RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes.
OBJECTIVE
The RANK/RANKL pathway is critical in bone destruction in conditions such as rheumatoid arthritis (RA). Since RANK/RANKL-deficient mice show major lymph node (LN) abnormalities, undertook this study to investigate the expression of RANK/RANKL in paired samples of synovium and LNs from RA patients.


METHODS
Using immunohistochemistry, RANK/RANKL expression by dendritic cell (DC) and T cell subsets was studied in this unique set of samples and in RA synoviocytes stimulated with interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-17.


RESULTS
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 LNs, RANK+ and RANKL+ cells were diffusely expressed in the T cell zone and in germinal centers. Double staining of paired RA synovium and LN sections showed that some immature CD1a+ DCs expressed RANK and RANKL, while some mature DC-LAMP+ DCs expressed only RANK. Some CD3+, CD4+, interferon-gamma+, and IL-17+ cells expressed RANKL, while none expressed RANK. Treatment of synoviocytes with TNFalpha or IL-1beta in combination with IL-17 was particularly potent at inducing RANKL expression.


CONCLUSIONS
This study shows the involvement of RANK/RANKL in DC-T cell interactions during an inflammatory process. RANK expression appears to be limited to the sites of immune reaction, both in the synovium and in LNs. Therapeutic control of these targets may have both positive and negative consequences for the immune system.
Page
Guillaume
G
INSERM U403, Unité mixte Hospices civils de Lyon-BioMérieux, and Hôpital Edouard Herriot, France.
Miossec
Pierre
P
D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D003713:Dendritic Cells; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013583:Synovial Membrane / Q000473:pathology / Q000503:physiopathology*; D013601:T-Lymphocytes; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha