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Immunity. Author manuscript; available in PMC 2011 April 23.
Published in final edited form as:
PMCID: PMC2859971

Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis


Autoimmune diseases like type 1 diabetes are complex in their pathogenesis. One approach to improving our understanding of type 1 diabetes is the study of diseases that represent more extreme examples of autoimmunity. Autoimmune polyendocrine syndromes (APS) are relatively rare diseases that often include type 1 diabetes as part of the disease phenotype. Recently there has been tremendous progress in unraveling some of the underlying mechanisms of APS. Here we highlight the APS disorders with the perspective of the clues they can offer to the pathogenesis and treatment of type 1 diabetes.

Keywords: autoimmune polyendocrine syndrome, autoantibodies, autoimmune regulator (Aire), FoxP3, type 1 diabetes mellitus, autoimmune thyroiditis, Addison's disease


Extreme disease phenotypes, although often being rare, can provide important insights into more common diseases. In the case of type 1 diabetes (T1D), autoimmune polyendocrine syndromes are such an example and have provided a wealth of new information about disease pathogenesis. It has been long noticed that patients with T1D have an increased risk for autoimmunity targeting of other endocrine tissues like the thyroid and adrenal glands. In addition, there are collections of patients that develop unique patterns of autoimmune endocrine phenotypes that are segregated into different syndrome groupings. Here we describe these syndromes, our current understanding of their pathogenesis, and how they relate to improving our knowledge about the etiology of T1D.


Autoimmune polyendocrine syndromes (APS) are characterized by functional insufficiency of multiple endocrine organs secondary to an immunologically mediated destructive process (Anderson, 2008). The name “polyendocrine” in these syndromes is a bit of a misnomer as autoimmunity to non-endocrine organs is also seen in these disorders. Nonetheless, many of the autoimmune processes in these disorders appears to be associated with a progressive T cell-directed response that results in organ damage and the production of organ-specific autoantibodies similar to what is observed in isolated T1D. A number of types of APS have been defined based on genetic background and clinical features (Table 1) (Eisenbarth and Gottlieb, 2004). At one end of the spectrum are the rare monogenic polyendocrinopathies of APS type I (APS1) (OMIM 240300) (Perheentupa, 2006), as well as Immunodeficiency, Polyendocrinopathy, and Enteropathy, X-Linked Syndrome (IPEX) (OMIM 304790) (Ochs et al., 2007). On the other end of the spectrum, a much more common variation of the syndrome, APS 2, is complex in its inheritance. All three of the autoimmune polyglandular syndromes are characterized by a greatly increased risk for the development of T1D (with IPEX>APS2>APS1), thus making APS a suitable avenue to pursue pathogenic mechanisms of T1D. Table 1 summarizes some of the key distinctions of the three separate groups of APS, which are discussed below in further detail.

Table 1
Characteristics of autoimmune polyendocrine syndromes

Autoimmune polyendocrine syndrome type 1 (APS1)

APS1 is a childhood onset monogenic polyendocrine disease caused by mutations in the Autoimmune Regulator AIRE (The Finnish German APECED Consortium 1997; Nagamine et al., 1997). The prevalence in Norway which probably reflects the epidemiology in many countries, is 1:90,000 (Boe Wolff et al., 2008), but higher frequencies are found in certain populations including Finland (1:25,000), Sardinia (1:14000), as well as among Iranian Jews (Husebye et al., 2009). The other commonly used acronym for this disease, APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), illustrates the variety of clinical manifestations. The main components of the syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). The presence of two of these components (one if a first-degree relative already is diagnosed) is diagnostic (Ahonen et al., 1990). In addition, a host of other manifestations in other endocrine glands (thyroid, pancreatic islets, ovaries), the gastrointestinal tract and ectodermal structures are regularly seen (Table 1) (Ahonen et al., 1990; Husebye et al., 2009; Perheentupa, 2006). A large phenotypic diversity is seen even among siblings, but on average, each patient develops 4 components. Even if APS1 develops in early childhood, late manifestations have been reported making the distinction between APS1 and 2 difficult in some instances where candidiasis and/or hypoparathyroidism are missing.

The identification and characterization of a number of autoantibodies against tissue specific autoantigens has improved our ability to diagnose APS1. Type 1 interferon autoantibodies have proven to be particularly useful diagnostic tools to identify these patients since virtually all APS1 patients reveal antibody reactivity to interferon alfa and/or interferon omega subtypes (Meager et al., 2006; Wolff et al., 2007; Zhang et al., 2007). Myasthenia gravis patients, especially those with late-onset and thymoma are the only other patient group with similar autoantibodies (Meager et al., 2006). The clinical relevance of these type I interferon antibodies other than being a diagnostic marker, remains to be determined as APS1 patients do not demonstrate an increased susceptibility to viral infections. In contrast, two recent studies have suggested that similar autoantibodies to the T helper 17 (Th17) cell cytokines IL-17A, IL-17F, and IL-22 appear in APS1 subjects and may explain their increased susceptibility to candidal infections (Kisand et al.; Puel et al.). Although this data is strongly correlative, further study will be needed to prove if defects in the Th17 cell response are directly responsible for the candida susceptibility.

In addition to interferon and Th17cell-cytokine antibodies, APS1 patients have high-titer autoantibodies to a number of self-antigens, typically proteins with tissue restricted expression and often with a key function in their tissues (Soderbergh et al., 2004). Many are enzymes involved in neurotransmitter biosynthesis or P450-containing enzymes involved in steroid synthesis and metabolism. Autoantibody reactivity often correlates to organ-manifestations of the syndrome. For example, 21-hydroxylase (a key enzyme in adrenal steroidogenesis) antibodies correlate with adrenal insufficiency (Soderbergh et al., 2004), and tryptophan hydroxylase (involved in serotonin biosynthesis) antibodies correlate with intestinal malabosorption (Ekwall et al., 1999). Evidence that the hypoparathyroidism in the disorder is secondary to an autoimmune response against the parathyroids was bolstered by the recent identification of antibodies specific for the parathyroid specific protein NALP5 in APS1 patients with hypoparathyroidism (Alimohammadi et al., 2008).

As mentioned above, APS1 subjects do show an increased susceptibility to T1D; however, it does appear there are some islet autoantibody differences in these subjects when compared to isolated T1D subjects. For example, studies have shown that APS1 subjects commonly develop anti-glutamate decarboxylase 65 (GAD65) antibodies, but there does not appear to be a correlation of these antibodies to T1D (Gylling et al., 2000; Soderbergh et al., 2004). In contrast, both anti-insulin and anti-islet cell antigen 2 (IA2) antibodies do correlate with T1D in these subjects (Gylling et al., 2000; Soderbergh et al., 2004). It is important to note that GAD is an autoantigen that is not only expressed in the islets but also in the nervous system and may be part of the reason it is not a good marker in APS1 for T1D.

Because APS1 is inherited in a monogenic autosomal recessive fashion, human geneticists were able to identify the underlying defective gene through positional cloning efforts (The Finnish German APECED Consortium, 1997; Nagamine et al., 1997) and termed it AIRE (for Autoimmune regulator). Although autoantibodies are highly indicative of the diagnosis, identification of mutations in AIRE is the ultimate proof of APS1, and mutations are found in over 95 percent of analyzed cases. More than 60 different mutations have now been reported; the majority of which are translated into truncated and non-functional AIRE. It remains controversial as to whether carriers of AIRE mutations are predisposed to autoimmunity; however, experiments with T cell receptor transgenic mice that are heterozygous carriers of an Aire null mutation suggest that there could be a gene dosage effect in certain settings (Liston et al., 2004). One dominant-negative mutation has been reported in an Italian familiy that demonstrated an autosomal dominant inheritance pattern with a high frequency of autoimmune thyroiditis (Cetani et al., 2001). Importantly, a corresponding gene targeted mouse model of this mutation (G228W) in the SAND domain of Aire also develops autoimmunity in a dominant fashion but increased autoimmune susceptibility was not seen in mice heterozygous for the Aire null mutation in this study (Su et al., 2008).

APS1 is a challenge to treat and follow (Husebye et al., 2009; Perheentupa, 2006). The number of manifestations and severity of the disease varies greatly, and for many patients the morbidity and mortality is increased when compared to the general population. The mainstay is replacement therapy for endocrinopathies, e.g. for adrenal insufficiency (cortisol and fludrocortisones), diabetes mellitus (insulin), and hypoparathyroidism (calcium and vitamin D). Autoimmune hepatitis, nephritis, and exocrine pancreatic have responded to immunosuppressive treatment, sometimes with regress of other APS1 manifestations like alopecia and disappearance of circulating autoantibodies (Ulinski et al., 2006; Ward et al., 1999). It is important to note, however, that the use of immunosuppression in these patients is limited to isolated case reports with often mixed results. In addition, there is little published information on immunosuppression and the reversal or improvement of T1D in APS1 subjects.

