David Friedmann1,2,3, Susanne Unger1,2,4, Baerbel Keller1,2, Mirzokhid Rakhmanov1,2,5, Sigune Goldacker1,2, Gernot Zissel6, Björn C Frye6, Jonas C Schupp6,7, Antje Prasse8,9, Klaus Warnatz1,2. 1. Divison of Immunodeficiency, Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 2. Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 3. Faculty of Biology, University of Freiburg, Freiburg, Germany. 4. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. 5. Center for Human Genetics and Laboratory Diagnostics (AHC), Martinsried, Germany. 6. Department of Pneumology, University Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 7. Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, United States. 8. Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease Hannover, German Lung Research Center (DZL), Hannover, Germany. 9. Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
Abstract
Background: About 20% of patients with common variable immunodeficiency (CVID) suffer from interstitial lung disease (ILD) as part of a systemic immune dysregulation. Current understanding suggests a role of B cells in the pathogenesis based on histology and increased levels of BAFF and IgM associated with active disease corroborated by several reports which demonstrate the successful use of rituximab in CVID-ILD. It is debated whether histological confirmation by biopsy or even video-assisted thoracoscopy is required and currently not investigated whether less invasive methods like a bronchoalveolar lavage (BAL) might provide an informative diagnostic tool. Objective: To gain insight into potential immune mechanisms underlying granulomatous and lymphocytic interstitial lung disease (GLILD) and to define biomarkers for progressive ILD by characterizing the phenotype of B- and T-cell populations and cytokine profiles in BAL fluid (BALF) of CVID-ILD compared to sarcoidosis patients and healthy donors (HD). Methods: Sixty-four CVID, six sarcoidosis, and 25 HD BALF samples were analyzed by flow cytometric profiling of B- and T-cells and for cytokines by ELISA and Multiplexing LASER Bead technology. Results: Both sarcoidosis and CVID-ILD are characterized by a predominantly T-cell mediated lymphocytosis in the BALF. There is an increase in T follicular helper (TFH)-like memory and decrease of regulatory T cells in CVID-ILD BALF. This TFH-like cell subset is clearly skewed toward TH1 cells in CVID-ILD. In contrast to sarcoidosis, CVID-ILD BALF contains a higher percentage of B cells comprising mostly CD21low B cells, but less class-switched memory B cells. BALF analysis showed increased levels of APRIL, CXCL10, and IL-17. Conclusion: Unlike in sarcoidosis, B cells are expanded in BALF of CVID-ILD patients. This is associated with an expansion of TFH- and TPH-like cells and an increase in APRIL potentially supporting B-cell survival and differentiation and proinflammatory cytokines reflecting not only the previously described TH1 profile seen in CVID patients with secondary immune dysregulation. Thus, the analysis of BALF might be of diagnostic value not only in the diagnosis of CVID-ILD, but also in the evaluation of the activity of the disease and in determining potential treatment targets confirming the prominent role of B-cell targeted strategies.
Background: About 20% of patients with common variable immunodeficiency (CVID) suffer from interstitial lung disease (ILD) as part of a systemic immune dysregulation. Current understanding suggests a role of B cells in the pathogenesis based on histology and increased levels of BAFF and IgM associated with active disease corroborated by several reports which demonstrate the successful use of rituximab in CVID-ILD. It is debated whether histological confirmation by biopsy or even video-assisted thoracoscopy is required and currently not investigated whether less invasive methods like a bronchoalveolar lavage (BAL) might provide an informative diagnostic tool. Objective: To gain insight into potential immune mechanisms underlying granulomatous and lymphocytic interstitial lung disease (GLILD) and to define biomarkers for progressive ILD by characterizing the phenotype of B- and T-cell populations and cytokine profiles in BAL fluid (BALF) of CVID-ILD compared to sarcoidosispatients and healthy donors (HD). Methods: Sixty-four CVID, six sarcoidosis, and 25 HD BALF samples were analyzed by flow cytometric profiling of B- and T-cells and for cytokines by ELISA and Multiplexing LASER Bead technology. Results: Both sarcoidosis and CVID-ILD are characterized by a predominantly T-cell mediated lymphocytosis in the BALF. There is an increase in T follicular helper (TFH)-like memory and decrease of regulatory T cells in CVID-ILD BALF. This TFH-like cell subset is clearly skewed toward TH1 cells in CVID-ILD. In contrast to sarcoidosis, CVID-ILD BALF contains a higher percentage of B cells comprising mostly CD21low B cells, but less class-switched memory B cells. BALF analysis showed increased levels of APRIL, CXCL10, and IL-17. Conclusion: Unlike in sarcoidosis, B cells are expanded in BALF of CVID-ILDpatients. This is associated with an expansion of TFH- and TPH-like cells and an increase in APRIL potentially supporting B-cell survival and differentiation and proinflammatory cytokines reflecting not only the previously described TH1 profile seen in CVIDpatients with secondary immune dysregulation. Thus, the analysis of BALF might be of diagnostic value not only in the diagnosis of CVID-ILD, but also in the evaluation of the activity of the disease and in determining potential treatment targets confirming the prominent role of B-cell targeted strategies.
