Reduced Diabetes in btk-Deficient Nonobese Diabetic Mice and Restoration of Diabetes with Provision of an Anti-Insulin IgH Chain Transgene

Abstract

Type 1 diabetes results from T cell-mediated destruction of insulin-producing β cells. Although elimination of B lymphocytes has proven successful at preventing disease, modulation of B cell function as a means to prevent type 1 diabetes has not been investigated. The development, fate, and function of B lymphocytes depend upon BCR signaling, which is mediated in part by Bruton’s tyrosine kinase (BTK). When introduced into NOD mice, btk deficiency only modestly reduces B cell numbers, but dramatically protects against diabetes. In NOD, btk deficiency mirrors changes in B cell subsets seen in other strains, but also improves B cell-related tolerance, as indicated by failure to generate insulin autoantibodies. Introduction of an anti-insulin BCR H chain transgene restores diabetes in btk-deficient NOD mice, indicating that btk-deficient B cells are functionally capable of promoting autoimmune diabetes if they have a critical autoimmune specificity. This suggests that the disease-protective effect of btk deficiency may reflect a lack of autoreactive specificities in the B cell repertoire. Thus, signaling via BTK can be modulated to improve B cell tolerance, and prevent T cell-mediated autoimmune diabetes.

Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice

“…A number of lines of evidence suggest that B cells may play multiple roles in the development of diabetes. B cell-deficient NOD mice do not develop diabetes (3,6), and impaired signaling of the B cell receptor protects NOD mice from diabetes development as well (27). The antigen-presenting function of B cells is also important for T1D development (2,28).…”

Autoimmune Markers in Diabetes

“…Although T1DM can occur in humans in the absence of B lymphocytes on a congenital (70 ) or an acquired basis (71,72 ), btk-deficient NOD mice that are antibody deficient are protected from T1DM (73 ). In humans, btk is the tyrosine kinase that is deficient in Bruton's X-linked recessive agammaglobulinemia.…”

Bruton’s Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice

“…Notch2 +/− mice were crossed with NOD mice and backcrossed for >10 generations. Offspring were homozygous for all NOD idd loci tested, as previously described (25) and shown in Table I. Briefly, DNA was prepared from tail biopsies using DNeasy Blood and Tissue Kit from Qiagen (cat# 69506).…”

“…All samples were run on 4% NuSieve 3:1 agarose (Lonza, cat #50090) and visualized with BioRad GelDoc XR+ system. 125Tg/NOD, V H 125Tg/NOD mice and Btk -deficient ( Btk null ) NOD mice were generated as previously described (25-27). All mice were housed in specific pathogen-free conditions, with autoclaved food and water.…”