Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell–derived factor-1– and CD106 (VCAM-1)–dependent mechanism
Jan A. Burger, Nathan J. Zvaifler, Nobuhiro Tsukada, Gary S. Firestein, Thomas J. Kipps
Jan A. Burger, Nathan J. Zvaifler, Nobuhiro Tsukada, Gary S. Firestein, Thomas J. Kipps
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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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Inhibition of B-cell pseudoemperipolesis of RA FLSs by CXCR4 and VLA-4 a...
Inhibition of B-cell pseudoemperipolesis of RA FLSs by CXCR4 and VLA-4 antagonists. (a) Nalm-6 (open bars) or Ramos cells (filled bars) were preincubated with pertussis toxin (PT), αCXCR4 mAb’s, control mAb’s, αVLA-4 mAb’s, 100 μg/ml or 10 μg/ml of CS1 peptide, or a control peptide, as indicated on the left-hand side. Cells then were incubated on RA FLSs and allowed to migrate beneath the FLSs for 2 hours. Then, the FLS layer containing the migrated cells was harvested, and the relative numbers of migrated cells were determined by flow cytometry. The bars represent the mean (± SD) B-cell migration relative to that of untreated samples. AThe difference between the percent migration under a given condition is significantly less than that noted for same cell population for FLSs in the absence of inhibitors (e.g., P values < 0.05, Bonferroni’s t test). (b) Pseudoemperipolesis of normal blood B cells beneath RA FLSs was also inhibited by PT, αCXCR4 mAb’s, or CS1 peptide. The bars represent the mean (± SD) relative B-cell migration of B cells from five different donors. ASignificant inhibition of migration with P values < 0.05 using Bonferroni’s t test.