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Functional defects of dendritic cells in patients with CD40 deficiency.

Authors
  • Fontana, Stefania
  • Moratto, Daniele
  • Mangal, Surinder
  • De Francesco, Maria
  • Vermi, William
  • Ferrari, Simona
  • Facchetti, Fabio
  • Kutukculer, Necil
  • Fiorini, Claudia
  • Duse, Marzia
  • Das, Pranab K
  • Notarangelo, Luigi D
  • Plebani, Alessandro
  • Badolato, Raffaele
Type
Published Article
Journal
Blood
Publication Date
Dec 01, 2003
Volume
102
Issue
12
Pages
4099–4106
Identifiers
PMID: 12893749
Source
Medline
License
Unknown

Abstract

We have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in the CD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) combined with interferon-gamma (IFN-gamma) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-alpha secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients.

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