Authors: Deepak A Rao; Michael F Gurish; Jennifer L Marshall; Kamil Slowikowski; Chamith Y Fonseka; Yanyan Liu; Laura T Donlin; Lauren A Henderson; Kevin Wei; Fumitaka Mizoguchi; Nikola C Teslovich; Michael E Weinblatt; Elena M Massarotti; Jonathan S Coblyn; Simon M Helfgott; Yvonne C Lee; Derrick J Todd; Vivian P Bykerk; Susan M Goodman; Alessandra B Pernis; Lionel B Ivashkiv; Elizabeth W Karlson; Peter A Nigrovic; Andrew Filer; Christopher D Buckley; James A Lederer; Soumya Raychaudhuri; Michael B Brenner Journal: Nature Date: 2017-02-01 Impact factor: 49.962
Authors: Helen Chapel; Mary Lucas; Smita Patel; Martin Lee; Charlotte Cunningham-Rundles; Elena Resnick; Laurence Gerard; Eric Oksenhendler Journal: J Allergy Clin Immunol Date: 2012-07-20 Impact factor: 10.793
Authors: Claudia Wehr; Teemu Kivioja; Christian Schmitt; Berne Ferry; Torsten Witte; Efrem Eren; Marcela Vlkova; Manuel Hernandez; Drahomira Detkova; Philip R Bos; Gonke Poerksen; Horst von Bernuth; Ulrich Baumann; Sigune Goldacker; Sylvia Gutenberger; Michael Schlesier; Florence Bergeron-van der Cruyssen; Magali Le Garff; Patrice Debré; Roland Jacobs; John Jones; Elizabeth Bateman; Jiri Litzman; P Martin van Hagen; Alessandro Plebani; Reinhold E Schmidt; Vojtech Thon; Isabella Quinti; Teresa Espanol; A David Webster; Helen Chapel; Mauno Vihinen; Eric Oksenhendler; Hans Hartmut Peter; Klaus Warnatz Journal: Blood Date: 2007-09-26 Impact factor: 22.113
Authors: Arnon Arazi; Deepak A Rao; Celine C Berthier; Anne Davidson; Yanyan Liu; Paul J Hoover; Adam Chicoine; Thomas M Eisenhaure; A Helena Jonsson; Shuqiang Li; David J Lieb; Fan Zhang; Kamil Slowikowski; Edward P Browne; Akiko Noma; Danielle Sutherby; Scott Steelman; Dawn E Smilek; Patti Tosta; William Apruzzese; Elena Massarotti; Maria Dall'Era; Meyeon Park; Diane L Kamen; Richard A Furie; Fernanda Payan-Schober; William F Pendergraft; Elizabeth A McInnis; Jill P Buyon; Michelle A Petri; Chaim Putterman; Kenneth C Kalunian; E Steve Woodle; James A Lederer; David A Hildeman; Chad Nusbaum; Soumya Raychaudhuri; Matthias Kretzler; Jennifer H Anolik; Michael B Brenner; David Wofsy; Nir Hacohen; Betty Diamond Journal: Nat Immunol Date: 2019-06-17 Impact factor: 31.250