Clinical Immunology and Allergy Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy.
Autoimmun Rev. 2013 Oct;12(12):1182-7. doi: 10.1016/j.autrev.2013.08.002. Epub 2013 Aug 16.
Autoantibody production is genetically controlled and anti-citrullinated protein/peptide antibodies (ACPA) are not an exception to the rule. ACPA are highly specific markers of rheumatoid arthritis (RA) and are also associated with a more severe disease course. The production of ACPA is almost invariably observed in HLA-shared epitope (SE) positive patients. The DRB1 alleles sharing SE are those conferring susceptibility to RA. SE alleles behave like immune response genes, controlling both the specificity and the amount of ACPA produced. These data suggest a role of SE in the presentation of citrullinated antigens. The ability of SE alleles to bind selectively to citrullinated sequences as compared to the native counterparts has been demonstrated in the case of peptides derived from several joint associated proteins (vimentin, fibrinogen and cartilage intermediate-layer protein). On the contrary, EBV-derived citrullinated peptides do not display a biologically relevant binding to SE alleles even if the immune response to VCPs is under the genetic control of these alleles (namely *0401 and *0404). Thus, the presentation of citrullinated epitopes does not represent the only molecular mechanisms underlying the HLA-DRB1 effect on ACPA production.
自身抗体的产生受基因控制，抗瓜氨酸化蛋白/肽抗体（ACPA）也不例外。ACPA 是类风湿关节炎（RA）的高度特异性标志物，并且与更严重的疾病过程相关。ACPA 的产生几乎总是在 HLA 共享表位（SE）阳性患者中观察到。共享 SE 的 DRB1 等位基因是导致 RA 易感性的等位基因。SE 等位基因的行为类似于免疫反应基因，控制 ACPA 的特异性和产生量。这些数据表明 SE 在瓜氨酸化抗原的呈递中起作用。SE 等位基因与天然序列相比，能够选择性地结合瓜氨酸化序列，这在源自几种关节相关蛋白（波形蛋白、纤维蛋白原和软骨中间层蛋白）的肽的情况下得到了证明。相反，EBV 衍生的瓜氨酸化肽即使对 VCPs 的免疫反应受这些等位基因（即0401 和0404）的遗传控制，也不会与 SE 等位基因显示出具有生物学意义的结合。因此，瓜氨酸化表位的呈递并不是 HLA-DRB1 对 ACPA 产生影响的唯一分子机制。
