Kim Seunghyun, Easterling Ellis R, Price Lauren C, Smith Savannah L, Coligan John E, Park Jeoung-Eun, Brand David D, Rosloniec Edward F, Stuart John M, Kang Andrew H, Myers Linda K
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163.
Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852.
J Immunol. 2017 Oct 15;199(8):2692-2700. doi: 10.4049/jimmunol.1700271. Epub 2017 Sep 8.
Several observations implicate a critical role for T cell dysregulation as a central problem in rheumatoid arthritis. We investigated a mechanism for suppressing T cell activation by stimulating a natural inhibitory receptor called leukocyte-associated Ig-like receptor-1 (LAIR-1). The collagen-induced arthritis (CIA) model and DR-1 transgenic mice were used to study the importance of LAIR-1 in autoimmune arthritis. Splenocytes from wild-type or LAIR-1 mice were stimulated with soluble anti-CD3 Ab in the presence or absence of α1(II) and supernatants were collected for cytokine analysis. B6.DR1 mice were immunized with type II collagen/CFA to induce arthritis and were treated with either the stimulatory mAb to LAIR-1 or a hamster IgG control. Finally, B6.DR1/LAIR-1 and B6.DR1/LAIR-1 mice were challenged for CIA and mean severity scores were recorded thrice weekly. Using splenocytes or purified CD4 cells that were sufficient in LAIR-1, CD3-induced cytokine secretion was significantly suppressed in the presence of collagen, whereas LAIR-1-deficient splenocytes had no attenuation. Treatment with a stimulatory mAb to LAIR-1 also significantly attenuated CIA in the LAIR mice. When B6.DR1/LAIR-1 mice were immunized with type II collagen they developed more severe arthritis and had a greater percentage of affected limbs than the wild-type mice. These data demonstrate that collagen can suppress the T cell cytokine response through the action of LAIR-1. Treatment with stimulating LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1 mice develop more severe arthritis than wild-type controls. These data suggest that LAIR-1 may be a potential therapeutic target for suppressing rheumatoid arthritis.
多项观察结果表明，T细胞失调作为类风湿性关节炎的核心问题发挥着关键作用。我们研究了一种通过刺激名为白细胞相关免疫球蛋白样受体-1（LAIR-1）的天然抑制性受体来抑制T细胞活化的机制。采用胶原诱导性关节炎（CIA）模型和DR-1转基因小鼠来研究LAIR-1在自身免疫性关节炎中的重要性。在存在或不存在α1（II）的情况下，用可溶性抗CD3抗体刺激野生型或LAIR-1基因敲除小鼠的脾细胞，并收集上清液进行细胞因子分析。用II型胶原/CFA免疫B6.DR1小鼠以诱导关节炎，并用LAIR-1刺激单克隆抗体或仓鼠IgG对照进行治疗。最后，对B6.DR1/LAIR-1基因敲除和B6.DR1/LAIR-1野生型小鼠进行CIA攻击，并每周三次记录平均严重程度评分。使用LAIR-1充足的脾细胞或纯化的CD4细胞时，在存在胶原的情况下，CD3诱导的细胞因子分泌显著受到抑制，而LAIR-1缺陷的脾细胞则没有减弱。用LAIR-1刺激单克隆抗体治疗也显著减轻了LAIR基因敲除小鼠的CIA。当用II型胶原免疫B6.DR1/LAIR-1基因敲除小鼠时，它们比野生型小鼠发展出更严重的关节炎，且受影响肢体的百分比更高。这些数据表明，胶原可通过LAIR-1的作用抑制T细胞细胞因子反应。用刺激LAIR-1的抗体治疗可抑制CIA，而B6.DR1/LAIR-1基因敲除小鼠比野生型对照发展出更严重的关节炎。这些数据表明，LAIR-1可能是抑制类风湿性关节炎的潜在治疗靶点。
