Lorentzen Aslaug R, Karlsen Tom H, Olsson Marita, Smestad Cathrine, Mero Inger-Lise, Woldseth Bente, Sun Ji-Yao, Senitzer David, Celius Elisabeth G, Thorsby Erik, Spurkland Anne, Lie Benedicte A, Harbo Hanne F
Department of Neurology, Faculty Division Ullevål, Oslo University Hospital, University of Oslo, Oslo, Norway.
Ann Neurol. 2009 Jun;65(6):658-66. doi: 10.1002/ana.21695.
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. A human leukocyte antigen (HLA) class II association is well established (DRB11501-DQB10602), but more recently HLA class II-independent associations with HLA class I variants have also been reported. The HLA class I (HLA-A, -B, -C) molecules serve as ligands for both T-cell receptors and killer immunoglobulin-like receptors (KIRs). We investigated the HLA class I alleles defined by their KIR binding motifs and the KIR genes to evaluate whether these genes could influence MS susceptibility or severity, alone or in combination.
We typed Norwegian MS patients (n = 631) and controls (n = 555) for HLA-A, -B, -C and -DRB1 alleles as well as the presence or absence of genes encoding inhibitory (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, KIR3DL2, KIR3DL3) and activating (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DL4, KIR2DS4, KIR2DS5, KIR3DS1) KIRs.
The frequency of the HLA-Bw4 specificity, which is the ligand for the inhibitory KIR3DL1, was significantly reduced in MS patients as compared with controls (41.4% vs 55.1%, p(uncorrected (uc)) = 4.6 x 10(-6)). Also after stratifying for known HLA class II associations, the HLA-Bw4 association was seen (p(uc) = 0.002). No significant differences in gene carrier frequencies of inhibitory and activating KIRs were observed. However, our data indicate that MS patients who carry the activating KIR2DS2 and the inhibitory KIR2DL2 genes have more severe disease than patients not carrying these genes.
Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA-Bw4, was found to protect against MS in an HLA-DRB1 independent manner.
多发性硬化症（MS）是一种影响中枢神经系统的慢性炎症性疾病。人类白细胞抗原（HLA）II类分子的关联已得到充分证实（DRB11501-DQB10602），但最近也有报道称HLA II类分子与HLA I类变体存在非依赖性关联。HLA I类（HLA-A、-B、-C）分子作为T细胞受体和杀伤细胞免疫球蛋白样受体（KIR）的配体。我们研究了由其KIR结合基序定义的HLA I类等位基因和KIR基因，以评估这些基因单独或联合起来是否会影响MS的易感性或严重程度。
我们对挪威的MS患者（n = 631）和对照组（n = 555）进行了HLA-A、-B、-C和-DRB1等位基因分型，以及编码抑制性（KIR2DL1、KIR2DL2、KIR2DL3、KIR2DL5、KIR3DL1、KIR3DL2、KIR3DL3）和激活性（KIR2DS1、KIR2DS2、KIR2DS3、KIR2DL4、KIR2DS4、KIR2DS5、KIR3DS1）KIR的基因的有无检测。
与对照组相比，MS患者中作为抑制性KIR3DL1配体的HLA-Bw4特异性频率显著降低（41.4%对55.1%，p（未校正（uc））= 4.6×10⁻⁶）。在对已知的HLA II类关联进行分层后，仍可见HLA-Bw4的关联（p（uc）= 0.002）。未观察到抑制性和激活性KIR基因携带者频率的显著差异。然而，我们的数据表明，携带激活性KIR2DS2和抑制性KIR2DL2基因的MS患者比未携带这些基因的患者病情更严重。
发现抑制性KIR3DL1受体的配体HLA-Bw4的携带以HLA-DRB1非依赖性方式预防MS。