Immunodeficiency, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX)

Immunodeficiency, polyendocrinopathy, and enteropathy, X-Linked syndrome (IPEX) is also an extremely rare, but important model disease characterized by a hyperactive T cells with both autoimmune and allergic manifestations. Acronyms are X-linked polyendocrinopathy, immune dysfunction, and diarrhea (XPID) and X-linked autoimmunity and allergic dysregulation (XLAAD), but IPEX is now the preferred name. Typically, IPEX manifests itself in the perinatal period or in early infancy with chronic diarrhea due to autoimmune enteropathy or diabetes mellitus. Other common manifestations are eczematous dermatitis, autoimmune thyroiditis (hypothyroidism predominates), autoimmune cytopenias, and glomerulonephritis. The symptoms can wax and wane; worsening can be precipitated by infections, vaccinations and dietary allergens. Eosinophilia and elevated serum amounts of IgE and IgA are often reported in these patients along with the generation of autoantibodies to many self-antigens. Although the disorder has been linked to a defect in regulatory T cell function (see below), there are reports that effector T cells in these patients have defective IL-2 and gamma-interferon production (Bacchetta et al., 2006). These patients also often display an increased susceptibility to a wide number of severe infections that include bacterial, viral, and fungal organisms (Powell et al., 1982; Torgerson and Ochs, 2007).

T1D is commonly seen in this syndrome affecting more than 60% of reported subjects (Moraes-Vasconcelos et al., 2008) and often manifests early with some infants already having hyperglycemia at birth. Pancreatic tissue typically reveals lymphocytic infiltration as seen in the more common form of autoimmune diabetes (Moraes-Vasconcelos et al., 2008; Powell et al., 1982; Wildin et al., 2002). Islet-specific antibodies are present in many cases (islet cell antibodies, glutamic acid decarboxylase antibodies), but this has not been studied extensively because of the rarity of IPEX. Even growth hormone deficiency and adrenal insufficiency have been described. Thus several of the manifestations in APS1 and IPEX overlap, but overall IPEX is a much more severe disease and many patients die in infancy. Limited success has been observed with long term immunosuppressive therapy and bone marrow transplantation appears to be the treatment of choice for the disorder in most cases (Mazzolari et al., 2005; Rao et al., 2007; Zhan et al., 2008).

IPEX is caused by mutations in the FOXP3 gene located on chromosome Xp11.3-q13.3. A wide number of mutations have been described for patients with the disorder and female carriers have not been demonstrated to have an autoimmune predisposition or related phenotype; however, there has been a demonstration of the skewing of regulatory T cells to selectively express the wildtype allele in these carriers (Di Nunzio et al., 2009). There are patients that manifest milder manifestations of the disorder and there is a report of a specific point mutations in FOXP3 being associated with this milder phenotype (De Benedetti et al., 2006; Rubio-Cabezas et al., 2009).

Autoimmune polyendocrine syndrome type-2 (APS2)

APS2 is much more common than APS1 and usually commences later in life than either APS1 or IPEX. APS2 is defined by the presence of at least two of the following three diseases in the same patient: T1D, Addison's disease, and autoimmune thyroid disease. Some investigators further subdivide this group of patients (i.e. APS2, III, and IV), but patients with each of these subgroup features can appear in the same family and we along with others (Eisenbarth and Gottlieb, 2004) prefer to “lump” all of these patients into the APS2 group. Females are more frequently affected than males and there is familial clustering of the disorder. Again, like in APS1, affected family members will often present with different autoimmune symptoms. In addition to the major clinical features highlighted above, these patients will often develop autoimmune gastritis, celiac disease, vitiligo, and in female patients oophoritis (Table 1) (Anderson, 2002; Eisenbarth and Gottlieb, 2004; Kahaly, 2009). Unlike APS1 subjects, these patients do not develop hypoparathyroidism or candidiasis.

Autoimmune Addison's disease deserves a special note in APS2 patients because it is more commonly associated with the development of other autoimmune diseases than isolated T1D or thyroiditis are. Addison's is rare and has a prevalence of about 100 per million inhabitants and an incidence is about 0.5 per 100 000 per year (Lovas and Husebye, 2002). Thyroiditis occurs in about 50% of patients with Addison's, while T1D occurs in about 15% of Addison's patients (Erichsen et al., 2009). In contrast, patients with thyroiditis more commonly do not develop another autoimmune problem while patients with T1D have a moderate risk for developing thyroiditis and Addison's (Barker, 2006; Eisenbarth and Gottlieb, 2004).

