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An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex

Authors

  • S. Kracker
  • M. Di Virgilio
  • J. Schwartzentruber
  • C. Cuenin
  • M. Forveille
  • M.C. Deau
  • K.M. McBride
  • J. Majewski
  • A. Gazumyan
  • S. Seneviratne
  • B. Grimbacher
  • N. Kutukculer
  • Z. Herceg
  • M. Cavazzana
  • N. Jabado
  • M.C. Nussenzweig
  • A. Fischer
  • A. Durandy

Journal

  • Journal of Allergy and Clinical Immunology

Citation

  • J Allergy Clin Immunol 135 (4): 998-1007

Abstract

  • BACKGROUND: Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. OBJECTIVE: This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). METHODS: Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. RESULTS: We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of gamma-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Salpha and Emu regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. CONCLUSION: INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.


DOI

doi:10.1016/j.jaci.2014.08.030