title: A novel polymorphism of the human CD40 receptor with enhanced function.
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.
authors.affiliation: Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Peters
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: 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
chemical_list: 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