Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T cell-mediated destruction of insulin-producing β cells. Its incidence has increased during the past several decades in developed countries 1, 2, suggesting that changes in the environment (including human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility3 or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products 4,5. Here we show that specific-pathogen free (SPF) NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes as germ-free (GF) MyD88-negative NOD mice develop robust diabetes, whereas colonization of these GF NOD.MyD88-negative mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88-deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of SPF NOD.MyD88-negative donors attenuates T1D in GF NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.

The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.

SummaryTsetse flies transmit the protozoan parasite African trypanosomes, the agents of human sleeping sickness in sub-Saharan Africa. Parasite transmission in the insect is restricted by a natural resistance phenomenon (refractoriness). Understanding the mechanism of parasite resistance is important as strengthening fly's response(s) via transgenic approaches can prevent parasite transmission and lead to the development of novel vector control strategies. Here, we investigated the role of one of the two major pathways regulating innate immunity in invertebrates, the immunodeficiency (Imd) pathway, for Glossina morsitans morsitans 's natural defence against Trypanosoma brucei spp. infections. We determined the molecular structure of the Imd pathway transcriptional activator Relish (GmmRel), which shows high amino acid identity and structural similarity to its Drosophila homologue. Through a doublestranded RNA-based interference approach, we showed that the pathogen-induced expression profile of the antimicrobial peptides (AMPs) attacin and cecropin is under the regulation of GmmRel. Unexpectedly, the AMP diptericin appears to be constitutively expressed in tsetse independent of the presence of the Rel factor. Through GmmRel knockdown, we could successfully block the induction of attacin and cecropin expression in the immune responsive tissues fat body and proventriculus (cardia) following microbial challenge. The midgut and salivary gland trypanosome infection prevalence, as well as the intensity of midgut parasite infections were found to be significantly higher in flies when attacin and relish expression were knocked down. Our results provide the first direct evidence for the involvement of antimicrobial peptides in trypanosome transmission in tsetse.

Studies in animal models and human subjects have shown that both innate and adaptive immunity contribute to the pathogenesis of type 1 diabetes (T1D). Whereas the role of TLR signaling pathways in T1D has been extensively studied, the contribution of the nucleotidebinding oligomerization domain, leucine-rich repeat and pyrin domaincontaining protein (NLRP) 3 inflammasome pathway remains to be explored. In this study, we report that NLRP3 plays an important role in the development of T1D in the nonobese diabetic (NOD) mouse model. NLRP3 deficiency not only affected T-cell activation and Th1 differentiation, but also modulated pathogenic T-cell migration to the pancreatic islet. The presence of NLRP3 is critical for the expression of the chemokine receptors CCR5 and CXCR3 on T cells. More importantly, NLRP3 ablation reduced the expression of chemokine genes CCL5 and CXCL10 on pancreatic islet cells in an IRF-1-dependent manner. Our results suggest that molecules involved in chemotaxis, accompanied by the activation of the NLRP3 inflammasome, may be effective targets for the treatment of T1D.NLRP3 | islet | type 1 diabetes | chemokine | NOD mouse

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