Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.
Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.
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DOI：
10.1126/scitranslmed.aaj1921
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发表时间：
2016-12-14
影响因子：
17.1
通讯作者：
Andrade F
中科院分区：
文献类型：
--
作者：
Konig MF;Abusleme L;Reinholdt J;Palmer RJ;Teles RP;Sampson K;Rosen A;Nigrovic PA;Sokolove J;Giles JT;Moutsopoulos NM;Andrade F
自从现代细菌理论开始，类风湿性关节炎（RA）的细菌病因一直被怀疑。最近的研究暗示粘膜表面是疾病的起始部位。RA中常见的牙周生态失调提示口腔病原体可能引发易感个体产生疾病特异性自身抗体和关节炎。我们使用质谱法确定牙周病患者和健康对照者龈沟液的微生物组成和抗原库。牙周炎的特点是存在瓜氨酸化自身抗原，这是RA的主要免疫靶点。牙周炎中的瓜素反映了类风湿关节中观察到的高瓜素化模式，暗示该粘膜部位与RA发病有关。在高牙周炎样品中检测到几种微生物的蛋白质组学特征。其中，放线菌聚集菌（Aa），而不是其他候选病原体，诱导宿主中性粒细胞的超细化。我们确定了成孔毒素白质毒素a （LtxA）作为Aa触发中性粒细胞中瓜氨酸化酶的失调激活的分子机制，模拟了在RA关节中维持自身抗原瓜氨酸化的膜溶解途径。此外，LtxA诱导中性粒细胞形态的变化，模拟细胞外陷阱的形成，从而释放高尿酸的货物。在RA患者中证实暴露于白毒性Aa菌株，并与抗瓜氨酸化蛋白抗体（ACPAs）和类风湿因子（RF）相关。HLA-DRB1共享表位等位基因对自身抗体阳性的影响仅限于暴露于Aa的RA患者。这些研究确定牙周病原体Aa是RA自身免疫的候选细菌触发因素。
A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin-A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The effect of HLA-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients that were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA.