Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis

Abstract

Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2) is an inhibitory receptor broadly expressed on leukocytes and recognizes HLA-class I and human cytomegalovirus UL18. LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE). In this study, we screened for polymorphisms of LILRB1 and examined their association with SLE and rheumatoid arthritis (RA). In the 5' portion of LILRB1, three haplotypes containing four non-synonymous substitutions within the ligand-binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03. In the 3' portion, two haplotypes (CY01, 02) containing a non-synonymous substitution of the cytoplasmic region were identified. CY01 and 02 did not co-segregate with PE01-03. Significant association with susceptibility to SLE or RA was not observed; however, among the subjects not carrying RA-associated HLA-DRB1 shared epitope (SE), LILRB1.PE01/01 diplotype was significantly associated with RA (odds ratio 2.05, P = 0.019 and Pc = 0.038). Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype. These findings demonstrated that LILRB1 is highly polymorphic and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes. In addition, these observations suggested that the polymorphisms of LILR family members may be substantially involved in the diversity of human immune responses.

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

“…Therefore, it is possible that the cis interaction influences trans NK-cell ligand recognition and binding in individuals expressing higher or lower levels of LIR-1 and with various polymorphisms [8]. Although the effect of D1D2 polymorphisms on HLA-class I binding in trans was reported to be minimal in a previous study [38], polymorphisms could alter the cis interaction. Gaining a better understanding of the mechanisms involved in regulating LIR-1 signaling and function will provide further insight into the susceptibility of individuals to infections such as HCMV.…”

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

“…Previous studies have shown that this gene is highly polymorphic (24) and can be alternatively spliced (25). However, a recent genome-wide association study did not reveal a significant association between LILRB1 and dengue shock syndrome (26); this is not surprising because, although LILRB1 activation is critical for initial replication with FcγR-mediated entry, multiple other host and viral factors contribute to eventual disease outcome.…”

Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production

“…ILTs are encoded by multiple genes with many polymorphisms (22,36,37), some of which may affect individual susceptibility to bacteria infection. Interestingly, several recent reports suggest that ILT polymorphisms are associated with some autoimmune diseases including rheumatoid arthritis (42)(43)(44). Thus, alteration of immune homeostasis by disruption of one member of an ILT pair may contribute to an increased risk for autoimmune disease.…”