Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy.
Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy.
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DOI：
10.3389/fimmu.2018.02352
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发表时间：
2018
影响因子：
7.3
通讯作者：
Andrade F
中科院分区：
文献类型：
--
作者：
Mukherjee A;Jantsch V;Khan R;Hartung W;Fischer R;Jantsch J;Ehrenstein B;Konig MF;Andrade F
背景资料：伴放线菌聚集杆菌（Aggregatibacteractinomycetemcomitans，Aa）是一种革兰氏阴性球杆菌，是牙周炎和感染性心内膜炎的病原菌。通过产生一种毒素（白细胞毒素A，LtxA），触发中性粒细胞中的整体高瓜氨酸血症，Aa最近已与类风湿性关节炎（RA）的发病机制。虽然机制和临床关联研究暗示Aa感染在类风湿关节炎自身免疫的启动，在人类的直接证据是缺乏的。病例：我们描述了一位59岁的抗瓜氨酸蛋白抗体（ACPA）阳性的RA患者，他因难治性疾病而就诊。他被发现患有心内膜炎。抗生素治疗后，关节症状消退，ACPA正常化。鉴于RA免疫发病机制的影响，我们进一步研究了可能导致患者临床和自身免疫表型的细菌，遗传和免疫因素。方法：从血清中提取DNA，PCR扩增Aa白细胞毒素（ltx）基因启动子区，并进行桑格测序。HLA等位基因的高分辨率鉴定通过基于测序的分型（SBT）进行。通过多重免疫测定法定量血清中的TNF-α、IFN-γ、GM-CSF、IL-1β、IL-6、IL-8、IL-17 A、IL-18、IL-21和IL-22。通过ELISA测定抗Aa LtxA的IgG和伊加抗体。结果：Aa基因分型证实了携带530 bp ltx启动子缺失的高白细胞毒性菌株的感染，该菌株导致LtxA的细菌表达增加10至20倍。免疫表型分析显示高抗LtxA抗体，RA发病机制中涉及的细胞因子升高（Th 1/Th 17），以及与ACPA和RA密切相关的三个HLA等位基因（DRB 1 *04：04，DRB 1 *15：01和DPB 1 *04：01）赋予的特异性宿主易感性。Aa根除后一年，患者仍然没有关节炎和抗CCP抗体。结论：在RA遗传风险的背景下，Aa白细胞毒性菌株的全身亚急性感染可驱动ACPA产生和与RA相似的临床表型。
Background: Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis (RA) pathogenesis. Although mechanistic and clinical association studies implicate Aa infection in the initiation of autoimmunity in RA, direct evidence in humans is lacking. Case:We describe a 59-year-old man with anti-citrullinated protein antibody (ACPA)-positive RA who presented for evaluation of refractory disease. He was found to have Aa endocarditis. Following antibiotic treatment, joint symptoms resolved and ACPAs normalized. Given the implications for RA immunopathogenesis, we further investigated the bacterial, genetic and immune factors that may have contributed to the patient's clinical and autoimmune phenotypes. Methods:DNA was extracted from serum and used to amplify the Aa leukotoxin (ltx) promoter region by PCR, which was further analyzed by Sanger sequencing. High-resolution identification of HLA alleles was performed by sequenced based typing (SBT). TNF-α, IFN-γ, GM-CSF, IL-1β, IL-6, IL-8, IL-17A, IL-18, IL-21, and IL-22 were quantified in serum by a multiplex immunoassay. IgG and IgA antibodies to Aa LtxA were assayed by ELISA. Results:Aa genotyping confirmed infection with a highly leukotoxic strain carrying a 530-bp ltx promoter deletion, shown to result in 10- to 20-fold higher bacterial expression of LtxA. Immuno-phenotyping showed high anti-LtxA antibodies, elevated cytokines implicated in RA pathogenesis (Th1/Th17), and specific host susceptibility conferred by three HLA alleles strongly linked to ACPAs and RA (DRB1*04:04, DRB1*15:01, and DPB1*04:01). One year after eradication of Aa, the patient remained free of arthritis and anti-CCP antibodies. Conclusion: In the context of genetic risk for RA, systemic subacute infection with a leukotoxic strain of Aa can drive ACPA production and a clinical phenotype similar to RA.
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通讯作者：
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