Exaggerated T Follicular Helper Cell Responses in LRBA Deficiency Due to Failure of CTLA4-Mediated Regulation

Publication date: Available online 7 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Fayhan J. Alroqi, Louis-Marie Charbonnier, Safa Baris, Ayca Kiykim, Janet Chou, Craig D. Platt, Abdulrahman Algassim, Sevgi Keles, Bandar K. Al Saud, Fowzan S. Alkuraya, Michael Jordan, Raif S. Geha, Talal A. Chatila
PurposeLRBA (lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (cytotoxic T lymphocyte antigen 4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating T Follicular helper (cTFH) cells. We sought to determine the mechanisms of cTFH cell dysregulation in LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy.MethodscTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro TFH cell differentiation and cTFH/naïve B cell co-cultures. Serum soluble IL-2 receptor alpha chain (sIL-2Rα), and in vitro immunoglobulin production by cultured B cells were quantified by ELISA.ResultscTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply declined with CTLA4-Ig therapy, in parallel with other markers of immune dysregulation including sIL-2Rα, CD45RO⁺CD4⁺ effector T cells and auto-antibodies, and predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased towards a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not -deficient regulatory T (Treg) cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA deficient TFH cells supported in vitro antibody production by naïve LRBA-sufficient B cells.ConclusionscTFH cell dysregulation in LRBA deficiency reflects impaired control of TFH differentiation due to profoundly decreased CTLA4 expression on Treg cells, and probably contributes to autoimmunity in this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA deficient patients to CTLA4-Ig therapy.

Teaser

LRBA and CTLA4 deficiencies are associated with dysregulated TFH cell responses, which may contribute to autoimmunity in these disorders. Monitoring circulating TFH cells may help gauge response to therapy.


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