Role of humoral beta-cell autoimmunity in type 1 diabetes

Abstract

Islet cell antibodies (ICA) were found for the first time more than 40 yr ago in patients with autoimmune endocrine deficiencies, including type 1 diabetes (T1D). ICA detected by indirect immunofluorescence represent a heterogeneous group of autoantibodies targeting a series of biochemical autoantigens, such as the protein tyrosine phosphatase related islet antigen 2 (IA-2), the 65 kD isoform of glutamic acid decarboxylase (GA65), and zinc transporter 8 (ZnT8) as well as currently unidentified autoantigens. The general view is that the diabetes-associated autoantibodies are not directly involved in beta-cell destruction but function as biomarkers of an ongoing destructive process. The diabetes-associated autoantibodies remain the strongest predictive marker for future development of T1D. Positivity for multiple (≥2) autoantibodies is highly predictive of clinical disease both among first-degree relatives and in the general population. Autoantibody titers are highly variable during the preclinical phase, but in many cases the titers tend to decrease before diagnosis. The first signs of beta-cell autoimmunity may appear early during the first months of life. The majority of those individuals diagnosed with T1D before puberty seroconvert to autoantibody positivity before the age of 3 yr. The natural course and duration of preclinical diabetes vary substantially from one individual to another. The characteristics of the isotype-specific response during preclinical diabetes appear to be antigen-specific. Diabetes-associated autoantibodies may be useful surrogate markers of the subsequent development of T1D in primary prevention trials. T1D may occur, albeit rarely, in the absence of any signs of humoral autoimmunity at diagnosis.

Autoantibodies against zinc transporter 8 are related to age and metabolic state in patients with newly diagnosed autoimmune diabetes

“…In children, an aggressive autoimmune process may result in overt disease within a few months after the appearance of autoantibodies, whereas in older subjects the preclinical phase may continue for several years. The majority of children had IAA and GAD-ab as their first autoantibodies detectable in preclinical phase [ 35 ]. We demonstrated that children had very low titer of GAD-ab compared to adults.…”

Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children

“…The autoimmune nature of the disease is suggested by the presence of a pool of circulating autoantibodies against beta cell proteins even years before the clinical onset, such as autoantibodies to insulin (IAA), GAD (GADA), tyrosine phosphatase (IA-2A) and zinc transporter 8 (ZnT8A) [1]. …”

Extended family history of type 1 diabetes in HLA ‐predisposed children with and without islet autoantibodies

“…[3][4][5][6] It has also been observed that seroconversion occurs earlier and median autoantibody levels are higher in children who progress to clinical type 1 diabetes before puberty. [7][8][9][10] In all, over 80% of children with multiple islet autoantibodies progress to symptomatic, insulin-requiring diabetes within 15 years after developing multiple islet autoantibodies, whereas only a minority of the children who remain positive for only a single islet autoantibody develops type 1 diabetes.…”