title: 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.
authors: Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors: Kimiko
authors: K
authors: Kuroki
authors: Naoyuki
authors: N
authors: Tsuchiya
authors: Mitsunori
authors: M
authors: Shiroishi
authors: Linda
authors: L
authors: Rasubala
authors: Yumi
authors: Y
authors: Yamashita
authors: Kunio
authors: K
authors: Matsuta
authors: Toru
authors: T
authors: Fukazawa
authors: Makio
authors: M
authors: Kusaoi
authors: Yoshinori
authors: Y
authors: Murakami
authors: Masafumi
authors: M
authors: Takiguchi
authors: Takeo
authors: T
authors: Juji
authors: Hiroshi
authors: H
authors: Hashimoto
authors: Daisuke
authors: D
authors: Kohda
authors: Katsumi
authors: K
authors: Maenaka
authors: Katsushi
authors: K
authors: Tokunaga
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D000939:Epitopes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011110:Polymorphism, Genetic; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000939:Epitopes; D006023:Glycoproteins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic