Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis

Heiko Sic, Helene Kraus, Josef Madl, Karl Andreas Flittner, Audrey Lilly Von Münchow, Kathrin Pieper, Marta Rizzi, Anne Kathrin Kienzler, Korcan Ayata, Sebastian Rauer, Burkhard Kleuser, Ulrich Salzer, Meike Burger, Katja Zirlik, Vassilios Lougaris, Alessandro Plebani, Winfried Römer, Christoph Loeffler, Samantha Scaramuzza, Anna VillaEmiko Noguchi, Bodo Grimbacher, Hermann Eibel

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Issue number2
Publication statusPublished - 2014


  • autoimmunity
  • B cells
  • circulation
  • fingolimod
  • FTY720
  • migration
  • primary immunodeficiencies
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Medicine(all)


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