Yoshida Kohsuke, Komai Koichiro, Shiozawa Kazuko, Mashida Aya, Horiuchi Takahiko, Tanaka Yuki, Nose Masato, Hashiramoto Akira, Shiozawa Shunichi
Department of Medicine, Kobe University Graduate School of Health Sciences, and Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan.
Arthritis Rheum. 2011 Oct;63(10):3058-66. doi: 10.1002/art.30501.
To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE).
Japanese patients with SLE (n=716), those with rheumatoid arthritis (RA) (n=327), and healthy control subjects (n=351) were genotyped for the Val129 Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene. Recombinant human MICA-GST fusion proteins were tested on the NK cell line NK92MI for the expression of NK group 2, member D (NKG2-D), NK cell-mediated cytotoxicity, and interferon-γ (IFNγ) production.
The MICA 129Met allele, TMA9 allele, and 129Met/Met genotype were positively associated with SLE (corrected P [Pcorr]=0.01 and odds ratio [OR] 1.3, Pcorr=0.003 and OR 1.6, and Pcorr=0.02 and OR 1.8, respectively), while the MICA 129Val allele was negatively associated with SLE (Pcorr=0.01, OR 0.8). The MICA 129Met;A9 haplotype was also associated with SLE (Pcorr=0.0006, OR 1.8), and there was an additive genetic effect between the MICA 129Met;A9 haplotype and HLA-DRB1*15:01. When NK92MI cells were incubated in vitro with recombinant human disease-associated 129Met;A9 (the combination of polymorphisms at 129Met and TMA9), expression of NKG2-D on NK92MI cells and cytotoxicity of the NK cells were inhibited, but production of IFNγ from NK92MI cells was enhanced.
The MICA polymorphism is genetically associated with SLE, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function.
研究主要组织相容性复合体I类多肽相关序列A（MICA）在系统性红斑狼疮（SLE）患者中的遗传贡献，MICA在自然杀伤（NK）细胞功能中起重要作用。
对日本SLE患者（n = 716）、类风湿关节炎（RA）患者（n = 327）和健康对照者（n = 351）进行MICA基因Val129 Met多态性（rs1051792）以及跨膜（TM）丙氨酸编码GCT重复序列（称为A4、A5、A5.1、A6和A9）的基因分型。用重组人MICA - GST融合蛋白在NK细胞系NK92MI上检测NK组2成员D（NKG2 - D）的表达、NK细胞介导的细胞毒性以及干扰素-γ（IFNγ）的产生。
MICA 129Met等位基因、TMA9等位基因和129Met/Met基因型与SLE呈正相关（校正P值[Pcorr]=0.01，优势比[OR] 1.3；Pcorr = 0.003，OR 1.6；Pcorr = 0.02，OR 1.8），而MICA 129Val等位基因与SLE呈负相关（Pcorr = 0.01，OR 0.8）。MICA 129Met;A9单倍型也与SLE相关（Pcorr = 0.0006，OR 1.8），并且MICA 129Met;A9单倍型与HLA - DRB1*15:01之间存在累加遗传效应。当NK92MI细胞在体外与重组人疾病相关的129Met;A9（129Met和TMA9处多态性的组合）一起孵育时，NK92MI细胞上NKG2 - D的表达和NK细胞的细胞毒性受到抑制，但NK92MI细胞中IFNγ的产生增强。
MICA多态性与SLE存在遗传关联，并且MICA似乎通过调节NK细胞功能对SLE的发病机制起作用。
