Abstract：
Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin-21 (IL-21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL-6 and IL-21 receptors, thereby inhibiting the bindings of IL-6 and IL-21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides-mediated immunomodulation.
摘要：
新的证据强调了宿主微生物群对自身免疫性疾病病因的功能影响，包括类风湿性关节炎（RA）。然而,对微生物生物分子，特别是微生物肽对调节免疫稳态的贡献的机制见解有限。这里,通过挖掘扁桃体微生物组的宏基因组学数据，在RA患者中发现了抗生素肽唾液素编码基因的缺陷，与循环免疫细胞有很强的相关性。证据表明，唾液素在抑制T滤泡辅助（Tfh）细胞分化和白细胞介素21（IL-21）产生中发挥免疫调节作用。机械上,唾液素直接结合并诱导IL-6和IL-21受体的构象变化，从而抑制IL-6和IL-21与其受体的结合并抑制下游信号通路。最后,在RA小鼠模型中,唾液素的给药对实验性关节炎具有预防和治疗作用.一起,这些结果提供了微生物肽介导的免疫调节机制。
