Susanne Unger1, Maximilian Seidl2, Pauline van Schouwenburg3, Mirzokhid Rakhmanov4, Alla Bulashevska5, Natalie Frede5, Bodo Grimbacher5, Jens Pfeiffer6, Klaudia Schrenk2, Luis Munoz7, Leif Hanitsch8, Ina Stumpf5, Fabian Kaiser9, Oliver Hausmann10, Florian Kollert11, Sigune Goldacker5, Mirjam van der Burg3, Baerbel Keller5, Klaus Warnatz12. 1. Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. 2. Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute for Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany. 3. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. Center for Human Genetics and Laboratory Diagnostics (AHC), Martinsried, Germany. 5. Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 6. Department of Otorhinolaryngology-Head and Neck Surgery, University of Freiburg, Freiburg, Germany. 7. Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 8. Institute of Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. 9. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 10. Löwenpraxis and Klinik St Anna, Luzern, Switzerland. 11. Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany. 12. Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: klaus.warnatz@uniklinik-freiburg.de.
Abstract
BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T-bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.
BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS:Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T-bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.
Authors: Stuart G Tangye; Julia Bier; Anthony Lau; Tina Nguyen; Gulbu Uzel; Elissa K Deenick Journal: J Clin Immunol Date: 2019-03-25 Impact factor: 8.317
Authors: Carole Le Coz; Bertram Bengsch; Caroline Khanna; Melissa Trofa; Takuya Ohtani; Brian E Nolan; Sarah E Henrickson; Michele P Lambert; Taylor Olmsted Kim; Jenny M Despotovic; Scott Feldman; Olajumoke O Fadugba; Patricia Takach; Melanie Ruffner; Soma Jyonouchi; Jennifer Heimall; Kathleen E Sullivan; E John Wherry; Neil Romberg Journal: J Allergy Clin Immunol Date: 2019-08-22 Impact factor: 10.793
Authors: Julia Bier; Geetha Rao; Kathryn Payne; Henry Brigden; Elise French; Simon J Pelham; Anthony Lau; Helen Lenthall; Emily S J Edwards; Joanne M Smart; Theresa S Cole; Sharon Choo; Avni Y Joshi; Roshini S Abraham; Michael O'Sullivan; Kaan Boztug; Isabelle Meyts; Paul E Gray; Lucinda J Berglund; Peter Hsu; Melanie Wong; Steven M Holland; Luigi D Notarangelo; Gulbu Uzel; Cindy S Ma; Robert Brink; Stuart G Tangye; Elissa K Deenick Journal: J Allergy Clin Immunol Date: 2019-02-06 Impact factor: 10.793
Authors: Paul J Maglione; Gavin Gyimesi; Montserrat Cols; Lin Radigan; Huaibin M Ko; Tamar Weinberger; Brian H Lee; Emilie K Grasset; Adeeb H Rahman; Andrea Cerutti; Charlotte Cunningham-Rundles Journal: JCI Insight Date: 2019-03-07
Authors: Miranda L Abyazi; Kayla A Bell; Gavin Gyimesi; Turner S Baker; Minji Byun; Huaibin M Ko; Charlotte Cunningham-Rundles; Feng Feng; Paul J Maglione Journal: J Allergy Clin Immunol Date: 2021-06-17 Impact factor: 10.793