Article
IL-21-expressing effector T cells drive B-cell dysregulation in the joints of patients with Antinuclear Antibody positive Juvenile Idiopathic Arthritis
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Authors
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Jonas Fischer
- University Hospital Würzburg, Pediatric Rheumatology, Würzburg
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Johannes Dirks
- University Hospital Würzburg, Pediatric Rheumatology, Würzburg
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Annette Holl-Wieden
- Universitäts-Kinderklinik Würzburg, Kinderrheumatologie, Würzburg
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Stephan Hackenberg
- University Hospital Würzburg, Department of Otorhinolaryngology, Head and Neck Surgery, Würzburg
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Hermann Girschick
- Vivantes Klinikum im Friedrichshain, Klinik für Kinder- und Jugendmedizin, Berlin
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Henner Morbach
- Universitäts-Kinderklinik, Würzburg
| Published: | October 8, 2019 |
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Outline
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Background: Antinuclear antibody (ANA) positivity encompass a clinically homogenous group of patients with juvenile idiopathic arthritis (JIA) characterized by early diseases onset, high risk of uveitis and female preponderance. However, less is known whether ANA+ JIA patients also share a common disease pathogenesis. Our aim was to analyze the cytokine pattern and phenotype of CD4+ T cells in the synovial fluid of ANA+ JIA patients.
Methods: Mononuclear cells were separated from peripheral blood and synovial fluid of 32 JIA patients. The phenotype and cytokine profile of synovial fluid CD4+ cells was analyzed by flow cytometry and compared between JIA subgroups and to TFH cells derived from tonsils. The functional impact of T-cell subsets on B cell activation was assessed in in vitro assay using sorted T cells and B cells.
Results: ANA+ JIA patients showed increased frequencies of IL-21 expressing synovial fluid CD4+ T cells compared to ANA- patients. These IL-21+ CD4+ T-cells co-expressed IFN-y and TNF-a but not IL-17. IL-21 expression of CD4+ synovial fluid T-cells was confined to a PD-1hi T-cell subset which could mimic follicular helper cells (TFH). However, unlike tonsillar TFH cells, synovial fluid PD-1hi T-cells did not express CXCR5 or BCL-6 and rather displayed a phenotype of effector memory T-cells. Both, tonsillar TFH cells and synovial fluid PD-1hi T-cells induced plasma cell differentiation in vitro, however, unlike classical TFH cells the synovial fluid PD-1hi T-cells additionally shifted B-cells towards a CD21lo/-CD11c+T-bet+ B-cell phenotype in vitro. Additionally, CD21lo/-T-bet+ atypical memory B-cells were enriched in the joints of ANA+ JIA patients and their frequency significantly correlated with the presence of IL-21 expressing CD4+ T-cells.
Conclusion: A distinct population of poly-functional “Th-1/21” effector T-cell cells are expanded in the synovial fluid of ANA+ JIA patients. The correlation between this T-cell subset and CD21lo/- T-bet+ atypical memory B-cells and the presence of ANAs suggests a role of these T-cells in the uncontrolled activation of autoreactive B cells. Additionally, IL-21 expression in activated CD4+ effector T-cells seems to be a characteristic signature in the joints of ANA+ JIA patients.
