Early autoantibody responses in prediabetes are IgG1 dominated and suggestantigen-specific regulation

The islet autoimmunity of preclinical type 1 diabetes remains poorly charac terized in humans. In this paper, the IgG subclass response to the islet au toantigens insulin, glutamic acid decarboxylase, and IA-2 was studied seque ntially from birth to diabetes onset or current follow-up in 26 autoantibod y positive offspring of parents with diabetes, Islet autoantibody appearanc e was characterized by an early IgG1 peak response to one or more Ags, most commonly to insulin, at a median age of 2.2 yr (interquartile range, 2-2.9 yr), In five offspring, an acute fulminant beta-cell destruction and diabe tes onset occurred during this initial Ab response. In the remainder, early Ab levels declined markedly, and Ab peaks against other beta cell Ags aros e sequentially over several years suggesting regulation and spreading of au toimmunity. Second peak Ab responses to the same Ag were observed in only t wo offspring, both developing diabetes at this time. Two others developed d iabetes with declining Ab levels, Abs of IgG1 subclass dominated against ea ch Ag, and other subclasses, were usually only detected during peak IgG1 re sponses. The IgG4 response to insulin was exceptional, being dominant over IgG1 in four offspring and in five others appeared and/or persisted after I gG1 levels declined. These Th2-associated IgG4 responses were not correlate d with protection from diabetes. The presence of IgG1-restricted responses to DA2 were associated with diabetes development. These findings suggest th at type 1 diabetes has an early acute destructive phase of beta cell autoim munity, which may be regulated and which spreads chronically until diabetes onset.