Role of B Lymphocytes in the Pathogenesis of Type 1 Diabetes

Abstract

Though type 1 diabetes (T1D) is considered a T cell-mediated autoimmune disorder, recent evidence indicates that B cells play a critical role in disease. This conclusion is based in part on the success of anti-CD20 (rituximab) therapy, which by broadly depleting B cells delays disease progression in non-obese diabetic (NOD) mice and new-onset patients. B cell receptor (BCR) specificity to islet autoantigen is key. NOD mice whose B cell repertoire is biased toward insulin reactivity show increased disease development, while bias away from insulin reactivity largely prevents disease. Although the operative disease-promoting B cell effector function remains undefined, islet-antigen reactive B cells function in antigen presentation to diabetogenic CD4 T cells. Other studies implicate B cells in antigen presentation to CD8 T cells. B cell participation in TID appears predicated on faulty B cell tolerance. Here, we review extant findings implicating B cells in T1D in mice and men.

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

“…Genetic ablation of B cells prevents T1D [67]; antibody-mediated depletion of B cells ameliorates the disease in mice [68, 69] and delays T1D progression in human prediabetic children [70]. Autoreactive B cells may present islet antigens to self-reactive T cells, whereas mechanisms depending on autoantibody secretion are thought to be less important [71–73]. NOD mice have impaired peripheral B cell tolerance at the transitional check point [74], which involves BAFF (also known as BLyS), a B-cell stimulating cytokine elevated in autoimmune conditions [75].…”

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

“…Moreover, TCR overlap among pathogenic CD4 + effector T cells and protective Treg have yet to be investigated in human T1D. Likewise, B cell receptor (BCR) sequencing efforts have been limited overall (15,16) and, in particular, in patients with T1D (17), despite a known role for B cells in contributing to T1D through their capacity to present antigens (18).…”

Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

“…Similarly, NOD transgenic mice with B lymphocytes that cannot secrete antibodies still develop diabetes (74). B lymphocytes do heighten the immune response toward β-cells in NOD mice (55), and research suggests that B lymphocytes may play a role in human T1D, likely through antigen presentation (75). To date, no studies have specifically investigated B lymphocytes in canine diabetes.…”