Type 1 diabetes: the role of commensal microbiota

1型糖尿病(T1D)是一种衰弱的自身免疫性疾病，其发病率在 发达国家，建议环境的变化(包括微生物环境的变化) 可能要对此负责。我们已经开创了并仍在继续研究先天免疫的作用。 受体在启动和预防T1D中的作用我们和许多其他参与微生物区系研究的研究人员 都面临着同样的问题--如何解释宿主遗传学与微生物区系相互作用的影响。我们的 在授权期内获得的结果现在表明，多种无关的细菌谱系可以保护MyD88 来自T1D的KO小鼠。这使得我们专注于识别重要的耐受受体，而不是 特定的微生物谱系，正如我们早先提出的。我们发现MyD88阴性的B细胞提供了 强大的保护程度。我们提出了一种新的假设，即B细胞允许T细胞避免 特雷格人的镇压。微生物区系和MyD88在这种反抑制中的作用需要被发现。 我们发现信号转接子TRIF对MyD88KO小鼠也有保护作用(我们不知道 是否与B细胞有联系)。此外，在最近几年，关于 微生物区系复活，包括微生物区系参与病毒感染[参考文献]。我们不能忽视这样一个事实 在MyD88 KO NOD小鼠体内上调了一种生态型小鼠白血病病毒(MuLV)。这种组合是否 逆转录病毒和细菌阻碍了T1D的发展？最后，我们确信微生物不是必需的 对于T1D发育(就像在GF NOD小鼠中)，但我们现在有迹象表明，存在诱导T1D的微生物， L.Murinus就是其中之一。我们将进一步研究微生物的促糖尿病特性，包括 据称是人类T1D的促进者。 这是一个复杂的提议，但潜在的和统一的主题是肠道微生物区系在T1D中的作用 发展与预防。新的具体目标是： 1.依赖微生物区系控制自身免疫的细胞基础。我们将继续关注B细胞作为 MyD88阴性NOD小鼠的保护剂，并检测B细胞、树突状细胞和单核细胞的联合输入 在保护中； 2.TRIF在T1D保护作用中的作用我们将找到细胞基础和信号受体， 参与微生物触发的耐受信号； 3.测试微生物在新提出的B细胞在T1D中的作用中的作用。我们将检验新的假设 B细胞使T细胞对Tregs抑制不敏感并研究微生物区系和MyD88的作用 在这一过程中发出信号； 4.利用NADPH-1基因缺陷的NOD小鼠，确定糖尿病前期微生物区系的作用 氧化物酶。

Type 1 diabetes (T1D) is a debilitating autoimmune disease with the incidence on the increase in developed countries, suggesting that changes in environment (including changes in microbial environment) may be responsible. We have pioneered and still continue the studies to delineate the role of innate immune receptors in initiation and prevention of T1D. We and many other researchers involved in microbiota studies are faced with the same issue - how to explain the effects of host genetics interacting with microbiota. Our results acquired during the grant period now show that multiple unrelated bacterial lineages can protect MyD88 KO mice from T1D. That makes us focus on identification of important tolerizing receptors rather then on specific microbial lineages, as we proposed earlier. We have found that MyD88-negative B cells provided a strong degree of protection. We came up with a novel hypothesis that B cells allow Teff cells to avoid suppression by Tregs. The role of the microbiota and MyD88 in that anti-suppression needs to be uncovered. We found that signaling adaptor TRIF was also instrumental in protection of MyD88KO mice (we do not know whether there is a connection to B cells yet). Moreover, in the recent years new incredible facts concerning the microbiota came to life including participation of microbiota in viral infections [refs]. We cannot ignore the fact that an ecotropic murine leukemia virus (MuLV) is upregulated in MyD88 KO NOD mice. Does the combination of a retrovirus and bacteria block T1D development? Finally, we were convinced that microbes are not required for T1D development (as in GF NOD mice), but we now have an indication that T1D-inducing microbes exist, L.murinus being one of them. We will further investigate the pro-diabetic properties of microbes including alleged facilitators of the human T1D. It is a complex proposal, but underlying and unifying theme is the role of intestinal microbiota in T1D development and prevention. The new Specific Aims are:. 1. Cellular basis for microbiota-dependent control of autoimmunity. We will follow-up on the role of B cells as protectors in MyD88-negative NOD mice, and test the combined input of B cells, dendritic cells and monocytes in the protection; 2. The role of TRIF in protective effect in T1D. We will find the cellular basis and signaling receptors that participate in microbially-triggered tolerization signals; 3. Test the role of microbes in the newly proposed role for B cells in T1D. We will test the new hypothesis that B cells make Teff cells insensitive to suppression by Tregs and investigate the role of microbiota and MyD88 signaling in the process; 4. Determine the role of pro-diabetic microbiota taking advantage of NOD mice with genetic defect in NADPH- oxidase.