The Paradox of High Availability and Low Recognition of Soluble HLA-G by LILRB1 Receptor in Rheumatoid Arthritis Patients

Degani Veit, Tiago; Bogo Chies, José Artur; Switala, Magdalena; Wagner, Bettina; Horn, Peter A. LSF; Busatto, Mauricio; Viegas Brenol, Claiton; Tavares Brenol, João Carlos; Machado Xavier, Ricardo; Rebmann, Vera LSF

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.

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Degani Veit, T., Bogo Chies, J.A., Switala, M., Wagner, B., Horn, P.A., Busatto, M., Viegas Brenol, C., Tavares Brenol, J.C., Machado Xavier, R., Rebmann, V., 2016. The Paradox of High Availability and Low Recognition of Soluble HLA-G by LILRB1 Receptor in Rheumatoid Arthritis Patients. https://doi.org/10.1371/journal.pone.0123838
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