Immunoglobulin class-switch recombination deficiencies

Abstract

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

Figure 1

Schematic representation of class-switch recombination in germinal center. (a) T cell-B cell cooperation in immunoglobulin class-switch recombination (Ig-CSR). Impaired function of CD40 and CD40L (CD40 ligand) and, to a lesser extent, inducible co-stimulator (ICOS) and nuclear factor-kappa-B (NF-κB) essential modulator (NEMO) results in class-switch recombination deficiency (CSR-D). B, B cell; IL-R, interleukin receptor; T_FH, T follicular helper. (b) Schematic representation of Ig-CSR. Only part of the IgH locus with I (I exon), S (switch region), and C (constant region) is depicted. The intermediate steps of CSR are shown on the left. Impaired function of activation-induced cytidine deaminase (AID), uracil-N-glycosylase (UNG), mismatch repair (MMR), ataxia telangiectasia mutated (ATM), Nijmegen breakage syndrome (NBS1), and conventional non-homologous end joining (cNHEJ) results in variable CSR-D. AEJ, alternative end joining; APE, AP endonuclease; DSB, double-stranded DNA break; U, uracil.