Autoantibody Response to CD38 in Caucasian Patients With Type 1 and Type 2 Diabetes

Abstract

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 Arg 140 Trp 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 Ca 2؉ 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 Arg 140 Trp 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 ␤-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 Ca 2؉ mobilization. Diabetes 50:752-762, 2001

Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

“…Anti-CD38 + sera incubated with purified islet cells induced not only Ca 2+ mobilisation, but also insulin secretion, with a direct correlation between the two effects [24,30]. In agreement with these experimental findings, anti-CD38 + Type II diabetic patients were characterized by higher residual beta-cell function and higher BMI, i.e., a phenotype opposite to that of LADA [25].…”

“…Anti-CD38 aAbs have been described as new markers of beta-cell autoimmunity [23,24,25]. The CD38 target molecule is a membrane glycoprotein mainly expressed in the haematological compartment, functioning as a signalling receptor and an ectoenzyme capable of producing and degrading cyclic ADP-ribose (cADPR), a Ca 2+ -mobilising second messenger [26,27].…”

“…cADPR produced by CD38 has been implicated in the mechanisms of insulin secretion in rodents [28,29]. We have recently developed an anti-CD38 enzymatic immuno-assay, suitable for screening large cohorts of patients [25]. With this approach, prevalences of 19.1% and 16.7% were found among Caucasian Type I and Type II diabetic subjects with long-standing disease, respectively [25].…”

“…We have recently developed an anti-CD38 enzymatic immuno-assay, suitable for screening large cohorts of patients [25]. With this approach, prevalences of 19.1% and 16.7% were found among Caucasian Type I and Type II diabetic subjects with long-standing disease, respectively [25]. The majority of these aAbs showed agonistic properties, capable of triggering Ca 2+ release from CD38 + target cells [25].…”

“…With this approach, prevalences of 19.1% and 16.7% were found among Caucasian Type I and Type II diabetic subjects with long-standing disease, respectively [25]. The majority of these aAbs showed agonistic properties, capable of triggering Ca 2+ release from CD38 + target cells [25]. Anti-CD38 + sera incubated with purified islet cells induced not only Ca 2+ mobilisation, but also insulin secretion, with a direct correlation between the two effects [24,30].…”