Institution of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden.
Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Intern Med. 2019 Dec;286(6):627-643. doi: 10.1111/joim.12980. Epub 2019 Oct 21.
The aetiology of the autoimmune disease rheumatoid arthritis (RA) involves a complex interplay between genetic and environmental factors that initiate many years before the onset of clinical symptoms. These interactions likely include both protective and susceptibility factors which together determine the risk of developing RA. More than 100 susceptibility loci have been linked to RA. The strongest association is with HLA-DRB1 alleles encoding antigen presenting molecules containing a unique sequence in the peptide-binding grove called the 'shared epitope'. Female sex, infections during childhood, lifestyle habits (e.g. smoking and diet) and distinct microbial agents, amongst many others, are interacting risk factors thought to contribute to RA pathogenesis by dysregulating the immune system in individuals with genetic susceptibility. Interestingly, patients with RA develop autoantibodies many years before the clinical onset of disease, providing strong evidence that the lack of tolerance to arthritogenic antigens is amongst the earliest events in the initiation of seropositive RA. Here, we will discuss the clinical and mechanistic evidence surrounding the role of different environmental and genetic factors in the phases leading to the production of autoantibodies and the initiation of symptomatic RA. Understanding this complexity is critical in order to develop tools to identify drivers of disease initiation and propagation and to develop preventive therapeutics.
自身免疫性疾病类风湿关节炎（RA）的病因涉及遗传和环境因素之间的复杂相互作用，这些因素在临床症状出现前多年就开始起作用。这些相互作用可能包括保护性和易感性因素，它们共同决定了发生 RA 的风险。已经有超过 100 个易感性位点与 RA 相关。最强的关联是与 HLA-DRB1 等位基因有关，这些基因编码含有称为“共享表位”的肽结合槽中独特序列的抗原呈递分子。女性、儿童时期的感染、生活方式习惯（例如吸烟和饮食）以及独特的微生物因素等，都是被认为通过在具有遗传易感性的个体中调节免疫系统而导致 RA 发病机制的交互风险因素。有趣的是，RA 患者在疾病临床发作前多年就会产生自身抗体，这有力地证明了对关节炎抗原的缺乏耐受性是血清阳性 RA 起始的最早事件之一。在这里，我们将讨论围绕不同环境和遗传因素在导致产生自身抗体和引发有症状 RA 的各个阶段中所起作用的临床和机制证据。了解这种复杂性对于开发识别疾病起始和传播驱动因素的工具以及开发预防性治疗方法至关重要。
