Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin 1beta genes are associated with Wegener's granulomatosis.
OBJECTIVE
The genetic factors predisposing to Wegener's granulomatosis (WG) are largely unknown. T cells are clearly involved in the disease, as are the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta). The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) suppresses antigen-specific immune responses by opposing the CD28 pathway, and is crucial for a balanced T cell activation. Genetic variations in the TNF-alpha, IL-1beta, and CTLA-4 genes could thus be important in WG.


METHODS
Polymorphisms in the genes coding for TNF-alpha, IL-1beta, and CTLA-4 were analyzed in 32 Swedish Caucasian patients and 109 ethnically matched controls. Results. A strong association of Ctla-4 (AT)n microsatellite to WG contrasts to the negative finding of associations between TNF-alpha NcoI, IL-1beta TaqI restriction fragment length polymorphism, and WG. The prevalence of the shortest Ctla-4 allele was decreased in patients with WG compared with healthy individuals (p < 0.0001, pc < 0.0016).


CONCLUSIONS
This is the first report of a T cell related gene in association with WG. The Ctla-4 itself, or a gene close to Ctla-4, may thus contribute to the pathogenesis of WG by allowing an increased T cell activation by antigen.
Huang
D
D
Immunological Research Unit, Center for Molecular Medicine, Karolinska Institute, Solna, Stockholm, Sweden.
Giscombe
R
R
Zhou
Y
Y
Lefvert
A K
AK
D000069594:Abatacept; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept