Erin Janssen1, Henner Morbach2, Sumana Ullas3, Jason M Bannock2, Christopher Massad2, Laurence Menard2, Isil Barlan4, Gerard Lefranc5, Helen Su6, Majed Dasouki7, Waleed Al-Herz8, Sevgi Keles9, Talal Chatila1, Raif S Geha10, Eric Meffre11. 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.
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.
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