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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4099-4106.
Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-04-1244.
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IMMUNOBIOLOGY
Functional defects of dendritic cells in patients with CD40 deficiency
Stefania Fontana,
Daniele Moratto,
Surinder Mangal,
Maria De Francesco,
William Vermi,
Simona Ferrari,
Fabio Facchetti,
Necil Kutukculer,
Claudia Fiorini,
Marzia Duse,
Pranab K. Das,
Luigi D. Notarangelo,
Alessandro Plebani, and
Raffaele Badolato
From the Istituto di Medicina Molecolare "Angelo Nocivelli," Clinica Pediatrica, Cattedra di Anatomia Patologica, and the Istituto di Microbiologia, Università di Brescia, Italy; Department of Pediatrics, Ege University Medical School, Izmir, Turkey; and Department of Pathology (Experimental Dermato-Immunopathology Research Group), Academic Medical Center, University of Amsterdam, The Netherlands.
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- (TNF-) or lipopolysaccharide (LPS) combined with interferon- (IFN-) 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- 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. (Blood. 2003;102:
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