Background In patients with primary Sjögren’s syndrome (pSS), local T and B cell-driven inflammation contributes to destruction of exocrine glands associated with clinical symptoms of dryness. Recently increased IL-7 and IL7R expression in labial salivary glands (LSG) of pSS patients was documented. IL-7 causes T cell-dependent monocyte activation. Although there are indications that IL-7 affects the activity of developing human B-cells, the effect of IL-7 on mature B cell activation in human autoimmune diseases has not been reported previously. Because B cell activation plays a pivotal role in pSS pathology we investigated the capacity of IL-7 to induce (T cell-dependent) B-cell activation.
Objectives To study the association of proliferating cells and interleukin-7 (IL-7) in the labial salivary gland (LSG) of pSS and non-Sjögren’s syndrome sicca (nSS-sicca) patients and the role of IL-7 in vitro to induce (T cell-dependent) B cell activation in vitro.
Methods LSG from pSS and nSS-sicca patients were stained for Ki67 and correlated to the expression of IL-7. Peripheral blood mononuclear cells (PBMCs) and isolated CD4 T and B cells were analysed for ex vivo expression of the IL-7Rα. Analysis of activation markers (CD25, CD69 and HLA-DR) on CD4 T cells and B cells and proliferation of lymphocytes were determined after culture with IL-7 (3H-thymidine incorporation and Ki67 expression).
Results An increased number of Ki67-proliferating cells per mm2 was found in the LSG of pSS as compared to nSS patients (pSS vs. nSS; 141±24 vs. 49±4, p<0.001), mainly confined to lymphocytic infiltrates. The number of these proliferating cells significantly correlated to the expression of IL-7 in LSG (r=0.643, p<0.001). In contrast to abundant IL-7R expression on CD4 T cells, CD19 B cells did not express IL-7Rα on their surface. In line with this IL-7 did not activate B cells directly, however in PBMC and CD4/CD19 co-cultures IL-7 significantly increased proliferation of and activation markers on both CD4 T cells (Ki67+ cells from 1.1±0.2% to 14.4±3.7%, p<0.01; CD25+ cells from 28.8±4.0% to 79.8±2.4%, p≤0.001; HLA-DR+ cells from 6.3±0.9% to 7.8±1.2%, p<0.05), and CD19 B cells (KI67+ cells from 1.9±0.3% to 4.1±0.9%, p<0.05; HLA-DR MFI from 282±110 to 375±135, p<0.05; mean increase of 37%).
Conclusions To our knowledge, this is the first time that IL-7-induced T cell-dependent activation of mature B cells, which lack membrane expression of IL-7Rα, is demonstrated in humans. Together with the strong association of increased IL-7 expression and proliferating cells in the LSG of pSS, these results suggest that IL-7 is an important mediator in the immunopathology of pSS through activation of both T and indirectly B cells.
Disclosure of Interest None Declared
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