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* VirPatH, Université de Lyon, Université Lyon1, Centre National de la Recherche Scientifique FRE3011, Lyon, France;
Etablissement Français du Sang, Grenoble, France;
Centre Hospitalier Universitaire Clermont-Ferrand, Université d’Auvergne, Clermont-Ferrand, France;
Centre Hospitalier Universitaire Grenoble, Institut National de la Santé et de la Recherche Médicale, Unité 836, Université Joseph Fourier, Grenoble, France;
¶ Laboratoire d’Immunologie, Centre Hospitalier Universitaire Grenoble, Grenoble, France;
|| Institut National de la Santé et de la Recherche Médicale, Unité 823, Université Joseph Fourier, Grenoble, France;
# EA 41-69, Université Lyon1, Hôpital E. Herriot, Lyon, France; and
** GREPI/TIMC-IMAG Centre National de la Recherche Scientifique Unité Mixte de Recherche 5525, Université Joseph Fourier, Centre Hospitalier Universitaire Grenoble, Grenoble, France
Primary C3 deficiency, a rare autosomal inherited disease (OMIM 120700), was identified in a 2-year-old male suffering from recurrent pyogenic infections from early infancy with undetectable total complement hemolytic activity (CH50) and C3 values. The nonconsanguineous parents and the two patients’ two siblings had 50% normal serum C3 concentration. The molecular abnormality associated a paternal allele coding C3 with the missense mutation p.Ser550Pro and an apparently null maternal allele, with production of a defective protein that could no longer be secreted. Vaccination of the child did not induce a long-term Ab response. Accordingly, switched memory IgD–CD27+ B cells were barely detected, amounting to only 2.3% of peripheral blood CD19+ cells. Cells were significantly defective in stimulating alloreactive responses. The in vitro development of immature dendritic cells and their maturation capacity were greatly impaired, with decreased CD1a expression and IL-12p70 secretion ability. These cells were unable to induce autologous B cell proliferation and Ig secretion in the presence of CD40L and C3. Finally, the regulatory T cell development ability of CD4+ T cells after CD3 and CD46 activation in the presence of IL-2 was significantly impaired. Thus, the association of important functional defects of dendritic cells, acquisition of B cell memory, and regulatory T cells with human C3 deficiency strongly supports a major role for C3 in bridging innate and adaptive immunity in humans.
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1 This work was partly supported by Grant PHRC 2002 from the French Ministry of Health (to C.D.). A.G. is a recipient of a fellowship from Tishreen University, Syria.
J.-L.F. took care of the family; A.G., M.P., N.M., and D.P. performed experiments; A.G., M.-B.V., J.P.-N., A.T., J.L., and D.G. analyzed results; A.G., D.G., and C.D. made the figures; and A.G., D.G., and C.D. designed the research and wrote the paper. Part of this work was presented as an oral communication at the 11th European Meeting on Complement in Human Diseases (Cardiff, U.K.), with the abstract identification: Ghannam et al. 2007. Absence of memory B cells and unbalanced T cell responses in a C3 deficient patient. Mol. Immunol. 44: 3910 (Abstr.).
2 Address correspondence and reprint requests to Dr. Christian Drouet, GREPI/TIMC-IMAG CNRS UMR5525, Université Joseph Fourier, CHU Grenoble, PO Box 217, Grenoble, F-38043 France. E-mail address: CDrouet{at}chu-grenoble.fr
3 Abbreviations used in this paper: DC, dendritic cell; ACM, Ag preparation from Candida albicans; AT, tetanus toxoid; CH50, complement hemolytic activity; cTreg, complement-induced regulatory T cell; GC, germinal center; PPD, tuberculin purified derivative; SNP, single nucleotide polymorphisms; Treg, regulatory T cell.
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