Kuroki Kimiko, Tsuchiya Naoyuki, Shiroishi Mitsunori, Rasubala Linda, Yamashita Yumi, Matsuta Kunio, Fukazawa Toru, Kusaoi Makio, Murakami Yoshinori, Takiguchi Masafumi, Juji Takeo, Hashimoto Hiroshi, Kohda Daisuke, Maenaka Katsumi, Tokunaga Katsushi
Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Hum Mol Genet. 2005 Aug 15;14(16):2469-80. doi: 10.1093/hmg/ddi247. Epub 2005 Jul 13.
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.
白细胞免疫球蛋白样受体B亚家族成员1（LILRB1/LIR1/ILT2）是一种抑制性受体，广泛表达于白细胞上，可识别HLA-I类分子和人巨细胞病毒UL18。LILRB1由位于19q13.4的白细胞受体复合物编码，该区域先前被认为是系统性红斑狼疮（SLE）的易感区域。在本研究中，我们筛选了LILRB1的多态性，并检测了它们与SLE和类风湿关节炎（RA）的关联。在LILRB1的5'部分，鉴定出三种单倍型，其在配体结合域内含有四个非同义替换，在启动子区域内含有两个单核苷酸多态性，分别命名为PE01-03。在3'部分，鉴定出两种单倍型（CY01、02），其细胞质区域存在一个非同义替换。CY01和02与PE01-03不共分离。未观察到与SLE或RA易感性的显著关联；然而，在未携带与RA相关的HLA-DRB1共享表位（SE）的受试者中，LILRB1.PE01/01双倍型与RA显著相关（优势比2.05，P = 0.019，Pc = 0.038）。LILRB1.PE01-03单倍型产物在晶体结构、热稳定性以及与HLA-I类配体的结合亲和力方面未观察到明显差异；然而，PE01单倍型携带者的淋巴细胞和单核细胞中LILRB1的表面表达显著降低。这些发现表明，LILRB1具有高度多态性，在HLA-DRB1 SE阴性受试者中与RA易感性相关，可能是由于白细胞中抑制性信号不足所致。此外，这些观察结果提示，LILR家族成员的多态性可能在人类免疫反应的多样性中起重要作用。
