Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs) and vascular endothelial cells, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell-APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.
Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Deborah S
DS
Cunninghame Graham
Robert R
RR
Graham
Harinder
H
Manku
Andrew K
AK
Wong
John C
JC
Whittaker
Patrick M
PM
Gaffney
Kathy L
KL
Moser
John D
JD
Rioux
David
D
Altshuler
Timothy W
TW
Behrens
Timothy J
TJ
Vyse
D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D053278:OX40 Ligand / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D006113:United Kingdom
D053278:OX40 Ligand; C089251:TNFSF4 protein, human