title: Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies.
abstract: B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR) deficiencies, previously termed hyper-IgM syndromes, are genetically determined conditions characterized by normal or elevated serum IgM levels and an absence or very low levels of IgG, IgA, and IgE. As a function of the molecular mechanism, the defective CSR is variably associated to a defect in the generation of somatic hypermutations (SHMs) in the Ig variable region. The study of Ig-CSR deficiencies contributed to a better delineation of the mechanisms underlying CSR and SHM, the major events of antigen-triggered antibody maturation. Four Ig-CSR deficiency phenotypes have been so far reported: the description of the activation-induced cytidine deaminase (AID) deficiency (Ig-CSR deficiency 1), caused by recessive mutations of AICDA gene, characterized by a defect in CSR and SHM, clearly established the role of AID in the induction of the Ig gene rearrangements underlying CSR and SHM. A CSR-specific function of AID has, however, been detected by the observation of a selective CSR defect caused by mutations affecting the C-terminus of AID. Ig-CSR deficiency 2 is the consequence of uracil-N-glycosylase (UNG) deficiency. Because UNG, a molecule of the base excision repair machinery, removes uracils from DNA and AID deaminates cytosines into uracils, that observation indicates that the AID-UNG pathway directly targets DNA of switch regions from the Ig heavy-chain locus to induce the CSR process. Ig-CSR deficiencies 3 and 4 are characterized by a selective CSR defect resulting from blocks at distinct steps of CSR. A further understanding of the CSR machinery is expected from their molecular definition.
authors.affiliation: Inserm, U768, Paris F-75015, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Nadine
authors.initials: N
authors.lastname: Taubenheim
authors.forename: Sophie
authors.initials: S
authors.lastname: Peron
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003564:Cytidine Deaminase / Q000172:deficiency*; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000209:etiology* / Q000503:physiopathology*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin; D051981:Uracil-DNA Glycosidase / Q000172:deficiency*
chemical_list: D051981:Uracil-DNA Glycosidase; D003564:Cytidine Deaminase