A new model for an etiology of rheumatoid arthritis
A new model for an etiology of rheumatoid arthritis
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DOI：
10.1002/art.21575
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Alfredsson, L
中科院分区：
文献类型：
--
作者：
Klareskog, L;Stolt, P;Alfredsson, L
客观的。研究吸烟和 HLA-DR 共享表位 (SE) 基因是否可能相互作用，从而触发对瓜氨酸修饰蛋白的免疫反应。方法。在一项涉及新发类风湿性关节炎 (RA) 患者的病例对照研究中，我们研究了主要环境危险因素（吸烟）、HLA-DR SE 中包含的主要易感基因以及已知的 RA 最特异性自身免疫（即瓜氨酸修饰蛋白的抗体）之间的相互作用。使用支气管肺泡灌洗液细胞中瓜氨酸蛋白的免疫染色来研究吸烟是否与肺部瓜氨酸化相关。结果。既往吸烟与 RA 患者抗瓜氨酸抗体的出现呈剂量依赖性相关。 SE 基因的存在仅是抗瓜氨酸阳性 RA 的危险因素，而不是抗瓜氨酸阴性 RA 的危险因素。吸烟和 HLA-DR SE 基因之间的主要基因-环境相互作用对于抗瓜氨酸阳性 RA 很明显，但对于抗瓜氨酸阴性 RA 则不然，吸烟史和 HLA-DR SE 基因双拷贝的存在相结合，与不携带 SE 基因的不吸烟者相比，患 RA 的风险增加了 21 倍。在吸烟者的支气管肺泡灌洗细胞中记录到瓜氨酸蛋白的阳性免疫染色，但在非吸烟者的支气管肺泡灌洗细胞中没有记录到。结论。我们发现了一个环境因素——吸烟，在 HLA-DR SE 基因的背景下，它可能会引发针对瓜氨酸蛋白的 RA 特异性免疫反应。因此，这些数据表明，病因涉及特定基因型、环境刺激和特定自身免疫的诱导，所有这些都仅限于 RA 的一个独特子集。
Objective. To investigate whether smoking and HLA-DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline-modified proteins.Methods. In a case-control study involving patients with recent-onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk factor (smoking), major susceptibility genes included in the SE of HLA-DR, and the presence of the most specific autoimmunity known for RA (i.e., antibodies to proteins modified by citrullination). Immunostaining for citrullinated proteins in cells from bronchoalveolar lavage fluid was used to investigate whether smoking is associated with citrullination in the lungs.Results. Previous smoking was dose-dependently associated with occurrence of anticitrulline antibodies in RA patients. The presence of SE genes was a risk factor only for anticitrulline-positive RA, and not for anticitrulline-negative RA. A major gene-environment interaction between smoking and HLA-DR SE genes was evident for anticitrulline-positive RA, but not for anticitrulline-negative RA, and the combination of smoking history and the presence of double copies of HLA-DR SE genes increased the risk for RA 21-fold compared with the risk among nonsmokers carrying no SE genes. Positive immunostaining for citrullinated proteins was recorded in bronchoalveolar lavage cells from smokers but not in those from nonsmokers.Conclusion. We identified an environmental factor, smoking, that in the context of HLA-DR SE genes may trigger RA-specific immune reactions, to citrullinated proteins. These data thus suggest an etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity, all restricted to a distinct subset of RA.