APS2 has a complex inheritance pattern with a strong linkage to the HLA locus and association with a number of general autoimmunity associated genes (summarized in Table 2). Gene discovery efforts in these patients has been somewhat hampered by the relative rarity of APS2 and Addison's subjects when compared to isolated thyroidits or T1D. Thus, to date their have not been sufficiently large collections of subjects to perform adequately powered genome wide association studies to identify risk genes for Addison's disease and APS2. Despite these limitations, there has been some progress in understanding gene commonalities for T1D, thyroiditis, and Addison's which is discussed further below.

Table 2
Genes associated with Addison's disease, type 1 diabetes and autoimmune thyroid disease.

Treatment of APS2 has generally been limited to replacement hormone therapy. The disorder is generally not life threatening if the disease components are recognized (particularly Addison's) and treated with proper hormone replacement. These subjects rarely develop autoimmune features that require immunosuppression like autoimmune hepatitis or glomerulonephritis. Thus, there is little treatment data in these patients as it relates to immunomodulation or immunosuppression.

Molecular Mechanisms of APS:AIRE Function and central tolerance [Au; Change OK?]

As outlined above the defective gene in APS1 is the Autoimmune Regulator (AIRE). The AIRE protein is 545 amino acids long and contains protein domains that suggest it plays a role in transcription. A major clue into Aire function came from mapping its expression to thymic medullary epithelial cells (mTEC's) (Anderson et al., 2002; Derbinski et al., 2001; Zuklys et al., 2000), which we have come to appreciate as important regulators of thymocyte tolerance (Derbinski et al., 2001). Within mTEC's it appears that Aire helps promote tolerance by driving the transcription of a wide variety of tissue specific antigens (TSA's) that are then displayed to the developing thymocyte repertoire (Anderson et al., 2005; Anderson et al., 2002; Liston et al., 2003). Thus, defects in Aire result in a failure of central tolerance to a large number of TSA's and this is at least part of the explanation as to how APS1 subjects develop autoimmunity in multiple target organs. Importantly, it has been established that loss of thymic TSA expression even in the presence of Aire is sufficient to predispose to autoimmunity (DeVoss et al., 2006). Despite this evidence, Aire may also regulate other properties in the thymus like morphology, mTEC turnover, and cell trafficking that also influence tolerance (Gillard et al., 2007; Gray et al., 2007; Yano et al., 2008).

T1D also has been logically connected to this tolerance pathway (see Figure 1). First, it is clear that APS1 subjects have an increased risk of developing T1D (Perheentupa, 2006) and that Aire helps promote the expression of insulin within mTEC's (Anderson et al., 2002). Second, there has been a large body of data connecting quantitative changes in thymic insulin expression with diabetes genetic risk that maps to the variable number of tandem repeat (VNTR) elements in the human insulin promoter (Chentoufi and Polychronakos, 2002; Pugliese et al., 1997; Vafiadis et al., 1997). Individuals with short VNTR elements in the insulin promoter have an increased genetic risk of T1D and lower amounts of thymic insulin expression. Recently, it has also been demonstrated that these individuals harbor a higher frequency of insulin-specific T cells by tetramer analysis when compared to individuals with the protective insulin VNTR element (Durinovic-Bellow et al. 2010). Despite these logical connections, there is still much that remains to be learned about the tolerance pathway that Aire has helped reveal and its relationship to T1D. It is also interesting to note that variation in the thyroid specific gene product, the TSH-receptor, has been linked to disease risk (The Wellcome Trust Case Control Consortium, 2007; Dechairo et al., 2005) and it will be interesting to determine if this risk also maps to thymic expression.

Figure 1
Autoimmune polyendocrine syndrome (APS) clues to type 1 diabetes (T1D) pathogenesis

Molecular Mechanisms of APS:FOXP3 function and regulatory T cells

The defective gene in the IPEX syndrome was identified in 2001 through a complementary series of genetic studies involving IPEX patients and a spontaneous mutant mouse line called Scurfy (Bennett et al., 2001; Brunkow et al., 2001; Wildin et al., 2001). In these studies, the forkhead-winged helix protein Foxp3 was identified as the mutated gene in both mice and in humans. Subsequent studies went on to demonstrate that Foxp3 plays a critical role in the function of CD4+CD25+ regulatory T (Treg) cells (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003). This work has opened up a large area of investigation on Treg cells beyond the scope of this review, including studies on their development, stability, and functional activity (Sakaguchi et al., 2008). Interestingly, there have also been recent reports of patients with the clinical IPEX phenotype with no evidence of mutations in FOXP3 (Caudy et al., 2007; Owen et al., 2003; Zuber et al., 2007). One of these patients was found to have mutations in CD25 (IL-2 Receptor alpha subunit) (Caudy et al., 2007) which has been shown to play an important role in the survival and stability of Treg cells (D'Cruz and Klein, 2005; Fontenot et al., 2005). CD25 has also been known as a risk allele identified in genome wide association studies on T1D (Maier et al., 2009; Vella et al., 2005). Although expression amounts of CD25 have correlated with genotype (Dendrou et al., 2009), it remains open whether these risk alleles affect Treg cell function or activity. Interestingly, a recent study also suggests that T1D subjects may harbor other defects in functional IL-2 signaling that has an effect of FOXP3 expression (Long et al. 2010). Thus, CD25 defects in patients with T1D may be mapping to a similar pathway as that which leads to T1D in subjects with IPEX (Figure 1).

Functional Treg cell studies have also been pursued in subjects with T1D. There appears to be no significant change in the number or Treg cells in the peripheral blood of patients with T1D (Brusko et al., 2005; Putnam et al., 2005); however, several studies have demonstrated a defect in the in vitro suppression assay used to measure Treg cell activity in patients with T1D (Brusko et al., 2005; Lindley et al., 2005). Recently, it has been suggested that the defect in this assay maps to the resistance of T effector cells to suppression rather than a defect in Treg cell function (Schneider et al., 2008). Taken together, the IPEX syndrome has helped point the way towards pursuing Treg cells and their potential role in T1D pathogenesis (Figure 1).

APS2 molecular mechanisms

As outlined above, APS2 is not a single gene disorder and has a complex inheritance pattern. Certainly, one overarching reason for multiple autoimmune phenotypes in these patients is related to commonalities in genetic risk for the disease components. For example, T1D, thyroiditis, and Addison's disease all have had disease risk mapped to the HLA, CTLA4, and PTPN22 genes (Anderson, 2008). There are likely many other common genes of APS2 that have yet to be robustly identified, again, due to limitations in the numbers of patients that have been studied as discussed above. Similar to disease risk for isolated components of APS2, the highest genetic risk maps to the HLA locus with much lower risk conferred by non-HLA linked genes like CLTA4 and PTPN22. Study of the HLA types in Addison's and T1D has demonstrated that many disease risk haplotypes are shared between the disorders (Table 2). For example, the DR3/DR4, DQ2/DQ8 haplotype is observed in over 30% of Addison's patients which is also a risk haplotype for T1D (Yu et al., 1999) (see Table 2). Further parsing of this haplotype has determined that Addison's patients commonly harbor the DRB1*0404 subtype which is also seen in T1D, but T1D subjects that do not develop Addison's often display the DRB1*0401 subtype. Part of this may be explained by recent work that has suggested that the DRB1*404 allele can display epitopes of adrenal 21-hydroxylase that DRB1*401 cannot (Bratland et al., 2009).

Single nucleotide polymorphisms in the 3′ untranslated region of CTLA4 are associated with modest risk for thyroidits (odds ratio 1:5) and slight risk for T1D (odds ratio 1:15). To further explore the potential relationship of this gene to APS2, one recent study examined a large cohort of T1D patients (>4,000) and examined them for an association of thyroid autoantibodies and the frequency of the CTLA4 risk polymorphism (Howson et al., 2007). The authors found evidence for a stronger association of the CTLA4 risk polymorphism in T1D patients that had detectable thyroid autoantibodies than those that did not. Interestingly, despite PTPN22 being reported as a risk gene for both T1D and thyroiditis, there was no observable association in this study. In contrast, another report had suggested that the association of CTLA4 polymorphisms with T1D may be due to the subset of the T1D patients that also were developing thyroiditis (Ikegami et al., 2006). This was because no observable risk was associated with CTLA4 in the subset of patients that had T1D without thyroiditis. The differences in the studies may be explained by the differences in patient populations and also the clear data showing a weaker association of T1D with CTLA4.

A potential overlapping phenotype with APS2, are subsets of patients that have vitiligo and autoimmunity Many of these patients develop thyroiditis, T1D, and Addison's disease. Within families that have this pattern, it appears that inheritance of vitiligo is particularly strong when compared to the other autoimmune phenotypes. Because of this there have been large scale efforts to map genetic risk in families that have vitiligo with other autoimmune features and recently the NALP1 gene was reported to have an association (Jin et al., 2007). NALP1 is likely to play an important role in innate immune sensing and there is also evidence of association of this gene with Addison's and T1D (Magitta et al., 2009).

