van Heemst Jurgen, van der Woude Diane, Huizinga Tom W, Toes René E
Department of Rheumatology, Leiden University Medical Center , Leiden , The Netherlands.
Ann Med. 2014 Aug;46(5):304-10. doi: 10.3109/07853890.2014.907097. Epub 2014 May 9.
Rheumatoid arthritis (RA) is a destructive autoimmune disease that mainly affects synovial joints. RA patients can be subdivided in two distinct disease subsets based on the presence of anti-citrullinated protein antibodies (ACPA). These two disease phenotypes are associated with different environmental and genetic risk factors and clinical parameters. The HLA class II locus is the most important risk factor for ACPA-positive RA (ACPA+ RA). ACPA can be found up to 10 years before diagnosis and can be used as a predictive biomarker. During progression from breaking tolerance to a citrullinated protein to ACPA+ RA, the ACPA response matures. Recent work implicates the HLA class II locus as a risk factor in the progression from ACPA positivity to ACPA+ RA. We now propose that this locus directly influences the maturation of the ACPA response, most likely via antigen-specific T-cells providing help to ACPA-producing B-cells allowing for maturation of the citrullinated protein-specific autoantibody response. We present and discuss several models and underlying data, including antibody cross-reactivity, molecular mimicry, and neo-antigen formation, that could explain the HLA-RA connection.
类风湿性关节炎（RA）是一种主要影响滑膜关节的破坏性自身免疫性疾病。根据抗瓜氨酸化蛋白抗体（ACPA）的存在情况，RA患者可分为两个不同的疾病亚组。这两种疾病表型与不同的环境和遗传风险因素及临床参数相关。HLA II类基因座是ACPA阳性RA（ACPA+ RA）最重要的风险因素。ACPA在诊断前10年就可检测到，可作为一种预测性生物标志物。在从对瓜氨酸化蛋白的耐受性破坏发展到ACPA+ RA的过程中，ACPA反应逐渐成熟。最近的研究表明，HLA II类基因座是从ACPA阳性发展到ACPA+ RA的一个风险因素。我们现在提出，该基因座直接影响ACPA反应的成熟，最有可能是通过抗原特异性T细胞为产生ACPA的B细胞提供帮助，从而使瓜氨酸化蛋白特异性自身抗体反应成熟。我们展示并讨论了几种模型及相关基础数据，包括抗体交叉反应性、分子模拟和新抗原形成，这些都可以解释HLA与RA之间的联系。
