Systemic translocation of Staphylococcus drives autoantibody production in HIV disease
Systemic translocation of Staphylococcus drives autoantibody production in HIV disease
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DOI：
10.1186/s40168-019-0646-1
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发表时间：
2019-02-14
期刊：
影响因子：
15.5
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
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作者：
Luo, Zhenwu;Li, Min;Jiang, Wei
已经报道了HIV疾病中自身反应性抗体的增加;然而，HIV中自身抗体诱导的机制仍然未知。IgG抗核抗体（ANA）和抗双链DNA抗体（抗dsDNA））在一些病毒抑制抗逆转录病毒治疗（ART）治疗的HIV+受试者中，但在健康对照中没有。这些自身抗体不是来自抗原特异性B细胞，而是来自通过单细胞测定和通过研究来自血浆的纯化的多克隆ANA分析的活化的“旁观者”B细胞。为了探索HIV+受试者中自身抗体产生的机制，分析了微生物产物的血浆水平、B细胞的基因表达谱和B细胞受体（BCR）库。我们发现，自身抗体的产生与血浆中微生物易位水平的增加有关;自身抗体水平高的患者B细胞谱系偏斜，与先天免疫激活相关的基因上调，以应对微生物易位。通过分析血浆中循环微生物16 S rDNA，发现葡萄球菌的相对丰度与HIV+受试者中自身抗体的产生相关。最后，我们发现热灭活金黄色葡萄球菌注射促进小鼠生殖中心B细胞反应和自身抗体产生，这与HIV+患者自身抗体产生是由微生物制品触发的观点一致，我们的结果表明葡萄球菌易位可以通过增强生殖中心反应促进B细胞活化并诱导自身抗体产生。它揭示了HIV+疾病中微生物易位和自身免疫的潜在机制，并为靶向葡萄球菌以防止自身抗体产生提供了强有力的理论基础。
Increased autoreactive antibodies have been reported in HIV disease; however, the mechanism accounting for autoantibody induction in HIV remains unknown.Herein, we show that seasonal influenza vaccination induces autoantibody production (e.g., IgG anti-nuclear antibody (ANA) and anti-double-stranded DNA antibody (anti-dsDNA)) in some viral-suppressed antiretroviral therapy (ART)-treated HIV+ subjects, but not in healthy controls. These autoantibodies were not derived from antigen-specific B cells but from activated "bystander" B cells analyzed by single-cell assay and by study of purified polyclonal ANAs from plasma. To explore the mechanism of autoantibody generation in HIV+ subjects, plasma level of microbial products, gene expression profile of B cells, and B cell receptor (BCR) repertoires were analyzed. We found that autoantibody production was associated with increased plasma level of microbial translocation; the patients with high autoantibodies had skewed B cell repertoires and upregulation of genes related to innate immune activation in response to microbial translocation. By analyzing circulating microbial 16S rDNA in plasma, the relative abundance of Staphylococcus was found to be associated with autoantibody production in HIV+ subjects. Finally, we found that injection of heat-killed Staphylococcus aureus promoted germinal center B cell responses and autoantibody production in mice, consistent with the notion that autoantibody production in HIV+ patients is triggered by microbial products.Our results showed that translocation of Staphylococcus can promote B cell activation through enhancing germinal center response and induces autoantibody production. It uncovers a potential mechanism linking microbial translocation and autoimmunity in HIV+ disease and provides a strong rationale for targeting Staphylococcus to prevent autoantibody production.