TY  - JOUR
A1  - Sic, Heiko
A1  - Kraus, Helene
A1  - Madl, Josef
A1  - Flittner, Karl-Andreas
A1  - von Muenchow, Audrey Lilly
A1  - Pieper, Kathrin
A1  - Rizzi, Marta
A1  - Kienzler, Anne-Kathrin
A1  - Ayata, Korcan
A1  - Rauer, Sebastian
A1  - Kleuser, Burkhard
A1  - Salzer, Ulrich
A1  - Burger, Meike
A1  - Zirlik, Katja
A1  - Lougaris, Vassilios
A1  - Plebani, Alessandro
A1  - Roemer, Winfried
A1  - Loeffler, Christoph
A1  - Scaramuzza, Samantha
A1  - Villa, Anna
A1  - Noguchi, Emiko
A1  - Grimbacher, Bodo
A1  - Eibel, Hermann
T1  - Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis
JF  - The journal of allergy and clinical immunology
N2  - 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, beta-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.
KW  - Sphingosine-1-phosphate
KW  - B cells
KW  - migration
KW  - autoimmunity
KW  - circulation
KW  - fingolimod
KW  - FTY720
KW  - primary immunodeficiencies
Y1  - 2014
U6  - https://doi.org/10.1016/j.jaci.2014.01.037
SN  - 0091-6749
SN  - 1097-6825
VL  - 134
IS  - 2
SP  - 420
EP  - +
PB  - Elsevier
CY  - New York
ER  -