In addition to genetic approaches in APS2, there have been functional studies on peripheral blood lymphocytes from patients with the disorder. One recent study found that APS2 subjects harbored a defect in the suppressive function of CD4+CD25+ Treg cells but not in their frequency or marker expression pattern (Kriegel et al., 2004). Unlike the study from the Buckner group on T1D patients, this study mapped the defect directly to the Treg cell population. Another group reported a defect in activation induced cell death and caspase-3 function in lymphocytes from APS2 subjects, suggesting that a dysregulation of AICD could be in play in the disorder (Vendrame et al., 2006). In both cases, further study will be needed to confirm these observations and their molecular underpinnings, but again may help strengthen connections to T1D pathogenesis (Figure 1).

Future Opportunities and Conclusion

Despite the genetics of APS1 and IPEX being defined there is still much that can learned from these patients in regards to T1D. For example, now that we understand that a major defect in APS1 patients is a failure in thymic negative selection, these patients could be a great resource for measuring autoreactive T cells. With the advent of tetramer reagents to detect autoreactive T cells in T1D (Durinovic-Bello et al., 2010), T cells from APS1 subjects with the proper MHC alleles could be valuable in the development of tetramer assays given that they will likely harbor a larger number of high affinity T cells for self antigens like insulin. The recent identification of a unique extrathymic Aire-expressing cell (eTAC) that appears to play a role in tolerance and TSA expression (Gardner et al., 2008) also needs to be further explored as it relates to T1D (Figure 1). Like Treg cells these cells may be more tractable for the induction of tolerance and possible treatment of T1D since they appear to operate through peripheral tolerance mechanisms. Early bone marrow transplantation appears to be an effective treatment for IPEX and reverses many of the autoimmune problems in the disorder. However, in those subjects that have T1D it appears that diabetes is irreversible. Perhaps, optimization of the transplantation protocol and the use of islet-specific Treg cells (Tang and Bluestone, 2006) as an adjunct could be explored in these subjects as a means to improve T1D outcomes in these patients.

There are also a number of opportunities with APS subjects as it relates to genetics. Although it is clear that a component of APS2 pathogenesis is genetic, the identified shared risk genes only appear to offer part of the explanation as to why multiple autoimmune diseases are developing in these patients. The modest effects of non-HLA genes like PTPN22 and CTLA4 for disease risk in these subjects suggest that there may be as yet other unidentified genes (i.e. “dark matter”) at play in APS2. One attractive area that should be explored in these subjects are deep sequencing efforts to search for rare variants (rather than common SNP variants) that may be in play in exerting large effects that have not been appreciated (Altshuler et al., 2008). In terms of AIRE and FOXP3, there have been efforts to deep sequence both genes in large collections of subjects with T1D with negative results (Nejentsev et al., 2009). Despite this, there is precedent that unique mutations in AIRE and FOXP3 can give rise to distinct phenotypes from APS1 and IPEX respectively and thus, unique mutations in these genes may still contribute to T1D in settings that have not been tested to date. Gene-gene interaction effects also should be further explored in these disorders if possible and there is evidence already for this in APS1 for AIRE gene interactions with both the HLA (Halonen et al., 2002) and the VNTR of the insulin gene (Adamson et al., 2007) in relation to T1D risk.

Clearly, there has been substantial progress in our understanding of autoimmune polyendocrine syndromes and the pathogenic mechanisms that underlie these disorders. As outlined in Figure 1, a picture is emerging where mechanistic correlations between APS and T1D can now be made. Immune tolerance is controlled by multiple pathways that operate at many different layers of the immune system and the study of APS has helped reveal defects in both central and peripheral tolerance pathways that contribute to autoimmunity. The framework for these defects, as highlighted in Figure 1, has proven to be particularly useful in helping put together a working model of how the significant, but weaker gene influences identified in genome-wide association studies of T1D are contributing to disease pathogenesis. It is likely that in T1D, subtle defects in multiple pathways are working in concert to drive disease pathogenesis and the severe defects that are present in APS have provided a clearer picture of what the potential contribution of certain pathways are to the autoimmune process. Moving forward, the study of the immunology and genetics of APS will likely continue to provide new insights into immune tolerance and will also continue to help frame our understanding of T1D pathogenesis.


We thank Ms. Una Fan for her help with the figure.

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


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