title: Functional defects of dendritic cells in patients with CD40 deficiency.
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.
authors.affiliation: Clinica Pediatrica, Universita di Brescia, c/o Spedali Civili, 25123 Brescia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fontana
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Surinder
authors.initials: S
authors.lastname: Mangal
authors.forename: Maria
authors.initials: M
authors.lastname: De Francesco
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Simona
authors.initials: S
authors.lastname: Ferrari
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.forename: Marzia
authors.initials: M
authors.lastname: Duse
authors.forename: Pranab K
authors.initials: PK
authors.lastname: Das
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D019013:CD40 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000502:physiology; D007075:Immunoglobulin M; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D007075:Immunoglobulin M; D016898:Interferon-alpha