Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis
Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis
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EFNB1 和 EFNB2 在小鼠胶原诱导的关节炎和人类类风湿关节炎中的作用
DOI：
10.1002/art.39116
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发表时间：
2015-07-01
影响因子：
13.3
通讯作者：
Luo, Hongyu
中科院分区：
文献类型：
--
作者：
Hu, Yan;Wang, Xuehai;Luo, Hongyu
EFNB 1和EFNB 2是Eph受体酪氨酸激酶的配体。本研究旨在探讨小鼠T细胞上Efnb 1和Efnb 2的表达如何影响胶原诱导性关节炎（CIA）的发病机制，并评估这2种分子的T细胞表达与类风湿性关节炎（RA）患者疾病活动度指标之间的相关性。方法在Efnb 1和Efnb 2的T细胞特异性缺失（双基因敲除[dKO]）的小鼠中研究CIA。EFNB 1和EFNB 2的信使RNA（mRNA）在RA患者外周血T细胞的表达测定定量逆转录-聚合酶链反应。ResultsIn dKO小鼠，关节炎的临床评分减少相比，野生型（WT）对照小鼠。dKO小鼠的血清胶原特异性抗体滴度低于WT小鼠。在基于相等细胞数的分析中，与WT小鼠T细胞相比，dKO小鼠T细胞在体外产生胶原特异性抗体方面对B细胞提供的帮助差得多。来自dKO小鼠的T细胞在体内迁移到关节炎爪的能力和在体外对CXCL 12进行趋化的能力受到损害。Efnb 1和Efnb 2细胞内尾的缺失突变揭示了控制T细胞趋化性的关键区域。结论在CIA小鼠中，T细胞中的Efnb 1和Efnb 2在产生致病性抗体和T细胞向炎症足爪迁移中起重要作用。这些发现表明，T细胞中EFNB 1的表达可能是监测RA疾病活动和治疗反应的有用参数。
ObjectiveEFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of Efnb1 and Efnb2 on murine T cells influences the pathogenesis of collagen-induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA).MethodsCIA was studied in mice with T cell-specific deletion (double gene knockout [dKO]) of both Efnb1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription- polymerase chain reaction.ResultsIn dKO mice, clinical scores of arthritis were reduced compared to those in wild-type (WT) control mice. Serum collagen-specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen-specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of Efnb1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings.ConclusionEfnb1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.