Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis.
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 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.


CONCLUSIONS
Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA-Bw4, was found to protect against MS in an HLA-DRB1 independent manner.
Lorentzen
Aslaug R
AR
Department of Neurology, Faculty Division Ullevål, Oslo University Hospital, University of Oslo, Oslo, Norway. a.r.lorentzen@medisin.uio.no
Karlsen
Tom H
TH
Olsson
Marita
M
Smestad
Cathrine
C
Mero
Inger-Lise
IL
Woldseth
Bente
B
Sun
Ji-Yao
JY
Senitzer
David
D
Celius
Elisabeth G
EG
Thorsby
Erik
E
Spurkland
Anne
A
Lie
Benedicte A
BA
Harbo
Hanne F
HF
D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006580:Genetic Carrier Screening; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006684:HLA-DR Antigens / Q000502:physiology; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D011485:Protein Binding / Q000276:immunology; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D055815:Young Adult
D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D054340:Receptors, KIR