Toll-like receptors regulate B cell cytokine production in patients with diabetes.

M Jagannathan, M McDonnell, Y Liang, H Hasturk, J Hetzel, D Rubin, A Kantarci, T E Van Dyke, L M Ganley-Leal, B S Nikolajczyk

Diabetologia 2010 Jul

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Understanding cellular and molecular events in diabetes mellitus will identify new approaches for therapy. Immune system cells are important modulators of chronic inflammation in diabetes mellitus, but the role of B cells is not adequately studied. The aim of this work was to define the function of B cells in diabetes mellitus patients through focus on B cell responses to pattern recognition receptors. We measured expression and function of Toll-like receptors (TLRs) on peripheral blood B cells from diabetes mellitus patients by flow cytometry and multiplexed cytokine analysis. We similarly analysed B cells from non-diabetic donors and periodontal disease patients as comparative cohorts. B cells from diabetes mellitus patients secrete multiple pro-inflammatory cytokines, and IL-8 production is significantly elevated in B cells from diabetic patients compared with those from non-diabetic individuals. These data, plus modest elevation of TLR surface expression, suggest B cell IL-8 hyperproduction is a cytokine-specific outcome of altered TLR function in B cells from diabetes mellitus patients. Altered TLR function is further evidenced by demonstration of an unexpected, albeit modest 'anti-inflammatory' function for TLR4. Importantly, B cells from diabetes mellitus patients fail to secrete IL-10, an anti-inflammatory cytokine implicated in inflammatory disease resolution, under a variety of TLR-stimulating conditions. Comparative analyses of B cells from patients with a second chronic inflammatory disease, periodontal disease, indicated that some alterations in B cell TLR function associate specifically with diabetes mellitus. Altered TLR function in B cells from diabetes mellitus patients increases inflammation by two mechanisms: elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production.

Citation

M Jagannathan, M McDonnell, Y Liang, H Hasturk, J Hetzel, D Rubin, A Kantarci, T E Van Dyke, L M Ganley-Leal, B S Nikolajczyk. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia. 2010 Jul;53(7):1461-71