Investigating lactate as an inflammatory early signal in ectopic lymphoid neogenesis and its translational impact in patients with autoimmune diseases

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Ectopic lymphoid-like structures (ELS) are defined as lymphomonocytic cell clusters forming at sites of chronic inflammation which acquire phenotypic (i.e. segregation of T and B lymphocytes in discrete areas with differentiation of networks of stromal-derived follicular dendritic cells) and functional (i.e germinal centres) features of secondary lymphoid organs. The formation of ELS has been described in organ-specific autoimmune conditions, solid tumorigenesis, in chronic infections and graft rejection. In the context of Sjogren's syndrome (SS), the second most common rheumatic autoimmune disease with a prevalence between 100,000-250,000 in UK and a predominance in women (female to male ration 9:1), ELS develop in the salivary glands in 30/40% of the patients. In SS, the presence of ELS with germinal centres is associated with a more severe disease and a 16-fold higher risk of B cell lymphoma, frequently arising in the affected glands. The mechanisms of ELS formation are largely unknown but appear to be the result of the progressive accumulation and organization of T and B cells within chronically inflamed tissue whereby the activation of the lymphotoxin/lymphoid chemokine feedback loop is triggered by pro-inflammatory cytokines, most notably IL-17 and IL-17 related cytokines such as IL-22. These mediators are primarily released by CD4+ T cells which are critical also for the cognate interaction with B cells and the development of ectopic germinal centres. In previous work (as well as work currently under re-review at Cell Metabolism) we demonstrated that lactate, whose accumulation is a typical feature of chronically inflamed tissues, modulate CD4+ T cells via the specific lactate transporter SCL5A12 promoting an expansion of Th17 cells and their retention as site of inflammation. Thus, in this application, which is a Partnership between 2 UK Universities, we plan to perform a series of comprehensive ex vivo, in vivo and in vitro studies with the aim to: 1) investigate whether salivary glands and peripheral SLC5A12 and IL-17 expression in CD4+ T-cells is differentially regulated in ELS+ vs ELS- SS patients and in responders vs non-responders to B cell depletion; 2) assess the impact of knocking out SLC5A12 (genetic approach) and the therapeutic potential of blocking SLC5A12 (pharmacological approach) in modulating ELS in an inducible murine model of salivary gland ELS and in SS salivary gland organ cultures; 3) dissect the metabolic pathways underlying the observed effects of lactate/SLC5A12 on CD4+ T-cells from SS patients.Overall, this proposal will highlight the importance of a novel key pathway linking metabolism and immune cell function by addressing its impact on the development of immunopathology lesions which are extremely relevant to SS and common to many chronic autoimmune/inflammatory diseases. In the short term, it is envisaged that, if successful, this work will bring new knowledge to a poorly investigated field and to a condition, SS, which is considered an orphan disease with clear unmet knowledge and clinical needs. Importantly, our work has the potential to impact on other medical conditions characterised by the formation of ELS, including cancer, chronic infection and graft rejection. We also anticipate that by showing "clinical" and biological efficacy of blocking the lactate/SLC5A12 pathway with a novel anti-SLC512 monoclonal antibody - which we developed - in a murine model of ELS and in human organ cultures, in the long term we will pave the way towards translation of our research towards patient benefit.