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

Authors

  • Guillaume Page,

    1. INSERM U403, Unité mixte Hospices civils de Lyon-BioMérieux, and Hôpital Edouard Herriot, Lyon, France
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  • Pierre Miossec

    Corresponding author
    1. INSERM U403, Unité mixte Hospices civils de Lyon-BioMérieux, and Hôpital Edouard Herriot, Lyon, France
    • Clinical Immunology Unit, Departments of Immunology and Rheumatology, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France
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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-1β (IL-1β), tumor necrosis factor α (TNFα), 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-γ+, and IL-17+ cells expressed RANKL, while none expressed RANK. Treatment of synoviocytes with TNFα or IL-1β 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.

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