The role of the CD58 locus in multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x 10(-6), OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747(G) allele. This protective rs2300747(G) allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x 10(-10)) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4(+)CD25(high) regulatory T cells that are defective in subjects with MS.
De Jager
Philip L
PL
Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. pdejager@rics.bwh.harvard.edu
Baecher-Allan
Clare
C
Maier
Lisa M
LM
Arthur
Ariel T
AT
Ottoboni
Linda
L
Barcellos
Lisa
L
McCauley
Jacob L
JL
Sawcer
Stephen
S
Goris
An
A
Saarela
Janna
J
Yelensky
Roman
R
Price
Alkes
A
Leppa
Virpi
V
Patterson
Nick
N
de Bakker
Paul I W
PI
Tran
Dong
D
Aubin
Cristin
C
Pobywajlo
Susan
S
Rossin
Elizabeth
E
Hu
Xinli
X
Ashley
Charles W
CW
Choy
Edwin
E
Rioux
John D
JD
Pericak-Vance
Margaret A
MA
Ivinson
Adrian
A
Booth
David R
DR
Stewart
Graeme J
GJ
Palotie
Aarno
A
Peltonen
Leena
L
Dubois
Bénédicte
B
Haines
Jonathan L
JL
Weiner
Howard L
HL
Compston
Alastair
A
Hauser
Stephen L
SL
Daly
Mark J
MJ
Reich
David
D
Oksenberg
Jorge R
JR
Hafler
David A
DA
D000483:Alleles; D018801:CD2 Antigens; D018968:CD58 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D051858:Forkhead Transcription Factors; D006801:Humans; D007963:Leukocytes, Mononuclear; D009103:Multiple Sclerosis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D012074:Remission Induction; D017421:Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation
D018801:CD2 Antigens; D018968:CD58 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger