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Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation
| Content Provider | Scilit |
|---|---|
| Author | Alroqi, Fayhan J. Charbonnier, Louis-Marie Baris, Safa Kiykim, Ayca Chou, Janet Platt, Craig D. Algassim, Abdulrahman Keles, Sevgi Saud, Bandar K. Al Alkuraya, Fowzan S. Geha, Raif S. Chatila, Talal A. |
| Copyright Year | 2017 |
| Description | Journal: The Journal of Allergy and Clinical Immunology 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 $(cT_{FH}$) cells. We sought to determine the mechanisms of $cT_{FH}$ cell dysregulation in patients with LRBA deficiency and the utility of monitoring $cT_{FH}$ cells as a correlate of clinical response to CTLA4-Ig therapy. $cT_{FH}$ cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T $(T_{FH}$) cell differentiation and $cT_{FH}$/naive B-cell cocultures. Serum soluble IL-2 receptor α chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. $cT_{FH}$ 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 α chain, $CD45RO^{+}CD4^{+}$ effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. $cT_{FH}$ cells in patients with LRBA deficiency were biased toward a $T_{H}$1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro $T_{FH}$ cell differentiation in a CTLA4-dependent manner. LRBA-deficient $T_{FH}$ cells supported in vitro antibody production by naive LRBA-sufficient B cells. $cT_{FH}$ cell dysregulation in patients with LRBA deficiency reflects impaired control of $T_{FH}$ 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 $cT_{FH}$ cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743769/pdf http://www.jacionline.org/article/S0091674917309235/pdf |
| ISSN | 00916749 |
| e-ISSN | 10976825 |
| DOI | 10.1016/j.jaci.2017.05.022 |
| Journal | The Journal of Allergy and Clinical Immunology |
| Issue Number | 3 |
| Volume Number | 141 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2017-06-07 |
| Access Restriction | Open |
| Subject Keyword | Journal: The Journal of Allergy and Clinical Immunology Lps-responsive Beige-like Anchor Cytotoxic T Lymphocyte–associated Antigen 4 Regulatory T Cells Follicular Helper T Cells Follicular Regulatory T Cells Circulating Follicular Helper T Inducible T-cell Costimulator Immune Dysregulation Polyendocrinopathy Induced Follicular Helper T |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
