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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Janssen, Erin^1,2  Morbach, Henner³  Ullas, Sumana¹  Bannock, Jason M.³  Massad, Christopher³  Menard, Laurence³  Barlan, Isil⁴  Lefranc, Gerard^5,6  Su, Helen⁷  Dasouki, Majed^8,9  Al-Herz, Waleed¹⁰  Keles, Sevgi^1,11  Chatila, Talal^1,2  Geha, Raif S.^1,2  Meffre, Eric³ 

[1] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA

[4] Marmara Univ, Istanbul, Turkey

[5] Univ Montpellier, IMGT, F-34059 Montpellier, France

[6] CNRS, Inst Human Genet, Montpellier, France

[7] NIH, Human Immunol Dis Unit, Bethesda, MD 20892 USA

[8] Univ Kansas, Med Ctr, Div Genet Endocrinol & Metab, Dept Pediat, Kansas City, MO USA

[9] Univ Kansas, Med Ctr, Div Genet Endocrinol & Metab, Dept Internal Med, Kansas City, MO USA

[10] Kuwait Univ, Fac Med, Dept Pediat, Safat 13060, Kuwait

[11] Necmettin Erbakan Univ, Meram Med Fac, Div Pediat Immunol & Allergy, Konya, Turkey

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

DOI  :  10.1016/j.jaci.2014.07.042

来源: Elsevier

【 摘 要 】

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. RegulatoryT(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.

【 授权许可】

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