Mechanisms of immune homeostasis and regulation of intraocular inflammation

先天性淋巴细胞、单核细胞、调节性T细胞（T细胞）和调节性B细胞（B细胞）通过分泌IL-10和IL-35来抑制CNS自身免疫性疾病，例如葡萄膜炎或多发性硬化。这些免疫抑制性细胞因子的活性是通过激活JAK/STAT信号通路介导的，并且受到严格的调节。在这项研究中，我们试图确定主要的细胞类型，产生细胞因子在体内和表征机制，调节其生产。 与先天性或THP相比，我们发现在眼部炎症性疾病期间，BHP是体内IL-35和IL-10的主要产生者。我们还发现BATF、IFN调节因子（IRF）-4和IRF-8转录因子被募集并与il 12 a、ebi 3和/或il 10位点的AP 1-IRF复合元件（AICE）结合，表明这些转录因子通过活化的B细胞调节IL-10和IL-35表达。我们还发现，STAT 3依赖性和非依赖性途径控制眼部炎症。这些研究表明，靶向STAT 3通路和BATF/IRF-4/IRF-8轴可以在治疗上用于调节IL-10/IL-35-β的生理水平和眼部炎症。

Innate lymphocytes, monocytes, regulatory T cells (Tregs) and regulatory B cells (Bregs) suppress CNS autoimmune diseases such as Uveitis or Multiple Sclerosis by secreting IL-10 and IL-35. The activities of these immune suppressive cytokines are mediated through activation of JAK/STAT signaling pathway and are under stringent regulation. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Compared to innate or Tregs we found that Bregs are the major producers of IL-35 and IL-10 in vivo during ocular inflammatory diseases. We also found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors are recruited and bind to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting that these transcription factors regulate IL-10 and IL-35 expression by activated B cells. We also found that STAT3-dependent and independent pathways control ocular inflammation. These studies suggest that targeting STAT3 pathways and the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and ocular inflammation.