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J Allergy Clin Immunol. 2014 Dec;134(6):1365-1374. doi: 10.1016/j.jaci.2014.07.042. Epub 2014 Sep 11.

Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells.

Author information

1
Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
3
Division of Immunology, Boston Children's Hospital, Boston, Mass.
4
Marmara University, Istanbul, Turkey.
5
IMGT, University Montpellier, and CNRS Institute of Human Genetics, Montpellier, France.
6
Human Immunological Diseases Unit, National Institutes of Health, Bethesda, Md.
7
Department of Pediatrics and Department of Internal Medicine, Division of Genetics, Endocrinology & Metabolism, University of Kansas Medical Center, Kansas City, Kan.
8
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
9
Division of Immunology, Boston Children's Hospital, Boston, Mass; Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
10
Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
11
Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. Electronic address: eric.meffre@yale.edu.

Abstract

BACKGROUND:

Dedicator of cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, increased serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations.

OBJECTIVE:

We sought to determine the role of DOCK8 in the establishment and maintenance of human B-cell tolerance.

METHODS:

Autoantibodies were measured in the plasma of DOCK8-deficient patients. The antibody-coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. Regulatory T (Treg) cells in the blood were analyzed by means of flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4(+)CD25(-) effector T cells.

RESULTS:

DOCK8-deficient patients had increased levels of autoantibodies in their plasma. We determined that central B-cell tolerance did not require DOCK8, as evidenced by the normally low frequency of polyreactive new emigrant/transitional B cells in DOCK8-deficient patients. In contrast, autoreactive B cells were enriched in the mature naive B-cell compartment, revealing a defective peripheral B-cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8-deficient patients.

CONCLUSIONS:

Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B-cell tolerance.

KEYWORDS:

B-cell tolerance; Dedicator of cytokinesis 8; autoimmunity; regulatory T cells

PMID:
25218284
PMCID:
PMC4261031
DOI:
10.1016/j.jaci.2014.07.042
[Indexed for MEDLINE]
Free PMC Article

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