IL-7 and its receptor in T cell and B cell-driven immunity in primary Sjögren’s Syndrome

Abstract

The importance of IL-7 and its receptor has been investigated in several (rheumatic) autoimmune diseases, most extensively in rheumatoid arthritis. Based on growing evidence, it is believed that activation of the IL-7/IL-7R pathway leads to a cascade of immune−enhancing and proinflammatory responses both in vivo and in vitro in relation to these autoimmune diseases. We set out to identify a crucial role for IL-7 and its receptor in the immunopathology of primary Sjögren’s Syndrome (pSS). This research demonstrates that IL-7 and the IL-7R are elevated in the salivary glands of pSS patients and that their presence is strongly correlated to several important inflammatory parameters characteristic for pSS. IL-7 mainly promotes skewing towards the pro-inflammatory Th1 and Th17 immune responses. In suport, we have identified that IL-7R+ CD4 Th cells enhance pro-inflammatory responses in vitro, while IL-7R- CD4 Th cells are regulatory and suppressive in nature. As a consequence of the on-going inflammation in pSS patients, the regulatory IL-7R- CD4 Th cells are increased as an attempt to restore immune balance. Despite this effort, we show that in the presence of IL-7, these cells are not capable to suppress the Th1 and Th17 pro-inflammatory immune responses in vitro. IL-7 is well known for its T cell activating properties, but few data are available on the capacity of IL-7 to induce B cell activation. Here we report that IL-7 stimulates activation and proliferation of B cells in a CD4 T cell-dependent manner. Furthermore, IL-7 is shown to enhance B cell activation by Toll-like receptor 7 (TLR7), another molecule implicated in the immunopathology of pSS. IL-7 and TLR7 co-operate in an additive or even synergistic manner to induce proliferation and activation of CD4 Th cells and B cells, when cultured together. This effect is strongly enhanced by the presence of monocytes/machrophages, and for the secretion of pro-inflammatory cytokines and immunoglobulins, the presence of monocytes/macrophages is required. Surprisingly, TLR7−induced activation of (isolated) B cells can be potently blocked by inhibition of the IL-7/IL-7R pathway (shuIL7-R and human anti-huIL-7 mAb). Finally, we investigated the in vitro changes of in vivo blockade of T and B cell activation in pSS patients treated with leflunomide. In clinical responders to leflunomide a significant decrease of IFNγ and TNFα production is observed. Significant correlations between increased sialometry values and decreased IFNγ and TNFα production are found. Leflunomide reduces levels of inflammatory serum cytokines and CD40L expression, whereas it up-regulates IL-7Rα expression on CD4 T cells with persistent serum IL-7 concentrations. Previously it has been shown that IL-7 aggravates and IL-7/IL-7R blockade inhibits T/B cell−driven autoimmunity in animal models for several autoimmune diseases. This and the data from the current thesis indicate that targeting IL-7 or its receptor are potential novel strategies to prevent the continuing inflammation and immunopathology in pSS.