RANK and RANKL expression in rheumatoid arthritis synovium and lymph nodes as markers of dendritic cell – T cell interactions

The RANK/RANKL pathway is critical in osteoclastogenesis and bone destruction, and is implicated in focal bone erosion in rheumatoid arthritis (RA). Because deficient mice show major lymph node (LN) abnormalities, here we looked at its involvement in the immune response during chronic inflammation.

We investigated, by immunohistochemistry, RANK and RANKL expression by DC and T cell subsets in paired RA synovium–LN and also in normal peripheral blood mononuclear cells (PBMC) stimulated with PMA/PHA.

In RA synovium, RANKL⁺ cells were detected in the lining layer and the lymphocytic infiltrates whereas RANK expression was restricted to the perivascular infiltrates. In LN, RANK⁺ and RANKL⁺ cells were diffusely expressed in both T-cell zone and germinal centres. Double staining with anti-RANK or anti-RANKL and anti-CD1a or anti-DC-LAMP antibodies revealed that, in paired RA synovium-LN sections, some immature CD1a⁺ DC express RANK and RANKL whereas some mature DC-LAMP⁺ DC expressed only RANK. Double staining with the CD3, CD4 T-cell markers and the IFN-γ and IL-17 Th1 cell markers showed that some of CD3⁺, CD4⁺, IFN-γ⁺ and IL-17⁺ cells expressed RANKL, whereas none of them expressed RANK. The same pattern was observed on activated PBMC. The RANK⁺ cells, detected in unstimulated PBMC, were identified as CD14⁺ monocytes.

This study showed the involvement of RANK/RANKL in DC–T cell interactions occurring during the inflammatory process. In particular, RANK expression appears to be limited to the sites of immune reaction both in synovium and LN.