Expression of activating and inhibitory leukocyte immunoglobulin-like receptors in rheumatoid synovium: correlations to disease activity

Rheumatoid arthritis (RA) is a heterogeneous chronic inflammatory joint disease characterized by excessive activation of inflammatory cells of which the underlying mechanisms are not fully elucidated. Perturbed expression and function of immune regulatory molecules called leukocyte immunoglobulin-like receptors (LILRs) may contribute to uncontrolled inflammation. LILRs primarily expressed on the surface of leukocytes are emerging as critical regulators of the threshold and amplitude of leukocyte activation. Inhibitory LILRs (LILRBs) contain cytoplasmic tails with immunoreceptor tyrosine-based inhibitory motifs that provide negative signals. Activating LILRs (LILRAs) have short cytoplasmic domains lacking signaling motifs but transmit activating signals by linking to immunoreceptor tyrosine-based activation motifs of the FcR gamma-chain. Here we show that activating LILRA2, A5 and inhibitory LILRB2, B3 were abundantly expressed in synovial tissue of > 75% RA patients. Expression of LILRA2, A5, and B3 significantly correlated to disease activity. In contrast, LILRA1 and B4 were expressed in a subset of patients and no B1 or B5 expression was detected. LILRA2 and A5 were mainly expressed by synovial macrophages and endothelial cells but not lymphocytes, whereas B2 and B3 were expressed by macrophages and lymphocytes. Increase in the number of macrophages expressing activating LILRs and macrophages and lymphocytes expressing inhibitory LILRs suggest a crosstalk between these cells that may regulate the levels of cellular activation and disease severity, while differences in expression pattern may contribute to disease heterogeneity.