igk and Diabetes-Mellitus--Type-1

Autoreactive B lymphocytes are essential for the development of T cell-mediated type 1 diabetes (T1D). Cytoplasmic Bruton's tyrosine kinase (BTK) is a key component of B cell signaling, and its deletion in T1D-prone NOD mice significantly reduces diabetes. However, the role of BTK in the survival and function of autoreactive B cells is not clear. To evaluate the contributions of BTK, we used mice in which B cells express an anti-insulin BCR (125Tg) and promote T1D, despite being anergic. Crossing Btk deficiency onto 125Tg mice reveals that, in contrast to immature B cells, mature anti-insulin B cells are exquisitely dependent upon BTK, because their numbers are reduced by 95%. BTK kinase domain inhibition reproduces this effect in mature anti-insulin B cells, with less impact at transitional stages. The increased dependence of anti-insulin B cells on BTK became particularly evident in an Igκ locus site-directed model, in which 50% of B cells edit their BCRs to noninsulin specificities; Btk deficiency preferentially depletes insulin binders from the follicular and marginal zone B cell subsets. The persistent few Btk-deficient anti-insulin B cells remain competent to internalize Ag and invade pancreatic islets. As such, loss of BTK does not significantly reduce diabetes incidence in 125Tg/NOD mice as it does in NOD mice with a normal B cell repertoire. Thus, BTK targeting may not impair autoreactive anti-insulin B cell function, yet it may provide protection in an endogenous repertoire by decreasing the relative availability of mature autoreactive B cells.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Cells, Cultured; Diabetes Mellitus, Type 1; Immunoglobulins; Insulin; Insulin Antibodies; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Protein-Tyrosine Kinases; Receptors, Antigen, B-Cell

Two hundred sixty families, in which at least one family member had insulin-dependent (type I) diabetes mellitus (IDDM), were typed for HLA antigens and the Gm and Km allotypes. Frequencies of Gm and Km allotypes in the diabetic subjects were compared with family controls (oldest nondiabetic sibling within a family). There were no significant differences between patients and controls for either Gm or Km allotype frequencies considered individually. When the log-linear model was used to analyze subjects and sibling controls, three significant findings emerged. First, there was a significant HLA-Gm interaction, indicating nonrandom segregation of HLA antigens with Gm allotypes, regardless of disease status. Second, there was, as expected, a significant HLA-IDDM interaction, indicating that HLA type is nonrandom with respect to IDDM status. Third, there was a significant HLA-sex-Gm-IDDM interaction, indicating that combinations of HLA antigens, Gm allotypes, and sex may play an important role in defining risk for IDDM. Thus, Gm and sex interacting with HLA may reflect the influence of an unlinked modifier previously hypothesized for IDDM pathogenesis.

Topics: Adolescent; Diabetes Mellitus, Type 1; Female; Histocompatibility Antigens Class II; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DR Antigens; Humans; Immunoglobulin G; Immunoglobulins; Male