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Eur J Immunol. 2013 Oct;43(10):2588-97. doi: 10.1002/eji.201343376. Epub 2013 Aug 1.

Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice.

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  • 1Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.

Abstract

Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in nonobese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes in NOD mice, partially via activating autoreactive marginal zone-like B cells.

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

KEYWORDS:

Autoimmunity; Autoreactive B cells; Exosomes; NOD; type 1 diabetes (T1D)

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