Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell–derived factor-1– and CD106 (VCAM-1)–dependent mechanism
Jan A. Burger, … , Gary S. Firestein, Thomas J. Kipps
Jan A. Burger, … , Gary S. Firestein, Thomas J. Kipps
Published February 1, 2001
Citation Information: J Clin Invest. 2001;107(3):305-315. https://doi.org/10.1172/JCI11092.
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Article

Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell–derived factor-1– and CD106 (VCAM-1)–dependent mechanism

Abstract

B-cell accumulation and formation of ectopic germinal centers are characteristic changes in the diseased joints of patients with rheumatoid arthritis (RA). Earlier studies suggested that interactions between B lymphocytes and specialized synovial “nurse-like” cells peculiar to the RA synovium may be responsible for the homing and sustained survival of B cells in the synovium. However, in this study, we found that B cells spontaneously migrate beneath ordinary fibroblast-like synoviocytes (FLSs) and then experience prolonged survival. FLSs isolated from joints of patients with osteoarthritis also supported this activity, termed B-cell pseudoemperipolesis. We found that FLSs constitutively expressed the chemokine stromal cell–derived factor-1 (SDF-1), and that pertussis toxin or antibodies to the SDF-1 receptor (CXCR4) could inhibit B-cell pseudoemperipolesis. However, expression of SDF-1 is not sufficient, as dermal fibroblasts also expressed this chemokine but were unable to support B-cell pseudoemperipolesis unless previously stimulated with IL-4 to express CD106 (VCAM-1), a ligand for the α4β1 integrin, very-late-antigen-4 (VLA-4 or CD49d). Furthermore, mAb’s specific for CD49d and CD106, or the synthetic CS1 fibronectin peptide, could inhibit B-cell pseudoemperipolesis. We conclude that ordinary FLSs can support B-cell pseudoemperipolesis via a mechanism dependent upon fibroblast expression of SDF-1 and CD106.

Authors

Jan A. Burger, Nathan J. Zvaifler, Nobuhiro Tsukada, Gary S. Firestein, Thomas J. Kipps

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Figure 9

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(a–d) CD106 (VCAM-1) expression by RA FLSs (a), OA FLSs (b), dermal fibr...
(a–d) CD106 (VCAM-1) expression by RA FLSs (a), OA FLSs (b), dermal fibroblasts (c), or IL-4–stimulated dermal fibroblasts (d). a–d depict histogram graphs that display the relative red fluorescence intensity of cells stained with anti-CD106 mAb’s (shaded histograms) or a nonspecific isotype control antibody (open histograms). The mean fluorescence intensity ratios of cells stained for CD106 relative to that of control antibody–stained cells are displayed in the upper right-hand corner of each histogram. (e) B-cell migration beneath dermal fibroblasts (DFs) is significantly enhanced by IL-4 treatment of dermal fibroblasts. The bars represent the mean (± SD) Nalm-6 or Ramos B-cell migration beneath IL-4–treated dermal fibroblasts relative to the migration beneath untreated dermal fibroblasts, corresponding to 100%. ASignificant inhibition of migration with P values < 0.05 using Bonferroni’s t test. (f) Migration of Ramos B cells and Nalm-6 B cells beneath IL-4–treated dermal fibroblasts is significantly inhibited by anti-CD106 mAb’s. Compared with the migration beneath IL-4–treated dermal fibroblasts without antibody treatment (column 1), control antibody treatment did not significantly affect pseudoemperipolesis (PEP) of Ramos and Nalm-6 cells (column 2). In contrast, treatment with anti-CD106 mAb significantly decreased the migration of Ramos cells (column 3). ASignificant inhibition of migration compared with that of control cultures (P < 0.05, Bonferroni’s t test). The bars represent the mean (± SEM) PEP of Ramos B cells in test conditions relative to that of Ramos B cells in control conditions without antibody (n = 6).