Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response

IntroductionIn rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.MethodsThe level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.ResultsPlasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.ConclusionsThe plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.引言 类风湿关节炎（rheumatoid arthritis, RA）患者体内可出现免疫激活与自身抗体，且这些表现可能先于疾病的临床发作；即使疾病进入缓解期，关节破坏仍可持续进展。然而，在达标治疗（treat-to-target）策略实施期间，炎症反应中这类免疫系统异常的潜在时间动态变化仍有待阐明。我们此前曾报道，慢性类风湿关节炎与脊柱关节炎患者的血浆可溶性CD18（soluble form of CD18, sCD18）水平偏低。本研究旨在探讨早期类风湿关节炎患者接受治疗前后，以及类风湿关节炎小鼠模型诱导关节炎后sCD18的水平变化。 方法 本研究采用时间分辨免疫荧光分析法（time-resolved immunofluorometric assay）检测四类样本中的sCD18水平：1）接受达标治疗的初治早期类风湿关节炎患者血浆（OPERA队列）；2）慢性类风湿关节炎患者血浆；3）关节炎诱导后的SKG小鼠与CIA小鼠血清；4）6名类风湿关节炎患者的滑膜液单个核细胞（synovial fluid mononuclear cells, SFMCs）与外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）经肿瘤坏死因子α（tumor necrosis factor α, TNFα）或阿达木单抗（adalimumab）培养后的细胞上清液。 结果 与早期类风湿关节炎患者相比，慢性类风湿关节炎患者血浆sCD18水平更低；与健康对照者相比，早期类风湿关节炎患者血浆sCD18水平亦显著降低。经过12个月的达标治疗后，早期类风湿关节炎患者的血浆sCD18水平与健康对照者趋于一致。在极早期发病且早期达到ACR（American College of Rheumatology）应答的患者中，血浆sCD18水平的这种恢复正常现象更为突出。血浆sCD18水平与影像学疾病进展呈显著相关。相应地，关节炎诱导6周后，SKG小鼠血清sCD18水平较健康同窝小鼠显著降低。SKG与CIA小鼠的血清sCD18水平在关节炎诱导后均呈现双相变化模式：先升高至基线水平以上，随后逐渐下降。TNFα可促进类风湿关节炎患者滑膜液单个核细胞与外周血单个核细胞的CD18脱落，而阿达木单抗则可抑制这一过程。 结论 类风湿关节炎患者、自身免疫性关节炎小鼠模型，以及经TNFα与阿达木单抗处理的细胞培养体系中，血浆sCD18水平均发生显著改变。血浆sCD18水平降低可反映从早期向慢性疾病转变过程中的自身免疫活化状态，而治疗后血浆sCD18水平恢复正常则可反映疾病处于缓解期的自身免疫状态。