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J Allergy Clin Immunol. 2015 Apr;135(4):998-1007.e6. doi: 10.1016/j.jaci.2014.08.030. Epub 2014 Oct 11.

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

Author information

1
INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.
2
Laboratory of Molecular Immunology, Howard Hughes Medical Institute, the Rockefeller University, New York, NY.
3
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
4
International Agency for Research on Cancer, F-69008 Lyon, Lyon, France.
5
Center for Primary Immunodeficiencies, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France.
6
UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Tust, London, United Kingdom.
7
UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Tust, London, United Kingdom; Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, D-79106 Freiburg, Freiburg, Germany.
8
Ege University Faculty of Medicine, Department of Pediatric Immunology, 35100 Bornova, Izmir, Turkey.
9
INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Biotherapy, AP-HP Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France; Clinical Investigation Center (CIC)-Biotherapy GHU Ouest, INSERM-APHP (Assistance Publique des Hôpitaux de Paris), Paris, France.
10
Department of Pediatrics, McGill University and McGill University Health Center, Montreal, Quebec, Canada.
11
INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Immunology and Hematology, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France; Collège de France, Paris, France.
12
INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Immunology and Hematology, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France. Electronic address: anne.durandy@inserm.fr.

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 γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ 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.

KEYWORDS:

CSR synapse; Chromatin remodeling; class-switch recombination defect; cohesin

PMID:
25312759
PMCID:
PMC4382329
DOI:
10.1016/j.jaci.2014.08.030
[Indexed for MEDLINE]
Free PMC Article

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