Phagocyte-derived S100A12 complexes and T cell expression of IL-17/IFNγ as factors linking innate and adaptive immune dysregulation in systemic Juvenile Idiopathic Arthritis (sJIA)

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Systemic Juvenile Idiopathic Arthritis (sJIA) is the most severe form of rheumatic joint disease in childhood. In its systemic phase, it is an autoinflammatory disease with significant morbidity. We have previously shown that phagocyte-derived calcium-binding S100 proteins contribute to autoinflammation in this initiation phase. S100A12 spontaneously released from autoinflammatory patient neutrophils is a pro-inflammatory "alarmin" that activates monocytes via Toll-like receptor 4 (TLR4) signalling and appears at high concentrations in active sJIA serum. Importantly, we just demonstrated that serum S100A12, in concert with particularly IL-1b and IL-18, can promote overexpression of ydT cellular IL-17 in sJIA. IL-17 overexpression by ydT cells appears particularly sensitive to therapeutic IL-1b blockade. On the contrary, sJIA CD4+ T cells did not reveal increased IL-17 expression but mounted a surprisingly limited IFNy response. Our patient data are in striking line with a recently proposed sJIA mouse model, which presented its most pronounced clinical phenotype on IFNy-/- background and depends on IL-17 expressing ydT cells in disease pathology. IFNy is considered as potential master-switch in sJIA: Murine model as well as our patient data indicate low levels to contribute to the progression of autoimmune arthritis, while IFNy-overexpression may drive macrophage activation syndrome (MAS) as one of the most severe systemic sJIA complications. Our present proposal aims to understand the skewing of T cellular cytokine expression in sJIA, with emphasis on dysbalanced IFNy. CD4+ T cells will be studied for lineage differentiation and expansion of cytokine expressing cells, particularly in presence of serum factors such as S100A12, IL-1, IL-18 and IL-6 as over-expressed in sJIA, or IL-7 and IL-15 as differentially regulated by S100A12. Further, we will investigate the contribution of CD8+ T cells to cytokine signatures in sJIA and their role in modulating cytokine expression by CD4+ T cells. Yet unpublished data from our sJIA-patient studies suggest a massive upregulation of IFNy by particularly CD8+ T cells and these cells to negatively regulate CD4+ T cellular cytokine expression. Finally we aim to sudy the contribution of S100A12 to disease development in the sJIA mouse model, utilizing S100A12tg animals on wildtype as well as IFNylow or IFNy-/- background. Our overall goal is to understand whether the sterile inflammatory environment in sJIA, characterized by a strong overexpression of the endogenous TLR4 ligand S100A12, can result in a unique cytokine environment polarizing IL-17 and IFNy production to distinct cell populations, which are crucial for sJIA pathogenesis. Understanding the cross-talk between innate and adaptive immunity may help to better understand the natural course of this debilitating disease and foster the generation of more targeted approaches to monitor and treat sJIA.