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)
Immunology
Rheumatology
Final Report Abstract
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 drive autoinflammation in this initiation phase. S100A12 spontaneously released from autoinflammatory patients’ 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 γδT cellular IL-17 in sJIA. IL-17 overexpression by γδT 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 IFNg response. Our patient data are in striking line with a recently proposed sJIA mouse model, which presented its most pronounced clinical phenotype on IFNg-/- background and depends on IL-17 expressing γδT cells in disease pathology. IFNg 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 IFNg-overexpression may drive macrophage activation syndrome (MAS) as one of the most severe systemic sJIA complications. Addressing the central question whether and to what extend the sJIA serum factor and immune cell environment may impact T cell differentiation and effector phenotypes in disease, we found that our earlier observations on reduced CD4 T cellular IFNγ-expression may indeed result from an aberrant differentiation of particularly the Th1 lineage in sJIA. We further report, that depletion of IFNγ does indeed benefit γδT cellular IL-17A expression. These data illustrate, that in the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a phenotype more common in classical autoimmunity may indicate mechanisms driving progression towards chronic destructive arthritis. While these observations were very much in line with our initial hypothesis, our observations on the level of cytotoxic T cells contradicted our proposal, as those indicated an exhaustion phenotype even present in inactive disease, rather than T cellular overactivation. Beyond, our project was very much affected by the COVID pandemic. In direct response to this we demonstrated, that IFNg-related signatures and other dysregulated markers in sJIA-associated MAS clearly separate this from the cytokine storm in COVID-19, which helped to inform on determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions associated with severe SARS-CoV-2 infections.
Publications
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Die Rolle des endogenen TLR4-Liganden S100A12 für die IL-17A-Expression durch T-Zellen in der systemischen juvenilen idiopathischen Arthritis (sJIA)
Niklas Gruen
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Definition and validation of serum biomarkers for optimal differentiation of hyperferritinaemic cytokine storm conditions in children: a retrospective cohort study. The Lancet Rheumatology, 3(8), e563-e573.
Kessel, Christoph; Fall, Ndate; Grom, Alexei; de Jager, Wilco; Vastert, Sebastiaan; Strippoli, Raffaele; Bracaglia, Claudia; Sundberg, Erik; Horne, AnnaCarin; Ehl, Stephan; Ammann, Sandra; Wouters, Carine; Lehmberg, Kai; De Benedetti, Fabrizio; Park, Carolin; Hinze, Claas; Wittkowski, Helmut; Kessel, Katharina; Beutel, Karin ... & Holzinger, Dirk
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Discrimination of COVID‐19 From Inflammation‐Induced Cytokine Storm Syndromes Using Disease‐Related Blood Biomarkers. Arthritis & Rheumatology, 73(10), 1791-1799.
Kessel, Christoph; Vollenberg, Richard; Masjosthusmann, Katja; Hinze, Claas; Wittkowski, Helmut; Debaugnies, France; Nagant, Carole; Corazza, Francis; Vély, Frédéric; Kaplanski, Gilles; Girard‐Guyonvarc’h., Charlotte; Gabay, Cem; Schmidt, Hartmut; Foell, Dirk & Tepasse, Phil‐Robin
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Aberrant Naive CD4 –Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help. Arthritis & Rheumatology, 75(5), 826-841.
Kuehn, Julia; Schleifenbaum, Susanne; Hendling, Michaela; Siebenhandl, Sandra; Krainer, Julie; Fuehner, Sabrina; Hellige, Antje; Park, Carolin; Hinze, Claas; Wittkowski, Helmut; Holzinger, Dirk; Thurner, Lorenz; Weinhäusel, Andreas; Foell, Dirk & Kessel, Christoph
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Cytotoxic T cell phenotyping reveals overactivation and exhaustion as potentially inherent features in systemic JIA. Pediatric Rheumatology 21:122
A. Swoboda, S. Schleifenbaum, C. Hinze, H. Wittkowski, D. Foell & C. Kessel
