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Type 1 Diabetes-Associated Autoimmunity: Natural History, Genetic Associations, and Screening

The Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver Health Sciences Center, Aurora, Colorado 80010

Address all correspondence and requests for reprints to: Jennifer M. Barker, M.D., The Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver Health Sciences Center, P.O. Box 6511 A-140, Aurora, Colorado 80010. E-mail: jennifer.barker{at}uchsc.edu.

	Abstract

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
Context: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison’s disease (AD), and other autoimmune diseases. These diseases can occur together in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndrome I, autoimmune polyendocrine syndrome II, and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome.

Evidence Acquisition: Review of the medical literature was performed with particular attention to the natural history, genetic factors, and syndromes associated with T1D, AIT, CD, and AD.

Evidence synthesis: Genetic risk for these diseases overlaps and includes genes within the major histocompatibility complex (MHC) such as the human leukocyte antigens (HLA) DR and DQ alleles and the MHC I-related gene A (MIC-A). Other genes outside of the MHC have been associated with these autoimmune diseases, including the gene encoding the lymphoid tyrosine phosphatase (PTPN22) and the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene.

Conclusion: Genetic risk for T1D overlaps with AIT, CD, and AD. Disease risk is associated with organ-specific autoantibodies, which can be used to screen subjects with T1D.

	Introduction

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
FIFTEEN TO 30% of subjects with type 1 diabetes (T1D) have autoimmune thyroid disease (AIT) (1, 2, 3), 4–9% have celiac disease (CD) (4, 5, 6, 7, 8, 9), and 0.5% have Addison’s disease (AD) (3). The risk for autoimmune disease is increased in relatives of patients with T1D. Eight percent of first-degree relatives have AIT (10), and up to 6% have CD (10, 11, 12). These diseases are associated with organ-specific autoantibodies: thyroid peroxidase (TPO) and thyroglobulin (TG) with AIT, endomysial (EMA) autoantibodies and transglutaminase (TTG) autoantibodies with CD, and 21-hydroxylase (21-OH) autoantibodies with AD. Using these autoantibodies, organ-specific autoimmunity may be detected before the development of clinical disease. Early detection has the potential to prevent significant morbidity related to unrecognized disease.

	Genetic Factors (Table 1 and Fig. 1)

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
Common genetic risk factors have been associated with T1D, AIT, CD, and AD. Analyses of these associations are mostly performed in subjects affected with one autoimmune disease. Where analysis occurred in subjects with multiple autoimmune diseases, it is described as such.

View larger version (18K): [in this window] [in a new window]   FIG. 1. The development of pathogenic and regulatory T cells is schematically depicted in this figure and is shown on the left and right side of the diagram, respectively. The figure is further subdivided into thymic selection and peripheral expansion. Proposed sites of actions for described genes are placed into at least one of the four quadrants (thymic selection of pathogenic and regulatory T cells and peripheral expansion of pathogenic and regulatory T cells). Some genes may act in more than one area (e.g. MHC), although others have a very specific site of action (FOXP3 and AIRE). Only genes discussed within the text are included.

DR3-DQ2 shows a strong association with CD. Homozygosity for DR3-DQ2 in a population with T1D carries a 33% risk for the presence of TTG autoantibodies (8). Three percent of children from the general population with one or two DR3-DQ2 alleles have CD defined by intestinal biopsy or are persistently positive for TTG autoantibodies by 5 yr of age (14).

Screening blood donors for TPO autoantibodies has shown an association with DR3 and DR5 (15). Other studies have failed to confirm this association (16). Linkage studies in families with multiple members affected with AIT have not shown an association with DR3-DQ2 (17). In families with multiple members affected with T1D and AIT, DR3-DQ2 has been linked with AIT and T1D (18). Cross-sectional analysis in subjects with T1D has shown an association with the genotype DR3-DQ2, DR4-DQ8 (19) and the haplotype DR3-DQ2 (3).

AD has been associated with the presence of a rare subtype of DR3-DQ2, DR4-DQ8 in which the DR4 subtype is DRB1*0404. This subtype is found in less than 1% of the general population compared with 30% of the population with AD (20, 21, 22).

Some HLA alleles are protective for disease development. DQA1*0102, DQB1*0602 is associated with a low risk for T1D (23). This is disease specific because DQB1*0602 is associated with an increased risk for multiple sclerosis.

