编译者：李英，西京医院临床免疫科

摘  要  

血清中存在高信息量和预测性的RA相关自身抗体，特别是抗瓜氨酸蛋白抗体(ACPAS)的存在，可为类风湿关节炎(RA)的高风险患者进行翻译研究和疾病预防研究。在无关节炎的血清学阳性个体中，已证实存在与局部ACPA产生相关的黏膜炎症过程。在其他高危人群中，即使没有血清自身抗体，也存在与RA相关的自身抗体产生。此外，有一部分处于危险中的个体在肺中表现出局部粘膜ACPA的产生，以及X线小气道疾病、痰液高细胞性和增加中性粒细胞胞外陷阱的形成。在高危人群中的其他粘膜部位也表现出自身抗体的产生、炎症和/或失调的迹象。由于表现出这种局部炎症相关ACPA产生的个体比例大大高于个体发展为未来RA的可能性，这一发现提出了黏膜ACPA具有生物学相关性保护作用的假设。找出促进外部聚焦的粘膜ACPA产生和丢失的机制，促进全身自身抗体的表达，最终促进关节炎的发展，将为预防RA的新治疗方法提供深入的见解。

关键点  

最终发展为血清阳性类风湿关节炎(RA)的患者会经历一段时期RA相关的自身抗体阳性，这与细胞因子和趋化因子水平的增加有关。不同的黏膜过程会影响全身免疫和自身免疫的发展。对RA的未来发展有很高风险的个体显示出慢性系统性炎症和黏膜炎症的证据。免疫球蛋白A(IgA)抗瓜氨酸蛋白抗体(ACPA)通常是在局部产生的，而不是反映瓜氨酸抗原耐受性的丧失；系统性IgG反应可能是由于外部聚焦的分隔丧失所致。目前正在进行的研究将黏膜失调、炎症和自身抗体产生的发展与系统性自身免疫的下一个发展阶段联系起来。新的自身免疫促进过程很可能在RA的临床前阶段主要或完全发挥作用，并可能成为新的预防策略的目标。

参考文献：

Review Article | Published: 15 August 2018

Rheumatoidarthritis and the mucosal origins hypothesis: protection turnsto destruction

V. Michael Holers, M. Kristen Demoruelle, Kristine A. Kuhn, Jane H. Buckner, William H. Robinson, Yuko Okamoto, Jill M. Norris & Kevin D. Deane

Nature Reviews Rheumatologyvolume 14, pages542–557 (2018)

Abstract

Individuals at high risk of developing seropositiverheumatoid arthritis (RA) can be identified for translational research anddisease prevention studies through the presence of highly informative andpredictive patterns of RA-related autoantibodies, especially anti-citrullinatedprotein antibodies (ACPAs), in the serum. In serologically positive individualswithout arthritis, designated ACPA positive at risk, the presence of mucosalinflammatory processes associated with the presence of local ACPA productionhas been demonstrated. In other at-risk populations, local RA-relatedautoantibody production is present even in the absence of serum autoantibodies.Additionally, a proportion of at-risk individuals exhibit local mucosal ACPAproduction in the lung, as well as radiographic small-airway disease, sputumhypercellularity and increased neutrophil extracellular trap formation. Othermucosal sites in at-risk individuals also exhibit autoantibody production,inflammation and/or evidence of dysbiosis. As the proportion of individuals whoexhibit such localized inflammation-associated ACPA production is substantiallyhigher than the likelihood of an individual developing future RA, this findingraises the hypothesis that mucosal ACPAs have biologically relevant protectiveroles. Identifying the mechanisms that drive both the generation and loss ofexternally focused mucosal ACPA production and promote systemic autoantibodyexpression and ultimately arthritis development should provide insights intonew therapeutic approaches to prevent RA.

Key points

Patients who eventually developseropositive rheumatoid arthritis (RA) pass through a period of RA-relatedautoantibody positivity that is associated with increased levels of cytokinesand chemokines.

Various mucosal processes can influence thedevelopment of systemic immunity and autoimmunity.

Individuals who are at high risk of thefuture development of RA demonstrate evidence of chronic systemic and mucosalinflammation.

Rather than reflecting a loss ofcitrullinated antigen tolerance, immunoglobulin A (IgA) anti-citrullinatedprotein antibodies (ACPAs) are normally produced locally; a systemic IgGresponse likely results from loss of externally focused compartmentalization.

Ongoing studies are linking the developmentof mucosal dysbiosis, inflammation and autoantibody production to the nextstages of development of systemic autoimmunity.

Novel autoimmune-promoting processes arelikely to be identified that function primarily, or exclusively, in thepreclinical period of RA and could be the targets for new preventionstrategies.