A novel polymorphism of the human CD40 receptor with enhanced function.
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.
Peters
Anna L
AL
Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242, USA.
Plenge
Robert M
RM
Graham
Robert R
RR
Altshuler
David M
DM
Moser
Kathy L
KL
Gaffney
Patrick M
PM
Bishop
Gail A
GA
D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D005787:Gene Frequency; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019013:CD40 Antigens; C508600:IL6 protein, human; D007075:Immunoglobulin M; D015850:Interleukin-6; D011994:Recombinant Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases