Session Type: Abstract Submissions (ACR)
Interleukin(IL)-7 is increased in synovial fluid from rheumatoid arthritis (RA) patients as compared to osteoarthritis (OA) patients and has been attributed a proinflammatory role, especially due to its well established influence on T cells. However, B cells and synovial fibroblasts (SFs) also possess functional IL-7 receptors and stimulation of IL-7 receptors on B cells increases disease severity in collagen-induced arthritis. However, the mechanisms involved in this proinflammatory effect are not known. We therefore wanted to further characterize the effect of IL-7 on B cell antibody production and on the production of B cell activating factor of the tumor necrosis factor family (BAFF) and IL-6 in synovial fibroblasts (SFs).
Naive splenic mouse B cells were cultured in the presence of different activating stimuli (LPS, anti-IgM, anti-CD40, anti-CD40 + IL-4, antiCD40 + IFN-γ) in the absence or presence of IL-7 added at different timepoints (with the initial stimulus or three days after start of culture) and different concentrations (0.1, 1.0, 10 ng/ml). Levels of antibody isotypes (IgA, IgM, IgG1, IgG2a, IgG2b, IgG3, IgE) and light chains (lambda, kappa) were determined in supernatant by ELISA after 5 days. SFs were isolated from OA (n=15) and RA (n=7) knee joints and cultured in the presence or absence of IFN-γ at different concentrations (0.1, 0.5, 1.0, 5.0, 10, 50 ng/ml) to induce BAFF and IL-6 in the absence or presence of different concentrations of IL-7 (0.01, 0.1, 1.0, 10 ng/ml). BAFF and IL-6 were determined in culture supernatants by ELISA.
IL-7 shows a differential effect on B cell antibody production, depending on the co-stimulus used and the isotype analysed. Most prominent effects were observed when IL-7 was present from the beginning of B cell culture. IL-7 increased IgG2a (p=0.038), IgG3 (p<0.001), and lambda light chains (p=0.024) and decreased kappa light chains (p<0.001) in the presence of concomitant stimulation with IL-4 and anti-CD40. IL-7 further increased LPS-induced IgG3 (p<0.001) and IgE (p<0.001). IL-7 alone was able to induce IgE in B cells to some extent without any additional stimulus (p<0.001). IFN-induced BAFF was increased by IL-7 in a concentration dependent manner in RA (p<0.001) but not OA SFs (p=0.078). However, under hypoxic conditions (O2 2%) both, RA (p<0.001) and OA (p=0.008) SFs increased IFN-induced BAFF production in the presence of IL-7 in a concentration dependent manner. In contrast, IFN-induced IL-6 was not altered in SFs in the presence of IL-7.
Effects of IL-7 on the B cell compartment in arthritis can be direct by modulation of isotype production or indirect by increasing BAFF production in SFs. Therefore, IL-7 not only plays a role in modulating T cells but also modulates B cell function in arhtritis and therefore might be a valuable drug target.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-7-modulates-b-cell-immunoglobulin-isotype-production-and-increases-b-cell-activating-factor-of-the-tumor-necrosis-factor-family-baff-in-synovial-fibroblasts-from-osteoarthritis-oa-and-rheumatoi/