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.