. J Immunol 172:4285–4291[Abstract/Free Full Text]
30. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM 2004 CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477[Abstract/Free Full Text]
31. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA 2004 In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465[Abstract/Free Full Text]
32. Altshuler D, Daly M 2007 Guilt beyond a reasonable doubt. Nat Genet 39:813–815[CrossRef][Medline]
33. Manolio TA, Brooks LD, Collins FS 2008 A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118:1590–1605[CrossRef][Medline]
34. Pugliese A, Miceli D 2002 The insulin gene in diabetes. Diabetes Metab Res Rev 18:13–25[CrossRef][Medline]
35. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L, Barratt BJ, Guja C, Ionescu-Tirgoviste C, Savage DA, Dunger DB, Widmer B, Strachan DP, Ring SM, Walker N, Clayton DG, Twells RC, Gough SC, Todd JA 2004 Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53:3020–3023[Abstract/Free Full Text]
36. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC 2003 Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511[CrossRef][Medline]
37. Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Rebecca Twells CJ, Clayton DG, Todd JA 2005 Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–779[CrossRef][Medline]
38. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, Guja C, Ionescu-Tirgoviste C, Widmer B, Dunger DB, Savage DA, Walker NM, Clayton DG, Todd JA 2006 A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619[CrossRef][Medline]
39. Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678[CrossRef][Medline]
40. Hakonarson H, Grant SFA, Bradfield JP, Marchand L, Kim CE, Glessner JT, Grabs R, Casalunovo T, Taback SP, Frackelton EC, Lawson ML, Robinson LJ, Skraban R, Lu Y, Chiavacci RM, Stanley CA, Kirsch SE, Rappaport EF, Orange JS, Monos DS, Devoto M, Qu H-Q, Polychronakos C 2007 A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448:591–594[CrossRef][Medline]
41. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, Bailey R, Nejentsev S, Field SF, Payne F, Lowe CE, Szeszko JS, Hafler JP, Zeitels L, Yang JHM, Vella A, Nutland S, Stevens HE, Schuilenburg H, Coleman G, Maisuria M, Meadows W, Smink LJ, Healy B, Burren OS, Lam AAC, Ovington NR, Allen J, Adlem E, Leung HT, Wallace C, Howson JMM, Guja C, Ionescu-Tirgoviste C, Simmonds MJ, Heward JM, Gough SCL, Dunger DB, Wicker LS, Clayton DG 2007 Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864[CrossRef][Medline]
42. Taylor JC, Gough SC, Hunt PJ, Brix TH, Chatterjee K, Connell JM, Franklyn JA, Hegedus L, Robinson BG, Wiersinga WM, Wass JA, Zabaneh D, Mackay I, Weetman AP 2006 A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease. J Clin Endocrinol Metab 91:646–653[Abstract/Free Full Text]
43. Zeitlin AA, Heward JM, Newby PR, Carr-Smith JD, Franklyn JA, Gough SCL, Simmonds MJ 2008 Analysis of HLA class II genes in Hashimoto’s thyroiditis reveals differences compared to Graves’ disease. Genes Immun 9:358–363[CrossRef][Medline]
44. Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, Mackay I, Franklyn JA, Connell JM, Wass JA, Wiersinga WM, Hegedus L, Brix T, Robinson BG, Hunt PJ, Weetman AP, Carey AH, Gough SC 2005 Association of the TSHR gene with Graves’ disease: the first disease specific locus. Eur J Hum Genet 13:1223–1230[CrossRef][Medline]
45. Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium 2007 Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature 39:1329–1337
46. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH 2004 The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865[Abstract/Free Full Text]
47. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK 2005 Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76:561–571[CrossRef][Medline]
48. Newton-Cheh C, Hirschhorn JN 2005 Genetic association studies of complex traits: design and analysis issues. Mutat Res 573:54–69[Medline]
49. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA 2007 NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356:1216–1225[Abstract/Free Full Text]
50. Salomon B, Bluestone JA 2001 Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225–252[CrossRef][Medline]
51. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, Mychaleckyj JC, Todd JA, Bonella P, Fear AL, Lavant E, Louey A, Moonsamy P, Type 1 Diabetes Genetics Consortium 2008 HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57:1084–1092[Abstract/Free Full Text]
52. Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, Hulme J, Maier LM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Clayton DG, Todd JA 2007 Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892[CrossRef][Medline]
53. Simmonds MJ, Howson JMM, Heward JM, Carr-Smith J, Franklyn JA, Todd JA, Gough SCL 2007 A novel and major association of HLA-C in Graves’ disease that eclipses the classical HLA-DRB1 effect. Hum Mol Genet 16:2149–2153[Abstract/Free Full Text]
54. Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller M, Ekwall O, Kinkel S, Husebye E, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerström G, Westin G, Scott H, Holländer G, Kämpe O 2008 Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med 358:1018–1028[Abstract/Free Full Text]
55. Bensing S, Fetissov SO, Mulder J, Perheentupa J, Gustafsson J, Husebye ES, Oscarson M, Ekwall O, Crock PA, Hokfelt T, Hulting AL, Kampe O 2007 Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1. Proc Natl Acad Sci USA 104:949–954[Abstract/Free Full Text]
56. Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, Fougner KJ, Lima K, Knappskog PM, Husebye ES 2007 Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab 92:595–603[Abstract/Free Full Text]
57. Meager A, Visvalingam K, Peterson P, Moll K, Murumagi A, Krohn K, Eskelin P, Perheentupa J, Husebye E, Kadota Y, Willcox N 2006 Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med 3:e289
58. Zhang L, Barker JM, Babu S, Su M, Stenerson M, Cheng M, Shum A, Zamir E, Badolato R, Law A, Eisenbarth GS, Anderson MS 2007 A robust immunoassay for anti-interferon autoantibodies that is highly specific for patients with autoimmune polyglandular syndrome type 1. Clin Immunol 125:131–137[CrossRef][Medline]
59. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC 2007 The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 104:17040–17045[Abstract/Free Full Text]
60. Anderson MS, Bluestone JA 2005 The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485[CrossRef][Medline]
61. Braley-Mullen H, Sharp GC, Medling B, Tang H 1999 Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Autoimmun 12:157–165[CrossRef][Medline]
62. Quaratino S, Badami E, Pang YY, Bartok I, Dyson J, Kioussis D, Londei M, Maiuri L 2004 Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice. Nat Med 10:920–926[CrossRef][Medline]
63. Chase K, Sargan D, Miller K, Ostrander EA, Lark KG 2006 Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison’s disease in Portuguese water dogs. Int J Immunogenet 33:179–184[CrossRef][Medline]
64. Lovas K, Husebye ES 2002 High prevalence and increasing incidence of Addison’s disease in western Norway. Clin Endocrinol (Oxf) 56:787–791[CrossRef][Medline]
65. Harjutsalo V, Sjöberg L, Tuomilehto J Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 371:1777–1782
66. Writing Group for the SEARCH for Diabetes in Youth Study Group, Dabelea D, Bell RA, D'Agostino Jr RB, Imperatore G, Johansen JM, Linder B, Liu LL, Loots B, Marcovina S, Mayer-Davis EJ, Pettitt DJ, Waitzfelder B 2007 Incidence of diabetes in youth in the United States. JAMA [Erratum (2007) 298:627] 297:2716–2724[CrossRef]
67. Bach JF 2002 The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920[Free Full Text]
68. Kondrashova A, Viskari H, Haapala A-M, Seiskari T, Kulmala P, Ilonen J, Knip M, Hyoty H 2008 Serological evidence of thyroid autoimmunity among schoolchildren in two different socioeconomic environments. J Clin Endocrinol Metab 93:729–734[Abstract/Free Full Text]
69. Eisenbarth GS 2007 Update in type 1 diabetes. J Clin Endocrinol Metab 92:2403–2407[Abstract/Free Full Text]
70. Levesque MC, St. Clair EW 2008 B cell-directed therapies for autoimmune disease and correlates of disease response and relapse. J Allergy Clin Immunol 121:13–21[CrossRef][Medline]
71. Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, Guastella C, Avignone S, Pirola G, Ratiglia R, Beck-Peccoz P 2006 Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol 154:511–517[Abstract/Free Full Text]
72. El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L 2006 Treatment-resistant severe, active Graves’ ophthalmopathy successfully treated with B lymphocyte depletion. Thyroid 16:709–710[CrossRef][Medline]
73. Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P 2007 Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 156:33–40[Abstract/Free Full Text]
74. El Fassi D, Nielsen CH, Bonnema SJ, Hasselbalch HC, Hegedus L 2007 B lymphocyte depletion with the monoclonal antibody rituximab in Graves’ disease: a controlled pilot study. J Clin Endocrinol Metab 92:1769–1772[Abstract/Free Full Text]
75. El Fassi D, Nielsen CH, Kjeldsen J, Clemmensen O, Hegedus L 2008 Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease. Gut 57:714–715[Free Full Text]

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