title: Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination.
abstract: Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome - which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 - do not account for all cases. We investigated the clinical and immunological characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2, these patients exhibited a slightly milder HIGM syndrome with residual IgG production. We found that B cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this new HIGM entity (HIGM4) occurs downstream of the AID activity, as the AID gene was induced normally and AID-induced DNA double-strand breaks in the switch micro region of the Ig heavy chain locus were detected during CSR as normal. Thus, HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Nadia
authors.initials: N
authors.lastname: Catalan
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: László
authors.initials: L
authors.lastname: Maródi
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Satoru
authors.initials: S
authors.lastname: Kumaki
authors.forename: Vasantha
authors.initials: V
authors.lastname: Nagendran
authors.forename: Philip
authors.initials: P
authors.lastname: Wood
authors.forename: Catherine
authors.initials: C
authors.lastname: Glastre
authors.forename: Françoise
authors.initials: F
authors.lastname: Sarrot-Reynauld
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Monique
authors.initials: M
authors.lastname: Forveille
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003564:Cytidine Deaminase / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood*; D007223:Infant; D015847:Interleukin-4 / Q000494:pharmacology; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D013577:Syndrome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D015847:Interleukin-4; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase