B cells and type 1 diabetes ...in mice and men

Nearly 70% of newly produced B cells express autoreactive antigen receptors and must be silenced to prevent autoimmunity. Failure of silencing mechanisms is apparent in type 1 diabetes (T1D), where islet antigen-specific B cells appear critical for development of disease. Evidence for a B cell role in T1D includes success of B cell targeted anti-CD20 therapy, which delays T1D progression in both NOD mice and new onset patients. Demonstrating the importance of specificity, NOD mice whose B cell repertoire is biased toward insulin reactivity show increased disease development, while bias away from insulin reactivity largely prevents disease. Finally, though not required for illness, high affinity insulin autoantibodies are often the first harbingers of T1D. B cell cytokine production and auto-antigen presentation to self-reactive T cells are likely important in pathogenesis. Here we review B cell function, as described above, in T1D in humans and the non-obese diabetic (NOD) mouse. We will discuss recent broad-based B cell depletion studies and how they may provide the basis for refinement of future treatments for the disorder.