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

https://doi.org/10.1016/j.jaci.2014.01.037Get rights and content

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.

Section snippets

Methods

The Methods section in this article's Online Repository at www.jacionline.org contains detailed information on patients, materials, and methods.

S1P receptor expression in primary human B-cell subsets

Because the expression pattern of S1P receptors in human B cells was unknown, we analyzed S1P receptor expression and S1P-dependent migration in B cells from lymphoid tissue and blood. In tonsils S1P1 was detected in IgD+ mantle zone B cells but not in CD38+ extrafollicular PCs or GC B cells (Fig 1, A, and see Fig E1, A, in this article's Online Repository at www.jacionline.org). In the spleen CD19+IgMloIgDhigh mantle zone and IgMhighIgDlo/− MZ B cells expressed S1P1 (Fig 1, B, and see Fig E1, B

Discussion

Although B-cell circulation plays an important role in immune responses and immunopathology, S1P receptor expression and function of human B cells was largely unexplored. We found that different from mice,7 human B cells do not express S1P3, whereas S1P1, S1P2, and S1P4 are expressed at different levels and ratios by different B-cell subpopulations. Except for PCs, S1P1 was found to promote S1P-dependent migration and egress from bone marrow and from secondary lymphoid tissues for all B-cell

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    • Cited by (0)

    Supported by the Ei235/6-2 DFG Special Program: Sphingolipids–Signaling and Disease and the Deutsche Krebshilfe grant 109138 (to H.E.). W.R. is supported by the German excellence initiative of the Deutsche Forschungsgemeinschaft (EXC 294); by a grant from the Ministry of Science, Research and the Arts of Baden-Württemberg (Az: 33-7532.20); and by a starting grant of the European Research Council (Programme “Ideas”–call identifier: ERC-2011-StG 282105).

    Disclosure of potential conflict of interest: H. Sic has received research support and travel support from Deutsche Forschungsgemeinsch. H. Kraus and H. Eibel have received research support and travel support from the German Cancer Research Funds. M. Rizzi has received research support from the Novartis Foundation for Therapeutic Research, Germany. S. Rauer is a founding member of ravo Diagnostika GmbH; has provided expert testimony for Novartis, Biogen Idec, Merck-Serono, Bayer, Teva, Genzyme, and different courts; has received research support from Novartis, Bayer, and Biogen Idec; has received payment for lectures from Bayer, Baxter, Biogen Idec, Merck-Serono, Novartis, RG, Sanofi-Aventis, Genzyme, and Teva; and has received travel support from Bayer, Merck-Serono, Novartis, Biogen Idec, Teva, and Sanofi-Aventis. B. Grimbacher has received research support from BMBF (the German Federal Ministry of Education and Research), the European Union, and Helmholtz; is employed by University College London and University Medical Center Freiberg; and has received payment for lectures from CSL, Baxter, and Biotest. The rest of the authors declare that they have no relevant conflicts of interest.

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