Autoantibody response to CD38 in Caucasian patients with type 1 and type 2diabetes - Immunological and genetic characterization

Insulin secretion is one of the functions mediated by CD38, a nonlineage pl eiotropic cell surface receptor. The molecule is the target of an autoimmun e response, because serum autoantibodies (aAbs) to CD38 have been detected in diabetic patients. In the healthy Caucasian population, the CD38 gene is bi-allelic (86% CD38*B and 14% CD38*A), whereas an Arg(140)Trp mutation ha s been identified in Japanese diabetic patients. We investigated the relati onship between CD38 and diabetes in Caucasian patients by characterizing an ti-CD38 aAbs in terms of prevalence and function (agonistic/nonagonistic ac tivity) and by exploring the potential influence of the CD38 genetic backgr ound. A novel enzymatic immunoassay, using recombinant soluble CD38 as the target antigen, was developed for the analysis of anti-CD38 aAb titers. Ser a from 19.15% of type 1 and 16.67% of type 2 diabetic patients were positiv e. The majority of anti-CD38 aAbs (57.14%) displayed agonistic properties, i.e., they demonstrated the capability to trigger Ca2+ release in lymphocyt ic cell lines. In agreement with these functional features, the presence of anti-CD38 aAbs in type 2 diabetic patients was associated with significant ly higher levels of fasting plasma C-peptide and insulin, as compared with anti-CD38(-) counterparts. No diabetic subject carrying the Arg(140)Trp mut ation and no preferential association between diabetes or aAb status and th e CD38*A allele was found in the study population. These results show the s ignificance of anti-CD38 aAbs as a new diagnostic marker of beta -cell auto immunity in diabetes. Moreover, the prevalent agonistic activity of these a Abs suggests that they could mediate relevant effects on target cells by me ans of Ca2+ mobilization.