Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex
Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex
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DOI：
10.1002/art.23434
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发表时间：
2008-05-01
影响因子：
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通讯作者：
Lorentzen, Johnny C.
中科院分区：
文献类型：
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作者：
Guo, Jian Ping;Backdahl, Liselotte;Lorentzen, Johnny C.
Objective.抗原呈递凝集素样受体复合物（APLEC）最近被确定为关节炎易感性的遗传决定因素。我们进行了这项研究，以确定潜在的机制APLEC对关节炎的影响，以确定是否发生性别效应，并确定是否APLEC影响不同类型的关节炎和表型以外的易感性。将关节炎易感的DA大鼠与性别匹配的同类大鼠进行比较，其中APLEC等位基因被关节炎抗性PVG大鼠的等位基因取代。在尾根部注射六种不同的致关节炎剂：弗氏不完全佐剂、降植烷、角鲨烯、灭活分枝杆菌、酵母β-葡聚糖或大鼠II型胶原（CH）。关节炎进行视觉评分，体重测量，抗CII IgG和细胞因子信使RNA（mRNA）水平分别通过酶联免疫吸附试验和逆转录聚合酶链反应测定。在类风湿性关节炎（RA）的5个模型中，同源大鼠偏离DA大鼠关节炎易感性降低，延迟发作，严重程度降低，和/或体重减轻。注意到特异性相反的遗传效应，包括在降植烷诱导的关节炎中同源雄性动物中更严重的病程和胶原诱导的关节炎中临床体征降低，尽管自身抗体水平增加。有趣的是，抗CII IgG同种型分布在同种大鼠中是偏斜的，淋巴结白细胞介素-17 mRNA水平的显著降低表明自身反应性T辅助细胞的细胞因子分布也向致病性较低的方向偏斜。大鼠APLEC调节几种类型关节炎的自身免疫和多种表型。然而，描述遗传影响可能需要对性别或关节炎诱导模式进行分层。在评估炎症性和自身免疫性疾病（包括RA）中的APLEC时，应考虑这种发病机制的复杂性。
Objective. The antigen-presenting lectin-like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility.Methods. Arthritis-susceptible DA rats were compared with sex-matched congenic rats in which APLEC alleles were substituted with alleles from arthritis-resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast beta-glucan, or rat type II collagen (CH). Arthritis was visually scored, body weight was measured, and anti-CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively.Results. In 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane-induced arthritis and decreased clinical signs in collagen-induced arthritis despite increased autoantibody levels. Interestingly, the anti-CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin-17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction.Conclusion. Rat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.