Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis.
Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis.
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DOI：
10.1016/j.jaut.2016.02.005
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发表时间：
2016-05
影响因子：
12.8
通讯作者：
Steere AC
中科院分区：
文献类型：
--
作者：
Crowley JT;Strle K;Drouin EE;Pianta A;Arvikar SL;Wang Q;Costello CE;Steere AC
感染引起的自身免疫被认为是抗生素难治性莱姆关节炎的一个促成因素，但自身免疫的研究因难以识别相关自身抗原而受到阻碍。我们开发了一种新方法，首先使用串联质谱法鉴定滑膜组织中的 T 细胞表位。在此，我们鉴定了一种免疫原性 HLA-DR 呈递肽（T 细胞表位），其源自抗生素难治性关节炎患者滑膜的来源蛋白基质金属蛋白酶-10 (MMP-10)。这一发现为识别 MMP-10 的自身抗体反应提供了桥梁，MMP-10 是移行性红斑（感染的最初皮肤病变）患者亚组中的“第一次自身免疫打击”。几个月后，在早期感染中启动对 MMP-10 的免疫反应后，一部分抗生素反应性或抗生素难治性关节炎患者产生了 MMP-10 自身抗体，但只有抗生素难治性关节炎患者对该蛋白同时出现 T 和 B 细胞反应，这为“第二次自身免疫攻击”提供了证据。抗 MMP-10 自身抗体与不同滑膜病理学的正相关性进一步支持了生物学相关的自身免疫事件。这一经验证明了基于发现的新方法在识别慢性炎症性关节炎中相关自身免疫反应的力量。
Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant auto-antigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the “first autoimmune hit” in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory arthritis had both T and B cell responses to the protein, providing evidence for a “second autoimmune hit”. Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of arthritis.