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-, 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 syn-ergistic production of IL-6 and Ig. We have thus identified a novel genetic variant of hCD40 with a gain-of-function immune phenotype. (Blood. 2008;112: 1863-1871)

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

“…Fig. 2 shows that PG102 did not induce detectable phosphorylation of either JNK or IkBa in the human B cell line T5-1, which was previously reported as a robust model of CD40 signaling to human B cells (20,25). Fig.…”

“…The isotype-control Abs used were mIgG1 (Southern Biotech, Birmingham, AL) and hIgG4k (Sigma-Aldrich, St. Louis, MO) for G28.5 and PG102, respectively. The source of human CD154 was membranes of CD154-expressing Hi5 insect cells produced in the Bishop laboratory, as previously described (20). Hi5 cells grow at 25˚C; they die and form membrane fragments when cultured at 37˚C.…”

“…Cells were stimulated for the time periods indicated in the figure legends with anti-hCD40 or isotype-control mAbs at 10 mg/ml. Alternatively, cells were incubated with Hi5 insect cells, either wild-type or expressing hCD154, as described previously (20). Whole-cell lysates were prepared as described (21).…”

A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis

“…In view of the role of CD40, a tumour necrosis factor superfamily membrane member, in generating effective immune responses through interaction with its ligand CD40L, we reasoned that it may represent an excellent candidate susceptibility gene for various autoimmune diseases 30. The rs4810485 SNP has recently been associated with RA in individuals of European11 but not Korean ancestry 31.…”

Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions

“…Of particular biological interest, hCD40P227A is found in nearly 30% of persons of native Mexican and South/Central American ancestry but at < 1% frequency in all other populations (57). This observation correlates with the reported tendency to enhanced severity of certain autoimmune diseases in native Hispanic populations (58).…”