Submitted February 12, 2008
Accepted March 13, 2008
A novel polymorphism of the human CD40 receptor with enhanced function
Anna L. Peters, Robert M Plenge, Robert R Graham, David M Altshuler, Kathy L Moser, Patrick M Gaffney, and Gail A. Bishop*
MSTP and Immunology Graduate Program, University of Iowa, Iowa City, IA, United States
Broad Institute/Whitehead Institute for Biomedical Research, Boston, MA, United States
Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN, United States
Microbiology & Internal Medicine, University of Iowa, Iowa City, IA, United States
* Corresponding author; email: gail-bishop{at}uiowa.edu.
CD40 signaling is critical for innate and adaptive immunity against pathogens, and the cytoplasmic domain of CD40 is highly conserved both within and between species. A novel missense SNP in the cytoplasmic domain of CD40 at position 227 (P227A) was identified, which resides on a conserved ancestral haplotype highly enriched in individuals of Mexican and South American descent. Functional studies indicated that signaling via human (h)CD40-P227A stably expressed in several B cell lines led to increased phosphorylation of c-Jun, increased secretion of the pro-inflammatory cytokines IL-6 and TNF-
, and increased Ig production, compared to Wt hCD40. Cooperation between hCD40-P227A signaling and BCR- or TLR9-mediated signaling was also enhanced, resulting in elevated and synergistic production of IL-6 and Ig. We have thus identified a novel genetic variant of hCD40 with a gain-of-function immune phenotype.
