title: Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis.
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.
  
  
  CONCLUSIONS
  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.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Sic
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Kraus
authors.affiliation: Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Madl
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Karl-Andreas
authors.initials: KA
authors.lastname: Flittner
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Audrey Lilly
authors.initials: AL
authors.lastname: von Münchow
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Pieper
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Kienzler
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Korcan
authors.initials: K
authors.lastname: Ayata
authors.affiliation: Department of Neurology, University Medical Center, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rauer
authors.affiliation: Department Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
authors.affiliation: Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.affiliation: Pediatric Clinic and A. Nocivelli Institute of Molecular Medicine, Spedali Civili, Brescia, Italy.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.affiliation: Pediatric Clinic and A. Nocivelli Institute of Molecular Medicine, Spedali Civili, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.affiliation: Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Römer
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Loeffler
authors.affiliation: Institute for Gene Therapy, Hospital San Raffaele, Milan, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.affiliation: Institute for Gene Therapy, Hospital San Raffaele, Milan, Italy; UOS/IRGB, Milan Unit, CNR, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.affiliation: Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany. Electronic address: hermann.eibel@uniklinik-freiburg.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019390:Arrestins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D059008:Time-Lapse Imaging; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000099192:CD69 Antigens
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019390:Arrestins; D020662:Guanine Nucleotide Exchange Factors; D037181:Lectins, C-Type; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases; D049349:Receptors, Lysosphingolipid; D051316:Wiskott-Aldrich Syndrome Protein; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000099192:CD69 Antigens; C000605254:ARRB2 protein, human; C516591:DOCK8 protein, human; C428703:LRBA protein, human
keywords: B cells; FTY720; Sphingosine-1-phosphate; autoimmunity; circulation; fingolimod; migration; primary immunodeficiencies