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Diabetes. 2008 Feb;57(2):395-404. Epub 2007 Nov 19.

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

Author information

1
Senior Research Fellow, Gene Therapy and Autoimmunity Group, Arthritis and Inflammation Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, N5W 2010, Australia.

Abstract

OBJECTIVE:

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.

RESEARCH DESIGN AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
18025414
DOI:
10.2337/db07-0589
[Indexed for MEDLINE]
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