A novel polymorphism of the human CD40 receptor with enhanced function

Blood. 2008 Sep 1;112(5):1863-71. doi: 10.1182/blood-2008-02-138925. Epub 2008 Jun 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD40 Antigens / chemistry
  • CD40 Antigens / genetics*
  • CD40 Antigens / physiology*
  • Cell Line
  • Gene Frequency
  • Humans
  • Immunoglobulin M / biosynthesis
  • Interleukin-6 / biosynthesis
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Toll-Like Receptor 9 / metabolism
  • Transfection
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • CD40 Antigens
  • IL6 protein, human
  • Immunoglobulin M
  • Interleukin-6
  • Recombinant Proteins
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases