Premium
Killer immunoglobulin‐like receptor ligand HLA‐Bw4 protects against multiple sclerosis
Author(s) -
Lorentzen Åslaug R.,
Karlsen Tom H.,
Olsson Marita,
Smestad Cathrine,
Mero IngerLise,
Woldseth Bente,
Sun JiYao,
Senitzer David,
Celius Elisabeth G.,
Thorsby Erik,
Spurkland Anne,
Lie Benedicte A.,
Harbo Hanne F.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21695
Subject(s) - human leukocyte antigen , immunology , receptor , haplotype , hla b antigens , biology , allele , multiple sclerosis , gene , antigen , genetics
Objective Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. A human leukocyte antigen (HLA) class II association is well established (DRB1*1501‐DQB1*0602), 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. Methods 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. Results 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 × 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. Interpretation Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA‐Bw4, was found to protect against MS in an HLA‐DRB1 independent manner. Ann Neurol 2009;65:658–666