Veit Tiago Degani, Chies José Artur Bogo, Switala Magdalena, Wagner Bettina, Horn Peter A, Busatto Mauricio, Brenol Claiton Viegas, Tavares Brenol João Carlos, Machado Xavier Ricardo, Rebmann Vera
Laboratório de Imunogenética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany.
PLoS One. 2015 Apr 8;10(4):e0123838. doi: 10.1371/journal.pone.0123838. eCollection 2015.
HLA-G is a regulatory molecule involved in immunologic tolerance. Growing evidence indicates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. This study aimed at a systematic evaluation of soluble HLA-G (sHLA-G) in plasma of rheumatoid arthritis (RA) patients with long-lasting chronic inflammation. RA patients (n=68) and healthy controls (n=26) had their plasmatic sHLA-G measured by ELISA whereas the binding capability of sHLA-G to its cognate LILRB1 receptor was measured by a Luminex-based assay. All subjects were PCR-genotyped for HLA-G 14 bp polymorphism (rs66554220). Significantly higher sHLA-G levels were observed in patients (p<0.001), however no significant differences were observed in LILRB1 binding capacity between RA patients and controls. Remarkably, the proportion of patients presenting specific binding of sHLA-G to LILRB1 was significantly decreased as compared to controls (56% vs. 81%, p=0.027). Patients without rheumatoid factor (RF-) were significantly overrepresented in the group of patients positive for LILRB1 binding as compared to patients without LILRB1 binding (31% vs 10%, p=0.033). Furthermore, methotrexate treated patients (n=58) revealed significantly lower LILRB1 binding to sHLA-G molecules than non-treated patients (medians: 12.2 vs. 67.7 units/ml, p=0.031). Unlike in controls, no significant differences in sHLA-G levels were observed among patients grouped by 14 pb genotype. Thus, in a substantial number of late RA patients, the circulating sHLA-G molecules are impaired regarding LILRB1 recognition, meaning that although increased levels are observed; these molecules are not qualified to exert their protective functions against inflammation. Our findings offer new insights into the immunopathology of RA patients with long-lasting anti-RA-treatment and highlight the importance to also measure the binding capability of sHLA-G to LILRB1.
HLA - G是一种参与免疫耐受的调节分子。越来越多的证据表明，HLA - G在炎症过程和自身免疫性疾病的调节中发挥作用。本研究旨在系统评估患有长期慢性炎症的类风湿关节炎（RA）患者血浆中的可溶性HLA - G（sHLA - G）。通过酶联免疫吸附测定（ELISA）测量RA患者（n = 68）和健康对照者（n = 26）血浆中的sHLA - G，而通过基于Luminex的检测方法测量sHLA - G与其同源LILRB1受体的结合能力。所有受试者均进行HLA - G 14 bp多态性（rs66554220）的聚合酶链反应（PCR）基因分型。在患者中观察到sHLA - G水平显著更高（p < 0.001），然而，RA患者与对照者之间在LILRB1结合能力方面未观察到显著差异。值得注意的是，与对照者相比，sHLA - G与LILRB1呈现特异性结合的患者比例显著降低（56%对81%，p = 0.027）。与无LILRB1结合的患者相比，LILRB1结合阳性患者组中无类风湿因子（RF -）的患者明显过多（31%对10%，p = 0.033）。此外，接受甲氨蝶呤治疗的患者（n = 58）显示出LILRB1与sHLA - G分子的结合显著低于未治疗患者（中位数：12.2对vs. 67.7单位/毫升，p = 0.031）。与对照者不同，按14 pb基因型分组的患者之间在sHLA - G水平上未观察到显著差异。因此，在大量晚期RA患者中，循环中的sHLA - G分子在LILRB1识别方面受损，这意味着尽管观察到水平升高；但这些分子无资格发挥其对炎症的保护作用。我们的研究结果为长期接受抗RA治疗的RA患者的免疫病理学提供了新的见解，并强调了测量sHLA - G与LILRB1结合能力的重要性。
