A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair

J Exp Med. 2007 May 14;204(5):1207-16. doi: 10.1084/jem.20070087. Epub 2007 May 7.

Abstract

Immunoglobulin class switch recombination (CSR) deficiencies are rare primary immunodeficiencies, characterized by a lack of switched isotype (IgG, IgA, or IgE) production, variably associated with abnormal somatic hypermutation (SHM). Deficiencies in CD40 ligand, CD40, activation-induced cytidine deaminase, and uracil-N-glycosylase may account for this syndrome. We previously described another Ig CSR deficiency condition, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) mu regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, SHM was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19 / metabolism
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology
  • Base Pairing
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Breaks, Double-Stranded
  • DNA Repair / genetics*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Fibroblasts / radiation effects
  • Gamma Rays
  • Humans
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin M / genetics
  • Immunoglobulin Switch Region / genetics
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Male
  • Molecular Sequence Data
  • Recombination, Genetic / genetics*
  • Recombination, Genetic / immunology
  • Sequence Analysis, DNA
  • Somatic Hypermutation, Immunoglobulin / genetics*
  • Somatic Hypermutation, Immunoglobulin / physiology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism

Substances

  • Antigens, CD19
  • DNA-Binding Proteins
  • Immunoglobulin M
  • NHEJ1 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • DNA Repair Enzymes