Brief Report: Innate lymphoid cells and T-cells contribute to the IL-17A signature detected in the synovial fluid of patients with Juvenile Idiopathic Arthritis

OBJECTIVE: Evidence suggests that aberrant function of innate lymphoid cells (ILC), whose functional and transcriptional profile overlap with T helper (Th) cell subsets, contribute to immune-mediated pathologies. To date, analysis of Juvenile Idiopathic Arthritis (JIA) immune-pathology has concentrated on the contribution of CD4+ T-cells; we have previously identified an expansion of Th17 cells within the synovial fluid (SF) of JIA patients. Here, we extend this analysis to investigate a role for ILC and other IL-17 producing T-cell subsets. METHODS: ILC and CD3+ T-cell subsets were defined in peripheral blood mononuclear cells (PBMC) (healthy adult, healthy child and JIA patients) and JIA SF mononuclear cells (SFMC) using flow cytometry. Defined subsets in SFMC were correlated with clinical measures including physician's visual analogue scale (VAS), active joint count and erythrocyte sedimentation rate (ESR). Transcription factor and cytokine profiles of sorted ILC were assessed by qPCR. RESULTS: Group 1 ILC (ILC1), NKp44-group 3 ILC (NCR-ILC3) and NKp44+group 3 ILC (NCR+ILC3) were enriched in the JIA-SFMC compared to PBMC, which corresponded with an increase in transcripts for TBX21, IFNG and IL17A. Of the ILC subsets, NCR-ILC3 frequency in JIA-SFMC displayed the strongest positive association with clinical measures which was mirrored by an expansion in IL-17A+CD4+, IL-17A+CD8+ and IL-17A+γδ T-cells. CONCLUSION: We demonstrate that the strength of the IL-17A signature in JIA-SFMC is determined by multiple lymphoid cell-types, including NCR-ILC3, IL-17A+CD4+, IL-17A+CD8+ and IL-17A+γδ T-cells. These observations may have important implications for the development of stratified therapeutics. This article is protected by copyright. All rights reserved

Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273

BACKGROUND: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. METHODS: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. RESULTS: OCR-treated MS patients exhibit a preserved recall response of CD8(+) T central memory cells following first vaccination compared to HCs and a similar CD4(+) circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4(+) and CD8(+) T cells. CONCLUSIONS: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8(+) T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. FUNDING: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871)

CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNa) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNa may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype

Aanvullend archeologisch onderzoek in het plangebied Herkenbosch-Schaapsweg

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Aanvullend archeologisch onderzoek te Herkenbosch-centrum

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Aanvullend archeologisch onderzoek Maurik, gemeente Buren

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