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A novel polymorphism in human CD40 enhances B cell activation
Author(s) -
Peters Anna Louisa,
Gaffney Patrick M.,
Bishop Gail A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1066.2
Subject(s) - biology , cd40 , immune system , microbiology and biotechnology , population , genetics , cytotoxic t cell , in vitro , demography , sociology
CD40 is a member of the TNF‐receptor superfamily expressed on immune cells including B cells. A novel missense SNP in the cytoplasmic domain of human CD40 (hCD40P227A) was identified, and resides on a conserved ancestral haplotype highly enriched in indigenous populations from Mexico and South America. Functional studies indicated that signaling via hCD40P227A stably expressed in mouse B cell lines led to significantly increased phosphorylation of c‐Jun, increased secretion of the pro‐inflammatory cytokines IL‐6 and TNF‐α, and increased Ig production, compared to wild‐type hCD40 and to endogenous mouse CD40. Cooperation between hCD40P227A signaling and BCR‐ or TLR9‐mediated signaling was also enhanced, resulting in elevated synergistic production of IL‐6 and Ig. Binding and degradation of TRAFs by hCD40P227A was not detectably altered. Thus, hCD40P227A is a novel genetic variant with a gain‐of‐function immune phenotype and unique population stratification. Future directions include examination of effects of hCD40P227A in myeloid cells, and production of an hCD40P227A transgenic mouse to study in vivo effects. ALP is supported by an NIH training grant; PMG is supported by grants from the NIH and the Lupus Foundation of Minnesota; GAB is supported by grants from the NIH and a Career Award from the VA.