The MHC I-related gene A (MIC-A) has been associated with autoimmune diseases. Polymorphisms of MIC-A are based on the number of triplicate GCT repeats in exon 5 and are designated 4, 5, 6, and 9. An additional polymorphism, designated 5.1, is associated with the insertion of a base pair, which results in a premature stop codon. The protein is expressed in the thymus. It is thought to interact with a receptor, NKG2D, which may be important for thymic maturation of T cells (24). It is hypothesized that the loss of this interaction is a way in which immunological tolerance may be lost. It has been shown that NKG2D regulates the priming of human naive CD8+ T cells, providing an alternate explanation for associations with autoimmune diseases (25). Polymorphisms of MIC-A have been associated with T1D. In particular, the 5 allele and the 5.1 allele have shown strong associations with T1D (26, 27, 28). MIC-A polymorphisms have also been associated with CD, with allele 4 (29) and 5.1 (30, 31, 32) having reported associations. MIC-A is expressed on intestinal epithelial cells, and its expression has been shown to be induced by gliadin in in vitro testing of intestinal epithelium from patients with CD (33). This may lead to enhanced T-cell receptor-dependent CD8+ T-cell response (34, 35). Polymorphisms of MIC-A have been associated with AD (22, 36). In our population with T1D already positive for 21-OH autoantibodies, the development of AD was increased in subjects homozygous for the MIC-A 5.1 allele (22).

The PTPN22 gene is expressed in T cells and encodes lymphoid tyrosine phosphatase (LYP). LYP appears to be important in the signal cascade downstream from the T-cell receptor. It has been shown to interact with negative regulatory kinases such as Csk, which may act as a brake on the signal cascade. A specific polymorphism changes an arginine to tryptophan at position 620. It is hypothesized that this polymorphism decreases the ability of LYP to interact with its target molecules and down-regulate T-cell receptor signaling (37). This polymorphism has been associated with T1D (37, 38), rheumatoid arthritis (39, 40), systemic lupus erythematosus (40), and Graves disease (41) and weakly with AD (41). The association with many autoimmune diseases suggests that this gene may be playing a role in susceptibility to autoimmunity in general.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is expressed on activated CD4+ and CD8+ T-cell membranes. It binds costimulatory molecules inhibiting T-cell activation (42). Polymorphisms within the CTLA-4 gene have been linked to AIT (43). One polymorphism designated CTLA-4 G/G has been associated with increased proliferation of T cells (44). A second single-nucleotide polymorphism CT60 A/A is associated with protection from AIT, with a weaker affect in T1D. This polymorphism has been associated with an increase in the alternate splice product of the gene that is a soluble form of the protein (45). CTLA-4 has also been linked to AD and more strongly to subjects affected with AD in association with T1D and AIT compared with AD alone (46). CTLA-4 genes may plan an important role in synergy with HLA for the development of both T1D and AIT (45, 47).

	T1D

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
The model of T1D as a chronic autoimmune disease beginning with genetic susceptibility and progressing to autoimmunity leading to destruction of ß-cells is useful for conceptualizing other organ-specific autoimmune diseases.

Autoantibodies against the pancreatic islet, islet cell antibodies (ICA), are detected by reacting serum with frozen sections of human pancreas (48). In addition to these autoantibodies, many investigators are using antibodies against insulin (49), GAD65 (50), and IA-2 (51) as markers of the autoimmune process.

Autoantibodies appear to develop sequentially. Insulin autoantibodies are often the first expressed autoantibody, especially in young children (52, 53). Family members who expressed autoantibodies to insulin, GAD65, and IA-2 have a 75% 5-yr risk of diabetes compared with a 25% 5-yr risk in relatives who expressed one of those autoantibodies (54). These autoantibodies may be present for years before the diagnosis of diabetes (55, 56, 57). The risk for diabetes does not appear to decline over time. One report showed that after 5 yr of follow-up, 30% of relatives with multiple diabetes-associated autoantibodies developed diabetes, and the risk continued after 10 yr of the study (58).

Abnormalities of iv and oral glucose tolerance testing precede the diagnosis of overt diabetes. First-phase insulin response (FPIR) measured by iv glucose tolerance testing is the sum of insulin levels the first and third minute after administration of an iv glucose load. Many subjects with T1D have a low FPIR before the diagnosis of diabetes, and this may persist for years before clinical disease (59, 60). Some children already had low FPIR within 6 months of first autoantibody positivity (61), with over 50% of children expressing multiple autoantibodies having a decreased FPIR at first evaluation. The Diabetes Prevention Trial, type 1 (DPT-1) has shown that by following at-risk subjects for T1D with serial oral glucose tolerance testing, 60% of subjects diagnosed with diabetes are identified on the basis of elevated 2-h glucose alone. The remainder showed diagnostic 2-h glucose with impaired fasting glucose, not meeting the criteria for diabetes on fasting samples alone (62). These data suggest that subjects go through a phase of decreasing ß-cell mass marked first by the loss of FPIR and progressing to abnormalities of glucose tolerance and ultimately diabetes.

	Thyroid (Table 2)

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
Hypothyroidism affects 5–10% of the general population with increased prevalence in older individuals and females (63, 64, 65). Hyperthyroidism is less common, affecting 1% of the general population (63). Autoantibodies to TPO and TG are associated with AIT (63, 66). TPO and TG autoantibodies are expressed in 13 and 11% of the general population, respectively (63).

As much as 20–30% of the population with T1D express TPO and/or TG autoantibodies (3, 68, 70). Thyroid autoimmunity is increased in females and with longer duration of diabetes (3, 68). Prospective follow-up showed that the development of thyroid disease was related to female gender and presence of TPO antibodies (61). With follow-up of almost 20 yr, the development of hypothyroidism in the population with T1D and TPO autoantibodies approached 80% in life table analysis (2) with a hazard ratio of 8.99. This is similar to reported hazard ratios of 8 in women and 25 in men with positive TPO antibodies from a 20-yr population-based study of thyroid disease in the general population (66).

The presence of AIT in the population with T1D has the potential to affect growth, weight gain, diabetes control, menstrual regularity, and overall well-being. Current recommendations from the American Diabetes Association (ADA) are for screening TSH after stabilization at onset of diabetes, with symptoms of hypo- or hyperthyroidism, and every 1–2 yr thereafter (71). The recommendations note that the presence of thyroid autoantibodies may increase the risk for thyroid disease in this population but have no statement regarding thyroid autoantibody screening (71). It is our current practice to screen patients with T1D with TPO autoantibodies, TSH, and T₄ levels at onset and every 1–2 yr thereafter. Subjects with positive TPO autoantibodies and normal thyroid function are screened on a more frequent basis (every 6 months to 1 yr).

	CD (Table 2)

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
Wheat gluten and related components of rye and barley have been identified as the agents responsible for the induction of the autoimmune process associated with CD. This process ultimately results in blunting of the small intestinal villi and the varied clinical features of CD. Removal of gluten and related proteins from the diet results in resolution of the pathological abnormalities with improvement in clinical symptoms (72, 73).

CD has been described as a rare disease affecting primarily young children with prevalence in the general population of approximately 1 in 3000 (74). However, this likely represents the tip of the iceberg of CD. CD autoimmunity is present in 1 in 133 to 1 in 250 adult subjects (68, 69). Prospective follow-up of newborns showed a risk for evidence of CD by 5 yr in the general population of Denver, Colorado, to be 0.9% (14). Screening children in Finland revealed a prevalence of biopsy-proven CD of 1% (1 in 99 children) with a median age of evaluation of 12 yr (75).

The diagnosis of CD requires a high index of suspicion. Subjects can be screened for celiac-associated autoimmunity with EMA or TTG autoantibodies. TTG was identified as the autoantigen for EMA (76). Autoantibodies against TTG are a sensitive and specific marker of the autoimmune process and are present in more than 95% of subjects who have biopsy-proven CD (72, 77). Autoantibodies to antigliadin are much less sensitive and specific, and the use of these autoantibodies for screening is no longer recommended (72). A highly sensitive RIA for TTG may provide quantitative results with higher levels associated with abnormalities on small intestinal biopsy (78, 79). A definitive diagnosis of CD is obtained by performing a small intestinal biopsy looking for the characteristic pathological changes (72, 73).

Clinical features of CD may be subtle and include growth abnormalities mimicking constitutional growth delay (80, 81), mild abdominal pain and bloating (82), infertility (83, 84), abnormalities of bone mineralization (85, 86), and hypocalcaemia with vitamin D deficiency and compensatory hyperparathyroidism (87). Psychiatric (88) and neurological abnormalities (89, 90, 91, 92) have been reported. Association studies have suggested a link between CD and the development of malignancy, especially gastrointestinal lymphomas (93, 94). One such study found that the risk was the greatest in the first year after diagnosis of CD, with hazards ratios for gastrointestinal malignancy of 1.85 (1.22–2.81) and lymphoproliferative disease of 4.80 (2.71–8.58). After exclusion of events within 1 yr of CD diagnosis, the association remained significant only for lymphoproliferative disease, with a hazard ratio of 2.40 (1.58–7.34) (95). The significance of this association in young asymptomatic individuals identified through screening for autoantibodies is unclear.

