期刊
BLOOD
卷 112, 期 5, 页码 1863-1871出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-02-138925
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资金
- National Institutes of Health (NIH
- Bethesda, MD) [AI28847, AI49993, CA099997]
- Department of Veterans' Affairs
- NIH [AR052125, A1063274, T32 AI007533]
- Lupus Foundation of Minnesota (Bloomington, MN)
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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