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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Substitution
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Animals
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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CD40 Antigens / chemistry
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CD40 Antigens / genetics*
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CD40 Antigens / physiology*
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Cell Line
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Gene Frequency
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Humans
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Immunoglobulin M / biosynthesis
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Interleukin-6 / biosynthesis
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Phenotype
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Polymorphism, Single Nucleotide*
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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Toll-Like Receptor 9 / metabolism
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Transfection
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
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Tumor Necrosis Factor-alpha / metabolism
Substances
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CD40 Antigens
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IL6 protein, human
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Immunoglobulin M
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Interleukin-6
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Recombinant Proteins
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TLR9 protein, human
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Toll-Like Receptor 9
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Tumor Necrosis Factor-alpha
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JNK Mitogen-Activated Protein Kinases