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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.

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. This shows significant risk when compared with the general population risk of around 0. These data also show that there is a significant genetic contribution to disease risk and that other factors i. 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. 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. 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.

Through a positional cloning effort, the defective gene was identified in 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 , 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 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 — 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.

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 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.

Recent associations with variation in the thyroglobulin gene and thyroiditis 3 , 19 could involve a similar mechanism, but this has yet to be tested. 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.

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.

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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. Another monogenic autoimmune syndrome that has brought new mechanistic insights to immune tolerance is immune dysregulation, polyendocrinopathy, enteropathy, X-linked IPEX.

This is an X-linked disorder that is characterized by a severe autoimmunity syndrome in which most affected subjects usually die before the age of 2 yr if they do not receive bone marrow transplantation. Common autoimmune endocrine syndromes in these patients include type 1 diabetes and thyroiditis The defective gene in this disorder has been mapped to the transcription factor FoxP3, and recent studies have established that FoxP3 plays a critical role in the function of a special T-cell subset called regulatory T cells Tregs 23 — These cells develop within the thymus and are thought to have a preferential specificity for self-antigens, perhaps at least in part due to Aire-dependent mechanisms Preferential depletion 28 or loss of function of these cells through knocking out FoxP3 has been demonstrated in animal models to lead to catastrophic autoimmunity similar to that in IPEX patients.

FoxP3 likely plays a number of critical functions in allowing the suppressor activity of these cells to be promoted, but the exact details of the suppression mechanism remain unclear, especially in vivo Interestingly, Tregs have been used as a tool to suppress and reverse type 1 diabetes in animal models 30 , 31 , and this has important future clinical implications.

This is because the suppression mechanism in vivo appears to be dependent on the antigenic specificity of the Treg population that is used. Thus, it may someday be possible to induce antigen or organ-specific tolerance by treatment with clonal populations of Tregs as a method to cure or reverse a given autoimmune disease without conferring the risk of global immunosuppression. 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. 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. 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 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 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.

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. 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.

The association of innate immune response genes like MDA5 and NALP1 may help explain the bridge between environmental triggers and activation of autoimmune responses. Finally, there are some associations that are not completely clear, like KIAA, which may help identify unexpected pathways associated with disease. Autoimmune endocrine disease susceptibility genes identified or confirmed in recent high-powered genetic studies see text for references.

Another general emerging set of findings with large case control collections has been a more thorough analysis of the HLA region with high-density marker genotyping. The HLA poses a particular challenge to geneticists because it is such a polymorphic and gene-rich region. This makes identifying true risk associations more difficult because the identified risk may be in linkage disequilibrium with the true risk variant.

In type 1 diabetes, recent new data have emerged that have extended our growing knowledge of MHC class II alleles associated with disease risk and protection 51 , and also in identifying additional disease risk albeit lower associated with MHC class I alleles Additional studies have identified MHC haplotypes that provide extreme risk for the development of type 1 diabetes 6 , which likely contain several synergistic loci.

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Together, these findings reveal the rich complexity of the HLA region, and clearly a more detailed study of the region will be needed to unravel completely the risk associated with this locus. 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 A similar set of studies searching for pituitary autoantibodies has revealed tudor domain containing protein 6 as a pituitary autoantigen in APS1 subjects 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.

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Another set of recent studies has found that autoantibodies to type 1 interferons are generally predictive of the APS1 disorder 56 — 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 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. Murine functional genomics is thus of central importance in modem biomedical endocrine research. Although mice are at present, the preferred mammalian species for genetic manipulations because of the availability of pluripotent embryonic. The two basic techniques used in the creation of transgenic animal models are integration of foreign DNA into a fertilized oocyte by random chromosomal insertion and homologous recombination in embryonic stem cells that are then introduced into zygotes.

Transgenic mice and rats serve as sophisticted tools to probe protein function, as models of human disease, and as hosts for the testing of gene replacement and other therapies. Embryonic stem cell libraries for mouse gene deletion are being developed, which will make it possible to generate knockout mice rapidly and without the need to analyze gene structure, construct targeting vectors, and screen embryonic stem cell clones.