Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis
Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis
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DOI：
10.1093/hmg/ddi247
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发表时间：
2005-08-15
影响因子：
3.5
通讯作者：
Tokunaga, K
中科院分区：
文献类型：
--
作者：
Kuroki, K;Tsuchiya, N;Tokunaga, K
白细胞免疫球蛋白样受体亚家族B成员I（LILRB 1/LIR 1/ILT 2）是广泛表达于白细胞上的抑制性受体，并且识别HLA-I类和人巨细胞病毒UL 18。LILRB 1编码于19q13.4上的白细胞受体复合物内，先前被认为是系统性红斑狼疮（SLE）的易感区域。在这项研究中，我们筛选了LILRB 1的多态性，并研究了它们与SLE和类风湿性关节炎（RA）的关联。在LILRB 1的5'端，鉴定了三种单倍型，其中在配体结合结构域内含有四个非同义取代，在启动子区域内含有两个单核苷酸多态性，并将其命名为PE 01 -03。在3'部分，鉴定了两种单倍型（CY 01，02），其含有胞质区域的非同义取代。CY 01和02未与PE 01 -03共分离。未观察到与SLE或RA易感性的显著相关性;然而，在不携带RA相关HLA-DRB 1共享表位（SE）的受试者中，LILRB1.PE01/01双倍型与RA显著相关（比值比2.05，P = 0.019和Pc = 0.038）。PE 01 -03单倍型产物在晶体结构、热稳定性和与HLA I类配体的结合亲和力方面没有观察到总体差异;然而，PE 01单倍型携带者的淋巴细胞和单核细胞中LILRB 1的表面表达显著降低。这些发现表明LILRB 1是高度多态性的，并且与HLA-DRB 1 SE阴性受试者中对RA的易感性相关，可能是由于白细胞中抑制信号不足。此外，这些观察结果表明LILR家族成员的多态性可能在很大程度上参与了人类免疫反应的多样性。
Leukocyte immunoglobulin-like receptor subfamily B member I (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.