HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype.
The HLA region, and particularly the DR15 haplotype (containing the two DRB* genes DRB1*1501 and DRB5*0101 and the tightly linked DQ alleles DQA*0102 and DQB1*0602, which together form the DQw6 molecule) in Caucasians, shows the strongest genetic association with multiple sclerosis (MS). In the DR15 haplotype, two beta-chains HLA-DRB1*1501 and -DRB5*0101 are co-expressed resulting in two different surface HLA-DR alphabeta heterodimers, DR2b and DR2a. Most previous studies focused on DRB1*1501, however, both DR2a and DR2b may contribute to MS pathogenesis via antigen presentation to myelin-specific T lymphocytes. We therefore analyzed the expression of the two DR15 genes in various antigen presenting cells (APCs), central nervous system and thymic tissues. Transcript levels were higher for DRB5*0101 in all cell types and tissues. Both HLA-DR heterodimers were expressed at significant levels on the cell surface, where they showed a differential expression pattern in different APCs. They were similarly regulated after stimulation with interferon-gamma and interleukin-4. Finally, immunohistochemistry experiments indicated that both molecules were expressed in thymic tissue. Our results encourage future research to investigate the potential functional relevance of both genes for the pathogenesis of MS.
Prat
Elisabetta
E
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5B16, 10 Center DR, Bethesda, MD 20892-1400, USA.
Tomaru
Utano
U
Sabater
Lidia
L
Park
Deric M
DM
Granger
Rebekah
R
Kruse
Niels
N
Ohayon
Joan M
JM
Bettinotti
Maria P
MP
Martin
Roland
R
D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D006239:Haplotypes; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009103:Multiple Sclerosis / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014162:Transfection / Q000379:methods
D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D059847:HLA-DRB5 Chains; D012333:RNA, Messenger; D016899:Interferon-beta