Heiko Sic1, Helene Kraus1, Josef Madl2, Karl-Andreas Flittner3, Audrey Lilly von Münchow3, Kathrin Pieper1, Marta Rizzi3, Anne-Kathrin Kienzler3, Korcan Ayata3, Sebastian Rauer4, Burkhard Kleuser5, Ulrich Salzer3, Meike Burger6, Katja Zirlik6, Vassilios Lougaris7, Alessandro Plebani7, Winfried Römer2, Christoph Loeffler8, Samantha Scaramuzza9, Anna Villa10, Emiko Noguchi11, Bodo Grimbacher3, Hermann Eibel12. 1. Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany. 2. Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. 3. Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany. 4. Department of Neurology, University Medical Center, Freiburg, Germany. 5. Department Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany. 6. Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. 7. Pediatric Clinic and A. Nocivelli Institute of Molecular Medicine, Spedali Civili, Brescia, Italy. 8. Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center, Freiburg, Germany. 9. Institute for Gene Therapy, Hospital San Raffaele, Milan, Italy. 10. Institute for Gene Therapy, Hospital San Raffaele, Milan, Italy; UOS/IRGB, Milan Unit, CNR, Milan, Italy. 11. Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan. 12. Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany. Electronic address: hermann.eibel@uniklinik-freiburg.de.
Abstract
BACKGROUND: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells. OBJECTIVE: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies. METHODS: S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy. RESULTS: Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, β-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1. CONCLUSION: Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.
BACKGROUND: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells. OBJECTIVE: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies. METHODS: S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy. RESULTS: Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, β-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1. CONCLUSION: Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.
Authors: Sakari Simula; Tomi Laitinen; Tiina M Laitinen; Tuula Tarkiainen; Juha E K Hartikainen; Päivi Hartikainen Journal: J Neuroimmune Pharmacol Date: 2015-06-20 Impact factor: 4.147
Authors: Alexandra M Miggelbrink; Brent R Logan; Rebecca H Buckley; Roberta E Parrott; Christopher C Dvorak; Neena Kapoor; Hisham Abdel-Azim; Susan E Prockop; David Shyr; Hélène Decaluwe; Imelda C Hanson; Alfred Gillio; Blachy J Dávila Saldaña; Hermann Eibel; Gregory Hopkins; Jolan E Walter; Jennifer S Whangbo; Donald B Kohn; Jennifer M Puck; Morton J Cowan; Linda M Griffith; Elie Haddad; Richard J O'Reilly; Luigi D Notarangelo; Sung-Yun Pai Journal: Blood Date: 2018-05-04 Impact factor: 22.113
Authors: Na Chang; Jingjing Ge; Lei Xiu; Zhongxin Zhao; Xianghui Duan; Lei Tian; Jieshi Xie; Lin Yang; Liying Li Journal: J Mol Med (Berl) Date: 2016-08-20 Impact factor: 4.599