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.
Highlights
Immunoglobulin class-switch recombination de ciencies (Ig-class-switch recombination deficiency (CSR-D)) are rare primary immunode ciencies characterized by defective switched isotype (IgG/IgA/IgE) production
Ig-CSR-Ds associated with an unknown DNA repair deficiency We have described another subset of patients who very probably have an autosomal recessive CSR-D, as suggested by the gender ratio and the pedigree trees
Auto-immunity does not appear to be related to somatic hypermutation (SHM) since the latter occurs with the same frequency in both activationinduced cytidine deaminase (AID) deficiency and other Ig-CSR-Ds with normal SHM genera tion
Summary
Impaired CD40L expression leads to defective T-cell interactions with monocytes and dendritic cells This results in an abnormal cellular immune response and severe susceptibility to opportunistic infections with Pneumocystis jiroveci or Cryptosporidium. Intermittent or chronic neutropenia is a common feature of X-linked CD40L deficiency and may result from defective ‘stress’-induced CD40-dependent granulopoiesis since myeloid progenitors express CD40 molecules [36] Complications such as auto-immune manifestations or cancer have been reported but are not frequent. E. Uncharacterized Ig-CSR-D with normal in vitro CSR The involvement of CD40-L and ICOS molecule can be ruled out by the observation of normal protein expression or gene sequences (or both) in several CSR-deficient patients whose B cells display in vitro CSR following activation with CD40L and appropriate cytok ines.
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