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The participation of B-1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B-1 cells in streptozotocin (STZ) induced diabetes in mice. We demonstrated that XID (B-1 cell-deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level in response to STZ. Unexpectedly, the XID mice that were i.p. transferred with purified B-1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long-lasting protection for the XID mice against STZ-induced diabetes, suggesting that B-1 cells play an important role in the experimental diabetes pathobiology. We also showed that B-1 cell culture supernatants were able to regulate the blood glucose level of the diabetic XID mice, and we identified insulin-producing cells when B-1 cells were differentiated in B-1 cell-derived phagocyte in vitro. These findings provide a novel role for B-1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target. Keywords: B-1 cells r Experimental diabetes r Insulin r Streptozotocin r XID mice IntroductionType-1 diabetes is an organ-specific autoimmune disease in which T cells mediate the destruction of pancreatic β cells. The role played by T cells in the pathogenesis of diabetes has been extensively investigated. In 1996, Serreze et al. published the first study providing evidence that B lymphocytes play an important role in the development of diabetes [1]. Since then, the possible but controversial role of B cells in the outcome and evolution of this disease has been suggested in the literature. Although some authors have proposed the involvement of B cells in the development of autoimmune diabetes [2,3], others have suggested that B cells may not be necessary for the initiation of the autoimmune process [4].Correspondence: Prof. Mario Mariano e-mail: mariomu@uol.com.brThe different populations of B cells, denominated B-1 and B-2 cells, have been characterized in mice. B-1 cells differ from conventional B cells (B-2 cells) in their ontogeny, anatomical distribution, surface markers, antibody subtype production, selfrenewing ability, and the activity and localization of their precursors during adulthood [5,6]. B-1 cells are further subdivided into two subpopulations, B-1a and B-1b, based on the presence or absence of the CD5 molecule on their membrane, respectively [7,8], and are responsible for the secretion of "natural" antibodies that recognize polymeric antigens of high molecular weight [9,10]. B-1a cells produce autoreactive antibodies, suggesting the participation of these cells in autoimmune diseases in both humans and murine experimental models [11]. We have previously demonstrated that B-1 cells migrate toward a nonspecific inflammatory focus and that they are able to differentiate into mononuclear phagocytes (B-1 cell derived C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. ...

Chronic lymphocytic leukemia (CLL) is a malignancy disease characterized by the expansion of CD5 + B-1 cells. The NZB mouse model of CLL shows similarities to human CLL, has age-associated increase in malignant B-1 clones and decreased expression of miR-15a/16. It was demonstrated that systemic lentiviral delivery of miR-15a/16 ameliorates disease manifestations in this mouse model. Nowadays, new therapeutic approaches have been focus on miRNA in cancer cells. Natural compounds like quercetin can modulate these miRNAs, consequently, suppress oncogenes or stimulate tumor suppressor genes by altering miRNA expressions. Here we investigate the effects of quercetin on miRNA15a/16 expression by radio-resistant B-1 cells. It has been described that a small percentage of B-1 cell survives to irradiation in vitro, and these cells show similarities to B-CLL cells. In these cells, the level of miR15a/16 is diminished and Bcl-2 is overexpressed. Quercetin treatment restore both, miR15a/16 and Bcl-2, to normal levels. Furthermore, transference of radioresistant B-1 cells to NOD/SCID mice causes an expansion of this population and also a migration to the liver. However, after quercetin treatment, even radioresistant B-1 cells are not able to expand or disseminate in vivo, and the levels of miR15a/16 and Bcl-2 are also normalized. Our data support the hypothesis that quercetin is an important adjuvant molecule that acts on miRNA15a/16 level and leads cells more permissive to apoptosis. This work could help to design new approaches to therapy in CLL patients.