title: Hyper-immunoglobulin-M syndromes caused by an intrinsic B cell defect.
abstract: OBJECTIVE
  Elucidation of the molecular basis of hyper-immunoglobulin-M syndromes has provided considerable insight into the molecular events involved in antibody maturation, including immunoglobulin class switch recombination and the generation of somatic hypermutation.
  
  
  RESULTS
  The identification of activation-induced cytidine deaminase deficiency (hyper-immunoglobulin-M syndrome 2) has revealed the key role played by this inducible B cell-specific molecule in both class switch recombination and somatic hypermutation. Data from Escherichia coli and in-vitro assays have strongly suggested that activation-induced cytidine deaminase acts as a DNA-editing enzyme in these processes. The recent description of a new hyper-immunoglobulin-M syndrome caused by mutations in the gene encoding the uracil-N glycosylase provided further evidence that activation-induced cytidine deaminase acts on deoxycytidine in the switch and variable regions. Indeed, uracil-N glycosylase is required to remove the uracil residues integrated into DNA following deoxycytidine deamination by activation-induced cytidine deaminase. Another hyper-immunoglobulin-M condition has recently been described (hyper-immunoglobulin-M syndrome 4). Its molecular basis is unknown, but it appears to be a homogeneous entity characterized by an intrinsic B cell defective class switch recombination but normal generation of somatic hypermutation. It is probably caused by a class switch recombination-specific DNA repair defect because class switch recombination-induced DNA breaks in S regions are normally detected in patients with this condition.
  
  
  CONCLUSIONS
  The heterogeneity in hyper-immunoglobulin-M syndromes will continue to shed light on the molecular mechanisms of class switch recombination and somatic hypermutation. The description of hyper-immunoglobulin-M syndromes may therefore lead to improvements in the care of these patients.
authors: Inserm U429, Hospital Necker-Sick Children, Paris, France. durandy@necker.fr
authors: Anne
authors: A
authors: Durandy
authors: Patrick
authors: P
authors: Revy
authors: Alain
authors: A
authors: Fischer
mesh_terms: D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D003564:Cytidine Deaminase / Q000172:deficiency; D045647:DNA Glycosylases / Q000172:deficiency; D006801:Humans; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000097:blood* / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D013577:Syndrome; D051981:Uracil-DNA Glycosidase
chemical_list: D007075:Immunoglobulin M; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; D003564:Cytidine Deaminase