IA-2 antibody isotypes and epitope specificity during the prediabetic process in children with HLA-conferred susceptibility to type I diabetes

Abstract

SummaryThe natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to β β β β -cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)-related proteins (IA-2 and IA-2β β β β ) in preclinical type I diabetes (TID). Forty-five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA-2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA-2/IA-2β β β β epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and β β β β PTP-like domain) and isotype-specific IA-2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA-2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA-2 JM epitope response more frequently ( P = = = = 0·06), and this response was more often dominant during the observation period ( P < < < < 0·05). The children who did not progress to TID had IgE-IA-2 more frequently (70%; versus progressors 27%; P < < < < 0·05), and had higher integrated titres of IgE-IA-2 antibodies ( P < < < < 0·05). The occurrence of IgE-IA-2 antibodies was protective even when combined with positivity for IA-2 JM antibodies ( P = = = = 0·002). IgE-IA-2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA-2 antibody-positive young children with HLA-conferred disease susceptibility.

Role of humoral beta-cell autoimmunity in type 1 diabetes

“…In the DIPP study, we explored the maturation of the humoral immune response to IA‐2 and IA‐2β. We observed that the children who progressed to clinical T1D tended to have an initial JM‐specific response more often, and such a response was more frequently dominant during the observation period when compared to the non‐progressors .…”

“…We have studied the isotype response to IA‐2 in 45 DIPP children, out of whom 15 developed T1D during their follow‐up. The children, who remained non‐diabetic had IgE subclass IA‐2A more frequently and higher integrated levels of IgE‐IA‐2A than the progressors (Table ) .…”

Characteristics of the pre‐diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish population—The ABIS study

“…For instance, a difference in IAA affinity has been observed between individuals with low or high risk of disease progression, while this was not the case for IA2A where antibody titers rather than affinity had higher relevance for risk stratification . Making use of antibody properties might however not be uncomplicated, because even though IA2A affinity was not related to disease progression, IA2A epitope specificity has been shown to differ between those who developed diabetes or not . Progression to T1D has also been related to IA2A epitope spreading .…”

Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

“…There was no difference in the age at diagnosis between those positive for IgE subclass IA-2A and the negative ones. One would have expected IgE-positive children to be older at the time of diagnosis based on our earlier observation that an IgE class IA-2 response protects from progression to T1D among IA-2A-positive children (17,20).…”

“…For example, IgG4 subclass IA-2A (21) as well as IgE class IA-2A (17,20) have been associated with protection from progression to T1D. JM-specific IA-2A have been shown to be one of the first epitope-specific IA-2A to appear in young children (9), and they have been associated with a greater risk of progression to overt T1D (9,17,20). There are, however, fewer studies measuring the same parameters among patients with newly diagnosed T1D.…”