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© 2001 by the American Diabetes Association, Inc.
Autoantibody Response to CD38 in Caucasian Patients With Type 1 and Type 2 Diabetes
Immunological and Genetic Characterization
1 Department of Internal Medicine
2 Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, University of Torino, Torino
3 Institute of Biology and Genetics, University of Ancona, Ancona, Italy
Insulin secretion is one of the functions mediated by CD38, a nonlineage pleiotropic cell surface receptor. The molecule is the target of an autoimmune 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 Arg140Trp mutation has been identified in Japanese diabetic patients. We investigated the relationship between CD38 and diabetes in Caucasian patients by characterizing anti-CD38 aAbs in terms of prevalence and function (agonistic/nonagonistic activity) and by exploring the potential influence of the CD38 genetic background. A novel enzymatic immunoassay, using recombinant soluble CD38 as the target antigen, was developed for the analysis of anti-CD38 aAb titers. Sera from 19.15% of type 1 and 16.67% of type 2 diabetic patients were positive. The majority of anti-CD38 aAbs (57.14%) displayed agonistic properties, i.e., they demonstrated the capability to trigger Ca2+ release in lymphocytic cell lines. In agreement with these functional features, the presence of anti-CD38 aAbs in type 2 diabetic patients was associated with significantly higher levels of fasting plasma C-peptide and insulin, as compared with anti-CD38– counterparts. No diabetic subject carrying the Arg140Trp mutation and no preferential association between diabetes or aAb status and the CD38*A allele was found in the study population. These results show the significance of anti-CD38 aAbs as a new diagnostic marker of ß-cell autoimmunity in diabetes. Moreover, the prevalent agonistic activity of these aAbs suggests that they could mediate relevant effects on target cells by means of Ca2+ mobilization.
Abbreviations: aAb, autoantibody; BSA, bovine serum albumin; [Ca2+]i, intracellular Ca2+ level; cADPR, cyclic ADP-ribose; EIA, enzymatic immunoassay; FCS, fetal calf serum; IL, interleukin; LADA, latent autoimmune diabetes in the adult; mAb, monoclonal antibody; OD, optical density; PBMC, peripheral blood mononuclear cell; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PVDF, polyvinilydene difluoride; rsCD38, recombinant soluble CD38; TBST, Tris-buffered saline with Tween; WHO, World Health Organization
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