Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Increased Expression of the High Affinity IL-7 Receptor Alpha in Inflamed Joints of RA Patients Mediates Immune Activation That Is Blocked by Soluble IL-7R
van Roon, Joel A. G., Hartgring, Sarita A. Y., Wenting, Marion J. G., Jacobs, Kim M. G., Bijlsma, Johannes W. J., Lafeber, Floris P. J. G.
IL-7, a member of the IL-2 family, is a potent T cell stimulatory cytokine. Increased IL-7 levels are found in several inflammatory diseases including rheumatoid arthritis (RA). IL-7 effects are essentially mediated through the high affinity IL-7receptor-a chain (IL-7Ra) in conjunction with the common-gamma chain (gc). IL-7 stimulates proliferation, survival and differentiation of T cells and induces T-cell dependent monocyte, B cell activation and osteoclast formation. In addition, IL-7 induces TNFa dependent and independent immune activation. Our purpose was to evaluate the expression and the functional ability of the IL-7Ra in patients with RA.
IL-7Ra expression was determined by immunohistochemistry in synovial tissue of patients with RA (n=24), undifferentiated arthritis (n=27), and osteoarthritis (OA, disease control, n=15). In addition, CD3 and IL-7 expression was assessed by IHC. IL-7Ra expression on CD4 T cells, CD19 B cells and CD14 monocyte/macrophages from RA synovial fluid (SF), synovial tissue (ST) and peripheral blood (PB) was determined. Also, the proliferative capacity and FoxP3 expression of IL-7Rabright and IL-7Radim/- T cells was evaluated. Furthermore, the capacity of IL-7Ra blockade to prevent activation of CD4 T cells was studied in vitro.
Significantly higher IL-7Ra expression in the synovial tissue of RA and UA as compared to OA patients was found (both p<0.001). The IL-7Ra expression significantly correlated with CD3 and IL-7 expression levels in the synovial tissue (r = 0.769, p<0.001; r = 0.561, p< 0.001, resp). CD4 T cells from RA synovial fluid and tissue strongly expressed IL-7Ra. T cells from RA ST and SF predominantly expressed the IL-7Ra. In contrast to their circulating counterparts, a substantial percentage of B cells and macrophages from the synovial fluid and tissue also expressed IL-7Ra, although less prominent than T cells.
Interestingly, we found that IL-7Rabright T cells from blood that did not express FoxP3 were highly proliferating as compared to IL-7Radim/- T cells that expressed high levels of FoxP3. Finally, soluble human IL-7Ra inhibited IL-7-induced proliferation and IFNg production by mononuclear cells from RA patients.
Increased IL-7Ra expression in patients with RA could contribute to synovitis. IL-7 can activate IL-7Rabright arthritogenic T cells, overriding suppressive effects of IL-7Radim/- T cells as we have previously shown for CD25+ Tregs. In addition, decreased CD4 T-cell activation was achieved by inhibition of IL7Ra-mediated immune activation by soluble human IL-7Ra, indicating the therapeutic potential of targeting IL-7/IL-7Ra.
To cite this abstract, please use the following information:
van Roon, Joel A. G., Hartgring, Sarita A. Y., Wenting, Marion J. G., Jacobs, Kim M. G., Bijlsma, Johannes W. J., Lafeber, Floris P. J. G.; Increased Expression of the High Affinity IL-7 Receptor Alpha in Inflamed Joints of RA Patients Mediates Immune Activation That Is Blocked by Soluble IL-7R [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1089