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 Blood, 1 September 2008, Vol. 112, No. 5, pp. 1863-1871.
Prepublished online as a Blood First Edition Paper on June 30, 2008; DOI 10.1182/blood-2008-02-138925.

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IMMUNOBIOLOGY

A novel polymorphism of the human CD40 receptor with enhanced function

Anna L. Peters1, Robert M. Plenge2, Robert R. Graham2, David M. Altshuler2, Kathy L. Moser3, Patrick M. Gaffney3, and Gail A. Bishop1,4,5

1 Medical Scientist Training Program and Immunology Graduate Program, University of Iowa, Iowa City; 2 Broad Institute/Whitehead Institute for Biomedical Research, Boston, MA; 3 Department of Medicine, University of Minnesota School of Medicine, Minneapolis; 4 Departments of Microbiology and Internal Medicine, University of Iowa, Iowa City; and 5 VA Medical Center, Iowa City, IA

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 single nucleotide polymorphism (SNP) in the cytoplasmic domain of CD40 at position 227 (P227A) was identified, which resides on a conserved ancestral haplotype highly enriched in persons 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 interleukin (IL)–6 and TNF-{alpha}, and increased Ig production, compared with wild-type hCD40. Cooperation between hCD40-P227A signaling and B-cell receptor (BCR)– or Toll-like receptor 9 (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.


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