Association of Killer Cell Immunoglobulin- Like Receptor Genes in Iranian Patients with Rheumatoid Arthritis

Objectives
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by persistent synovitis, ultimately leading to cartilage and bone degeneration. Natural Killer cells and CD28 null T-cells are suspected as role players in RA pathogenesis. These cells are similar in feature and function, as they both exert their cytotoxic effect via Killer Cell Immunoglobulin- Like Receptors (KIR) on their surface. KIR genes have either an inhibitory or activating effect depending on their intracytoplasmic structure. Herein we genotyped 16 KIR genes, 3 pseudo genes and 6 HLA class І genes as their corresponding ligands in RA patients and control subjects.
Methods
In this case-control study, KIR and HLA genes were genotyped in 400 RA patients and 372 matched healthy controls using sequence-specific primers (SSP-PCR). Differences in the frequency of genes and haplotypes were determined by χ² test.
Results
KIR2DL2, 2DL5a, 2DL5b and activating KIR: KIR2DS5 and 3DS1 were all protective against RA. KIR2DL5 removal from a full Inhibitory KIR haplotype converted the mild protection (OR = 0.56) to a powerful predisposition to RA (OR = 16.47). Inhibitory haplotype No. 7 comprising KIR2DL5 in the absence of KIR2DL1 and KIR2DL3 confers a 14-fold protective effect against RA.
Conclusion
Individuals carrying the inhibitory KIR haplotype No. 6 have a high potential risk for developing RA.

研究目的：类风湿关节炎（Rheumatoid arthritis, RA）是一类以持续性滑膜炎为核心特征的慢性炎症性疾病，最终可引发软骨与骨退变。自然杀伤细胞（Natural Killer cells）与CD28阴性T细胞（CD28 null T-cells）被推测参与了RA的发病进程。二者在特征与功能上高度相似，均可通过表面的杀伤细胞免疫球蛋白样受体（Killer Cell Immunoglobulin-Like Receptors, KIR）介导细胞毒效应。KIR基因依据其胞质结构可分为抑制性与激活性两类。本研究对400例RA患者与372例匹配健康对照者的16个KIR基因、3个假基因及6个作为其对应配体的HLA I类基因（HLA class І genes）开展了基因分型检测。
研究方法：本病例对照研究采用序列特异性引物聚合酶链反应（sequence-specific primers, SSP-PCR）技术，对400例RA患者及372例匹配健康对照者的KIR与HLA基因进行分型。通过卡方（χ²）检验分析各组间基因及单倍型的频率差异。
研究结果：KIR2DL2、2DL5a、2DL5b及激活性KIR家族成员KIR2DS5与3DS1均对RA具有保护作用。若将KIR2DL5从完整抑制性KIR单倍型中剔除，该单倍型对RA的轻度保护作用（比值比OR=0.56）会转变为极强的RA易感性（OR=16.47）。不含KIR2DL1与KIR2DL3、但携带KIR2DL5的7号抑制性单倍型可使RA发病风险降低14倍。
结论：携带6号抑制性KIR单倍型的个体罹患RA的风险极高。