Approximately 5–10% of subjects with T1D have positive EMA or TTG autoantibodies, and a significant proportion (up to 75%) have abnormalities on biopsy of the intestine (4, 5, 6, 7, 8, 9). Patients with T1D can be identified with positive TTG autoantibodies at diagnosis of diabetes (96). However, a significant subset of patients with T1D have a negative first screen for CD autoimmunity and become positive (4), suggesting that a single screen may not identify all subjects at risk for CD. It appears that subjects with T1D and TTG autoantibodies are not at an increased risk for abnormalities on biopsy compared with the general population who are TTG positive, with rates of abnormalities on biopsy in the TTG-positive general population reported at 75% (75).

The current recommendations for screening subjects with T1D are to obtain autoantibodies at diagnosis of diabetes and with symptoms of CD (71). It is the current recommendation that subjects with positive TTG autoantibodies have a small intestinal biopsy to confirm the diagnosis (97). Some have recommended biopsy be performed on only those subjects who have intermediate autoantibody levels for diagnostic purposes, with treatment initiated in patients who have high autoantibody levels (98). Our current clinical practice is to measure TTG autoantibodies at diagnosis and every 2 yr after that. Individuals with a positive TTG autoantibody have the assay repeated for confirmation. If the autoantibody remains positive, subjects are referred for definitive diagnosis.

	Adrenal (Table 2)

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
AD affects approximately 1 in 10,000 of the general population (99). The autoimmune process resulting in AD can be identified by the detection of autoantibodies against the adrenal cortex (100, 101, 102). Adrenal cortical autoantibodies were the first identified autoantibodies associated with AD and are detected by the reaction of human sera against sections of adrenal cortex (100). Biochemical autoantibodies reacting to 21-OH are a sensitive marker of this autoimmune process (101, 102). The presence of this autoantibody in the general population is very rare (20). 21-OH autoantibodies are present in approximately 1–2% of subjects with T1D (3, 20, 103). In our population with T1D, approximately 1.5% expressed autoantibodies to 21-OH, 15% of those positive who did not have known AD developed AD with a relatively short follow-up time (22). The presence of adrenal autoimmunity was associated with thyroid autoimmunity; approximately 70% of the population with 21-OH autoantibodies also expressed thyroid autoimmunity (3).

Betterle et al. (104) have followed a large group of subjects with 21-OH autoantibodies for the development of adrenal insufficiency. They have described a progression of adrenal insufficiency that begins with elevated plasma renin activity and then progresses to increased ACTH, decreased stimulated cortisol, and eventually abnormalities of fasting cortisol.

Our current practice is to screen patients with T1D for the presence of 21-OH autoantibodies. Those patients with positive autoantibodies are followed for adrenal insufficiency by ACTH stimulation testing. In our cohort, the majority of our subjects who develop AD have an elevated plasma renin activity and ACTH at diagnosis (22). The subjects are mildly symptomatic with decreasing insulin doses and hemoglobin A1c (22). Rates of development of AD in the population without T1D and with 21-OH autoantibodies have been reported in ranges from 10–50% depending upon the follow-up time, similar to rates in other populations screened with 21-OH autoantibodies (105).

	Syndromes

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
Autoimmune polyendocrine syndrome I (APS-I)

APS-I, also known as autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED), is a rare polyendocrine autoimmune disease caused by mutations of the autoimmune regulator gene (AIRE). It is inherited in an autosomal recessive manner.

AIRE is located on chromosome 21q22.3 (106, 107, 108), has homology with transcription factors, and has been localized to the nucleus (109, 110). Common mutations affect the ability of AIRE to localize to the nucleus and decreased transcription activation (111, 112). AIRE-deficient mice have a mild phenotype compared with the human disease (113, 114). These experiments have demonstrated that AIRE acts to initiate transcription of peripheral antigens (antigens normally expressed in tissues outside of the immune system) within the thymic medullary epithelial cells (114). It is proposed that this expression is important for the thymic maturation of T cells and participates in negative selection of T cells that react with self-antigens.

APS-I is defined by the presence of two or three of the following components: mucocutaneous candidiasis, adrenal insufficiency, and/or hypoparathyroidism. Affected individuals generally develop persistent or recurrent mucocutaneous candidiasis within the first several years of life. Autoimmune hypoparathyroidism is usually the first autoimmune disorder to present, followed by AD, additional autoimmune disease developing sequentially over time (115, 116, 117). Follow-up of subjects with this disorder has revealed that many organ systems may be involved in the autoimmune process including the pancreatic ß-cell. Approximately 20% of subjects with APS-I have T1D (117). The patient with APS-I must be followed closely for signs, symptoms and laboratory evidence of developing autoimmunity in a center experienced with the diagnosis and treatment of these disorders. For a more detailed review of the clinical presentation and recommendations for follow-up of these patients, refer to the recent review by Perheentupa (117).

