IL-15 Expression on RA Synovial Fibroblasts Promotes B Cell Survival

Abstract

IntroductionThe purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival.MethodsMagnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib.ResultsRASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/−8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/−6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures.ConclusionIL-15 expression on RASFib significantly contributes to the anti-apoptotic effect of RASFib on B cells. IL-15 action is facilitated by BAFF and VCAM-1 expressed on RASFib, through an upregulation of IL-15R chains.

BAFF Suppresses IL-15 Expression in B Cells

“…Previous studies have shown that the survival signals maintaining memory T and B cells in the absence of Ag are provided by IL-15 (13)(14)(15). Our studies demonstrate that blockade of BAFF with TACI-IgG upregulates IL-15 levels in B cells but not in other cells, such as T cells (Figs.…”

“…IL-15 is an important cytokine for the survival and maintenance of memory T and B cells (13)(14)(15). Thus, we propose that blocking BAFF with TACI-IgG upregulates memory B cells by inducing IL-15 in lupus-like mice.…”

“…IL-15 provided survival signals that maintain memory T and B cells in the absence of Ag (13)(14)(15). Therefore, we propose that BAFF suppresses memory B cells by downregulating IL-15 expression.…”

Synovial fluid mononuclear cells provide an environment for long-term survival of antibody-secreting cells and promote the spontaneous production of anti-citrullinated protein antibodies

“…Also here, cell contact and factors derived from stromal cells, especially synovium-derived FLS in RA, were found to be critical for PC differentiation and survival 41. FLS express several relevant factors, such as vascular cell adhesion molecule 1 (VCAM-1),24 42 BAFF43 and IL-15 22 23. The expression of Bcl-x L induced in B cells upon interaction with FLS also supports PC longevity 25.…”

New Developments in Transcriptomic Analysis of Synovial Tissue

“…Fibroblasts play key roles within the RA synovium both in the regulation of leukocyte influx and efflux, and in damaging cartilage and driving indirect damage to bone (5)(6)(7)(8)(9)(10)(11). In RA, fibroblasts within the synovium become persistently activated, resulting in reduced responses to apoptotic signals, increased proliferation, production of proinflammatory molecules, such as IL-6 and CCL5, and the release of matrix remodeling enzymes, such as matrix metalloproteinase-3 (MMP-3) and MMP-9 (12)(13)(14)(15)(16)(17)(18)(19).…”