Abstract
ObjectiveType 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. Research Design and MethodsWe assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. ResultsT1D patients had elevated IgE (median, 56.7U/ml; p<0.0001) compared with T2D patients (22.5U/ml) and controls (43.3U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03–6.97; p=0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27–4.35; p=0.003). InterpretationAnti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.
Highlights
Type 1 diabetes (T1D) is caused by extensive destruction of insulin-producing pancreatic beta-cells leading to absolute insulin deficiency, and the incidence has been increasing worldwide at a rate of 3% every year (American Diabetes Association, 2014; Atkinson et al, 2014; IDF Diabetes Atlas Seventh Edition 2015, 2015; Scully, 2012)
IgE levels have been reported as a potential risk factor of diabetes (Wang et al, 2011), and T1D may possibly be associated with a risk of self-reported presence of IgE-mediated allergies (Klamt et al, 2015)
We were able to show that T1D patients have overall elevated IgE and that their immune condition could be classified based on IgE and anti-GAD anti-glutamic acid decarboxylase antibody (Ab) profile into four subtypes
Summary
T1D is caused by extensive destruction of insulin-producing pancreatic beta-cells leading to absolute insulin deficiency, and the incidence has been increasing worldwide at a rate of 3% every year (American Diabetes Association, 2014; Atkinson et al, 2014; IDF Diabetes Atlas Seventh Edition 2015, 2015; Scully, 2012). The immune-mediated form of T1D results from cellular mediated autoimmune destruction of pancreatic beta-cells, has strong associations with HLA, and is characterized by the production of several autoantibodies including anti-insulin antibody (IAA), anti- GAD Ab, islet antigen 2 antibody (IA-2 Ab), anti-zinc transporter antibody (ZnT8 Ab), and historic anti-islet cell antibody (ICA Ab) (American Diabetes Association, 2014). Fulminant T1D in which a non-autoimmune process may associate with the onset was reported as an important subtype in East Asia (Imagawa and Hanafusa, 2011). These observations imply that T1D patients possibly possess a delicate Th1/Th2 balance. It was suggested that T1D seems to include heterogeneous diseases whose pathogenic processes, immunologic basis, genetics, and phenotypic characteristics present marked variations (Atkinson et al, 2014; Kawasaki and Eguchi, 2004)
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