ReviewImmunogenetics of type 1 diabetes mellitus
Introduction
Type 1 diabetes mellitus is a chronic autoimmune disease in which endogenous insulin production is severely compromised as a result of an immune-mediated injury of pancreatic β-cells (Eisenbarth, 1986). Genetic analyses of T1DM have linked the HLA complex, mainly class II alleles, to susceptibility to T1DM (Morel et al, 1988, Todd et al, 1987). Viral antigens may also play a role in the generation of beta cell autoimmunity (Lonnrot et al., 2000). The latter observations are supported by the increasing seasonal incidence of T1DM in many Western countries (Orchard et al., 1986) and that enteroviruses may be involved in the autoimmune pathogenesis of T1DM (Hyoty, 2002, Lonnrot et al, 2000, Zipris et al, 2007).
Type 1 diabetes was not always considered as the classical organ-specific disease it is now known to be. Insulin-dependent diabetes was known to occasionally occur in the Autoimmune Polyendocrine Syndrome I (APS I), a classic autoimmune syndrome with T-cell and B-cell antibody abnormalities directed at adrenal, parathyroid, gonadal, thyroid and other tissues. However, diabetes mellitus is not a constant, necessary or sufficient feature of APS I (Eisenbarth and Gottlieb, 2004). This condition is now known to be caused by mutations in the autoimmune regulator gene (AIRE) (Husebye and Anderson, 2010). Bottazzo et al. (1974) reported that sections of human pancreas treated with sera of diabetic patients who also had Addison's disease and myxedema, showed cytoplasmic fluorescence in the islets of Langerhans. This response was termed cytoplasmic islet cell antibodies (ICA) (Bottazzo et al., 1974). Furthermore, the existence of insulin autoantibodies and other autoantibodies against various islet proteins was not uncovered until years later. It was in 1983 that insulin autoantibodies were reported in sera of newly diagnosed patients with T1DM, before any treatment with exogenous insulin (Palmer et al., 1983). In this finding, improvements of the sensitivity of the insulin antibody assay were instrumental for the determination that about one-half of newly diagnosed patients had autoantibodies that bound 125I-labeled insulin.
Type 1 diabetes is primarily a T-cell mediated disease. Following the early discoveries on humoral autoimmunity in T1DM, there has been a remarkable expansion in the detection of T1DM-associated autoantibodies as well as in the characterization of the molecular basis of the antigenicity of their target proteins (Atkinson, Eisenbarth, 2001, Pietropaolo, Eisenbarth, 2001). This expansion has led to the uncovering of specific antigenic determinants, the development of biochemically defined immunoassays and also to coordinated efforts to standardize assays across laboratories (Bonifacio et al., 2010).
Section snippets
Association with other autoimmune diseases
For reasons not fully understood, patients with an organ-specific autoimmune disease have increased risks of developing autoimmune responses against other organs/tissues (Jaberi-Douraki et al, 2014, Pietropaolo et al, 2012). Patients with T1DM are at increased risk for developing other autoimmune diseases, most commonly autoimmune thyroiditis and celiac disease. Thyroid autoimmunity is particularly common among patients with type 1A diabetes, affecting more than one-fourth of individuals, and 2
Genetic susceptibility
In T1DM, familial aggregation is indicated by the notion that the overall risk for developing T1DM in North American Caucasian siblings, parents and offspring of individuals with T1DM ranges from 1% to 15% (Allen et al, 1986, Dorman et al, 1995, Wagener et al, 1982, Warram et al, 1984, Warram et al, 1994) as compared to less than 1% for individuals without T1DM relatives and 1.2/1,000 of the general population (LaPorte et al., 1995) (Table 1).
However, over 80% of cases of T1DM occur in
Environmental factors
Environmental influences are another important factor in the development of type 1 diabetes. Perhaps the best evidence for this influence is the demonstration in multiple populations of a rapid increase in the incidence of type 1A diabetes (Gale, 2002, Vehik et al, 2007). The etiology of the increase is unknown. One hypothesis, termed the hygiene hypothesis, relates improved “sanitation” to increasing immune-mediated disorders (Bach, 2002). Twin studies indicate that not all monozygotic twins
Islet autoantigens and humoral autoimmunity
An ongoing search has identified several autoantigens within the pancreatic ß-cells that may play important roles in the initiation or progression of autoimmune islet injury. Seminal studies have suggested that using a combination of humoral immunological markers gives a higher predictive value for T1DM progression, and great sensitivity without significant loss of specificity (Verge et al., 1996).
As autoimmunity in T1DM progresses from initial activation to a chronic state, there is often a
Role of cellular immunity
A strong indication that T1DM is an autoimmune disease is derived from a comprehensive histological examination of pancreata from T1DM patients who had died shortly after diagnosis (Bottazzo et al, 1985, Conrad et al, 1994, Foulis et al, 1986, Gianani et al, 2010). The majority of the subjects had significant lymphocytic infiltration of their islets concordant with loss of ß-cell mass. With the advent of monoclonal antibodies capable of identifying distinct lymphocyte sub-populations, more
Concluding remarks
Type 1 diabetes results from autoimmune destruction/dysfunction of pancreatic β cells. In physiologic conditions there is balance between pathogenic T cells that mediate disease such as T cells with marked conservation of their TCRs (e.g. insulin), and regulatory cells that control autoimmunity. In T1DM and other autoimmune disorders, there is an altered balance between pathogenic and regulatory T cells. Development of therapies targeting specific T and B lymphocytes is under way in animal
Acknowledgments
This work was supported by the National Institutes of Health (Grant Number: R01 DK53456, R01 DK56200) to MP, the Michigan Institute for Clinical & Health Research (MICHR), and the Clinical and Translational Science Award (CTSA) program: UL1RR024986 (MP), and by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant Number P30DK020572: MDRC, P30DK092926: MCDTR). We greatly acknowledge the McNair Medical Institute for its support.
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