Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:141

Article

Alroqi, Fayhan J.^1,2  Charbonnier, Louis-Marie^1,2  Baris, Safa³  Kiykim, Ayca³  Chou, Janet^1,2  Platt, Craig D.^1,2  Algassim, Abdulrahman^1,2  Keles, Sevgi^1,2,4  Al Saud, Bandar K.⁵  Alkuraya, Fowzan S.⁶  Jordan, Michael^7,8  Geha, Raif S.^1,2  Chatila, Talal A.^1,2 

[1] Harvard Med Sch, Boston Childrens Hosp, Div Immunol, Boston, MA USA

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

[3] Marmara Univ, Div Pediat Allergy Immunol, Istanbul, Turkey

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

[5] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh, Saudi Arabia

[6] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia

[7] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45221 USA

[8] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Immunobiol, Cincinnati, OH 45221 USA

关键词: Autoantibodies;    LPS-responsive beige-like anchor;    cytotoxic T lymphocyte-associated antigen 4;    regulatory T cells;    follicular helper T cells;    follicular regulatory T cells;   

DOI  :  10.1016/j.jaci.2017.05.022

来源: Elsevier

【 摘 要 】

Background: LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cTFH) cells. Objective: We sought to determine the mechanisms of cTFH cell dysregulation in patients with LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy. Methods: cTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (TFH) cell differentiation and cTFH naive B-cell cocultures. Serum soluble IL-2 receptor a chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. Results: cTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor a chain, CD45RO(+)CD4(+) effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased toward a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA-deficient TFH cells supported in vitro antibody production by naive LRBA-sufficient B cells. Conclusions: cTFH cell dysregulation in patients with LRBA deficiency reflects impaired control of TFH cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.

【 授权许可】

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