RANK and RANKL expression as markers of dendritic cell–t cell interactions in paired samples of rheumatoid synovium and lymph nodes

Abstract

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-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), 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-␥؉, and IL-17؉ cells expressed RANKL, while none expressed RANK. Treatment of synoviocytes with TNF␣ or IL-1␤ in combination with IL-17 was particularly potent at inducing RANKL expression.Conclusion. 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.

Interleukin‐17 in fashion, at last: Ten years after its description, its cellular source has been identified

“…Studies showed increased production of functional IL-17 by RA synovium but also by bone explants, demonstrating the role of T cells in juxtaarticular bone destruction (13,14). Not surprisingly, this effect was associated with RANKL expression by these T cells, which were then able to interact with RANK-expressing cells, osteoclasts, and also mature dendritic cells (14,15). Consistent with the role of IL-17 in chronicity, it was recently shown that in the mouse model of collagen-induced arthritis, IL-17 interacted with TNF in the early phase, whereas at a later stage the disease was mostly IL-17 driven, losing its TNF dependency (16).…”

Interleukin-17 bei chronisch-entzündlichen und autoimmunen Erkrankungen

“…Patienten mit rheumatoider Arthritis (RA) weisen erhöhte Serumspiegel von IL-17 und eine erhöhte IL-17-Produktion mononukleärer Zellen aus dem peripheren Blut (PBMC) auf. T H 17-Zellen wurden in der Synovialflüssigkeit und in der entzündeten Synovia in T-Zell-reichen Arealen bei Patienten mit RA gefunden [3,9,13,14]. Eigene Untersuchungen zeigen IL-17D-produzierende Zellen in …”

Zellbiologische Aspekte der Osteoimmunologie

“…A direct role of dendritic cells in inflammatory bone loss has also been proposed [59]. Dendritic cells aggregate at sites of chronic inflammation where they can interact with T-cells, as observed in rheumatoid arthritis [60] and periodontal disease [61]. Transfer models revealed that activated dendritic cells can cause symptoms of rheumatoid arthritis [62].…”