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Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells.

Diabetes (2007-11-21)
Eliana Mariño, Marcel Batten, Joanna Groom, Stacey Walters, David Liuwantara, Fabienne Mackay, Shane T Grey
ABSTRACT

B-cells are important for disease pathogenesis in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Recent studies demonstrate that marginal-zone B-cells (MZBs), which connect innate with adaptive immune responses, are increased in NOD mice. However, beyond this, the contribution of different B-cell subsets to diabetes pathogenesis is poorly understood. To better understand the role of different B-cell subsets in the etiology of type 1 diabetes, we have examined the MZB compartment in NOD mice, with respect to their number, distribution, and function. We demonstrate that splenic MZB numbers in female NOD mice undergo a marked, approximately threefold expansion between approximately 12 and 16 weeks of age, coincident with the onset of frank diabetes. Functionally, NOD MZBs are hyperresponsive to toll-like receptor 9 ligation and CD40 ligation, as well as sphingosine-1-phosphate-dependent chemotactic cues, suggesting an increased sensitivity to selective innate- and activation-induced stimuli. Intriguingly, at 16 weeks of age, approximately 80% of female NOD mice present with MZB-like cells in the pancreatic lymph node (PLN). These MZB-like cells express major histocompatibility complex class II and high levels of CD80 and CD86, and their presence in the PLN is associated with an increased frequency of activated Vbeta4(+) CD4(+) T-cells. Significantly, we demonstrate that purified MZBs are able to present the autoantigen insulin to diabetogenic T-cells. These data are consistent with MZBs contributing to the pathogenesis of type 1 diabetes as antigen-presenting cells. By integrating innate-derived inflammatory signals with the activation of autoreactive T-cells, MZBs may help to direct T-cell responses against beta-cell self-constituents.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Insulin from porcine pancreas, powder, ≥27 USP units/mg