APS-II

We generally define APS-II as the association of an autoimmune endocrine disorder with an additional autoimmune disease but not meeting the criteria for APS-I or having an identified mutation of the AIRE gene (118). Therefore, by definition, patients with T1D and an additional autoimmune disease meet the criteria for APS-II. The majority of patients with T1D who have another autoimmune disease are diagnosed with that disease after the onset of diabetes. Umpierrez et al. (2) followed over 50 patients with T1D and TPO autoantibodies, only two of 19 subjects with thyroid disease developed it before the diagnosis of diabetes. CD may be diagnosed at onset of diabetes; however, a significant subset of subjects with diabetes who develop CD-related autoimmunity do so after diabetes onset (4).

In contrast to APS-I, APS-II has a higher prevalence in females, has defined HLA associations (119), and has an older age of onset. Screening subjects with one autoimmune endocrine disease for additional autoimmune diseases can be done by careful history and physical exam with directed laboratory testing or by screening for organ-specific autoantibodies and following subjects with autoimmunity for the development of disease. The advantages to screening autoantibodies include the ability to identify subjects before they become significantly symptomatic with disease and to eliminate subjects from screening who are not at risk for disease. The drawback is that patients develop autoimmunity over time, and the presence of a single negative autoantibody test does not ensure that the patient will never develop autoimmunity. There is a small subset of patients who develop disease who never have positive autoantibodies. For example, hyperthyroidism may develop in the face of negative TPO autoantibodies, and patients on lithium would be at risk for hypothyroidism.

Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)

IPEX is a rare X-linked disorder that presents in infancy with insulin-dependent diabetes and severe enteropathy, which lead to failure to thrive and early mortality. The genetic defect causing IPEX has recently been identified as the FOX-P3 gene (120). FOX-P3 is expressed in regulatory CD4+ CD25+ regulatory T cells, and mutations result in the inability to generate these regulatory cells resulting in multi-organ autoimmunity.

	Conclusion

Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 
T1D is associated with the presence of additional autoimmune diseases such as AIT, CD, and AD, which are associated with the production of organ-specific autoantibodies. These autoantibodies can be used to screen individuals with T1D for autoimmunity associated with clinical disease. A subset of the subjects with organ-specific autoantibodies develops clinical disease. The frequency of screening for and the follow-up of patients with positive autoantibodies remain controversial, with some advocating regular screening, whereas others advocate screening in the presence of clinical symptoms. The current ADA recommendations are to screen for CD-associated autoantibodies at diagnosis of T1D and with symptoms. The ADA recommends screening for thyroid disease on an annual basis using a serum TSH. There are no current recommendations for screening for adrenal autoimmunity. Our current practice is to screen for thyroid disease on an annual basis with a serum TSH and TPO autoantibody, and for celiac and adrenal disease with autoantibody testing every 2 yr. Prospective studies will clarify the necessary frequency and duration of screening.

	Acknowledgments

 
We acknowledge the patients and families for their participation.

	Footnotes

 
This research was supported by National Institutes of Health Grants DK 32083, DK 32493, A146374, and DK57516 and grants to the General Clinical Research Centers (RR-00051 and RR-00069). J.M.B. is supported by the Juvenile Diabetes Research Foundation (11-2005-15).

The author has nothing to declare.

First Published Online January 10, 2006

Abbreviations: AD, Addison’s disease; AIRE, autoimmune regulator; AIT, autoimmune thyroid disease; APS, autoimmune polyendocrine syndrome; CD, celiac disease; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; EMA, endomysial; FPIR, first-phase insulin response; HLA, human leukocyte antigen; ICA, islet cell antibodies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked; LYP, lymphoid tyrosine phosphatase; MHC, major histocompatibility complex; MIC-A, MHC I-related gene A; 21-OH, 21-hydroxylase; T1D, type 1 diabetes; TG, thyroglobulin; TPO, thyroid peroxidase; TTG, transglutaminase.

Received July 28, 2005.

Accepted January 4, 2006.

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Top Abstract Introduction Genetic Factors (Table 1... T1D Thyroid (Table 2) CD (Table 2) Adrenal (Table 2) Syndromes Conclusion References

 

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