title: Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression.
abstract: The CD40-mediated activation pathway of B cells from 10 patients with hyper-IgM syndrome and normal expression of CD40 ligand was studied. In all 10 cases, B cells were found to be defective for IgG, IgA, and IgE production after stimulation by anti-CD40 mAbs and cytokines. In the patients tested, neither B cell proliferation (n = 6) nor CD23 molecule expression (n = 5) were observed in cultures stimulated with anti-CD40 mAb. These results point to an intrinsic B cell deficiency and a defect in the CD40-triggered B cell activation pathway; this conclusion was supported by a lack of detectable germinal centers in the spleen of two patients. CD40-triggered activation events, i.e., phosphatidylinositol 3 (PI3) kinase activation and induction of transcription factors NF-kappaB and AP-1, were next analyzed in B cell lines derived from five patients. Three distinct patterns were observed: an absence of detectable abnormalities (n = 1), defective PI3 kinase activation with normal induction of NF-kappaB and AP-1 (n = 3), and defects in both PI3 kinase activation and induction of NF-kappaB and AP-1 (n = 1). In three B cell lines, each exhibiting one of the CD40-mediated activation patterns, sequences of CD40 and CD40 binding protein coding regions were normal. The coding region of TNF receptor-associated factor 2 (TRAF2), which is known to interact with CD40 for NF-kappaB induction, was also found to be normal in B cell lines deficient in NF-kappaB induction. Altogether, these results suggest that CD40 ligand-positive hyper-IgM syndrome could be genetically heterogeneous, although phenotypic variability is not excluded, and that an early defect in the CD40-triggered activation cascade can account for defective Ig class switching in some patients with CD40 ligand-positive hyper-IgM syndrome.
authors.affiliation: INSERM Unit 429, Hospital Necker-Enfants Malades, Paris, France. durandy@ceylan.necker.fr
authors.forename: A
authors.initials: A
authors.lastname: Durandy
authors.forename: C
authors.initials: C
authors.lastname: Hivroz
authors.forename: F
authors.initials: F
authors.lastname: Mazerolles
authors.forename: C
authors.initials: C
authors.lastname: Schiff
authors.forename: F
authors.initials: F
authors.lastname: Bernard
authors.forename: E
authors.initials: E
authors.lastname: Jouanguy
authors.forename: P
authors.initials: P
authors.lastname: Revy
authors.forename: J P
authors.initials: JP
authors.lastname: DiSanto
authors.forename: J F
authors.initials: JF
authors.lastname: Gauchat
authors.forename: J Y
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: J L
authors.initials: JL
authors.lastname: Casanova
authors.forename: A
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000032:analysis; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D006801:Humans; D006942:Hypergammaglobulinemia / Q000276:immunology*; D007075:Immunoglobulin M; D007424:Intracellular Fluid / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D013577:Syndrome; D048008:TNF Receptor-Associated Factor 3; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
chemical_list: D019013:CD40 Antigens; D002352:Carrier Proteins; D003062:Codon; D018076:DNA, Complementary; D007075:Immunoglobulin M; D008024:Ligands; D008562:Membrane Glycoproteins; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D023201:CD40 Ligand