Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Orthopedics, Yale University School of Medicine, New Haven, Connecticut, USA.
Cell Microbiol. 2019 Feb;21(2):e12954. doi: 10.1111/cmi.12954. Epub 2018 Oct 17.
In most patients with Lyme arthritis (LA), antibiotic therapy results in Borrelia burgdorferi pathogen elimination, tissue repair, and return to homeostasis. However, despite spirochetal killing, some patients develop proliferative synovitis, characterised by synovial hyperplasia, inflammation, vascular damage, and fibrosis that persists for months to several years after antibiotic treatment, called postinfectious LA. In this study, we characterised the transcriptomes of postinfectious LA patients' synovial tissue, the target tissue of the immune response. High-throughput RNA sequencing to a depth of ~30 million reads per sample was used to profile gene expression in synovial tissue from 14 patients with postinfectious LA, compared with eight patients with other types of chronic inflammatory arthritis and five with minimally inflammatory osteoarthritis (OA). Synovium from postinfectious LA and other inflammatory arthritides shared gene signatures associated with antigen presentation, innate immune responses, and cell-mediated immune activation, whereas these responses were diminished in OA synovium. Unique to postinfectious LA was a particularly robust interferon-gamma (IFNγ) signature. Moreover, this heightened IFNγ signature inversely correlated with expression of genes involved in repair of damaged tissue, including genes associated with stromal cell proliferation and differentiation, neovascularisation, and extracellular matrix synthesis, which were markedly suppressed in postinfectious LA. Transcriptional observations were confirmed by cytokine profiling, histologic analyses, and clinical correlations. We propose that in patients with postinfectious LA, overexpression of IFNγ in synovium prevents appropriate repair of tissue damaged by B. burgdorferi infection, blocking return to tissue homeostasis long after completion of antibiotic therapy and resolution of active infection.
在大多数莱姆关节炎（LA）患者中，抗生素治疗可导致伯氏疏螺旋体病原体消除、组织修复和恢复内稳态。然而，尽管螺旋体被杀死，但一些患者仍会发展为增殖性滑膜炎，其特征为滑膜增生、炎症、血管损伤和纤维化，这些病变在抗生素治疗后持续数月至数年，称为感染后 LA。在这项研究中，我们对感染后 LA 患者的滑膜组织（免疫反应的靶组织）进行了转录组特征分析。使用高通量 RNA 测序，对每个样本进行了约 3000 万次读取的深度测序，以分析 14 例感染后 LA 患者和 8 例其他类型慢性炎症性关节炎患者以及 5 例轻度炎症性骨关节炎（OA）患者的滑膜组织基因表达情况。感染后 LA 和其他炎症性关节炎的滑膜组织共享与抗原呈递、固有免疫反应和细胞介导的免疫激活相关的基因特征，而 OA 滑膜组织的这些反应减弱。感染后 LA 特有的是一个特别强烈的干扰素-γ（IFNγ）特征。此外，这种升高的 IFNγ 特征与受损组织修复相关基因的表达呈负相关，包括与基质细胞增殖和分化、新血管生成和细胞外基质合成相关的基因，这些基因在感染后 LA 中明显受到抑制。转录观察结果通过细胞因子分析、组织学分析和临床相关性得到了证实。我们提出，在感染后 LA 患者中，滑膜中 IFNγ 的过度表达阻止了伯氏疏螺旋体感染引起的组织损伤的适当修复，从而在抗生素治疗完成和活动性感染消除后很久仍阻止组织恢复内稳态。
