Project description:Autoimmune diseases, such as rheumatoid arthritis, are associated with significant gut microbiota dysbiosis. Here we show that remodelling of 24h rhythms within the gut during inflammatory joint disease drives profound changes in the microbiome and gut permeability.
Project description:The study aimed to identify proteins associated with rheumatoid arthritis. Dysregulated proteins were linked to inflammation, immune response and oxidative stress.
Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 0.5-1% of the adult global population.. Immune and inflammatory tissue damage is the main pathogenic mechanism in RA, and involves a hyperactivation of both innate and adaptive immune systems. Trained immunity, an important feature of the innate immune system, allows the host to mount functionally altered immune responses based on their previous history of immune exposures, independently of the classical adaptive immunological memory. However, the role of trained immunity in systemic autoimmune and inflammatory disorders remains poorly understood, with the effects on monocyte and macrophage differentiation and function being most widely studied. We demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance the counts but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic affecting hematopoietic stem and progenitor cells (HSPCs) and persist independently of the inflammatory disease milieu. Importantly, these trained immunity mechanisms impact not only macrophages but also dendritic cells, which are the major professional antigen presenting cells, bridging the innate and adaptive immune responses. Such mechanisms result in changes in the global transcriptional profiles of dendritic cells, and significantly alter their responses to recall immune stimulation and capacity for T cell activation. This study therefore represents the first demonstration of ‘dendritic cell trained immunity’ in rheumatoid arthritis.
Project description:Single-cell analysis of the transcriptome, T cell immune receptors, and surface proteome (CITE-seq) from peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with pre-existing autoimmune diseases (rheumatoid arthritis n = 5, psoriasis n = 4, or multiple sclerosis n = 3), as well as COVID-19 patients without pre-existing autoimmunity as controls (n = 10) to investigate altered immune responses.
Project description:Periodontitis (PD) is one of the most common human inflammatory diseases, yet the immunological mechanism linking oral and systemic immune responses are not well defined. Here, we show that the accumulation of interleukin-17 (IL-17)-producing γδT (γδT17) cells occurs not only in the oral cavity, but also in the peripheral lymph nodes and spleens in experimental periodontitis in mice. Strikingly, oral γδT17 cells derived from experimental periodontitis migrated to the inflamed joint and led to an exacerbation of rheumatoid arthritis (RA) in a collagen-induced arthritis model in mice. Mechansitically, we demonstrated that the dysbiosis in periodontitis led to an increase in production of complement component 3 (C3)-enriched extracellular vesicles (EVs) derived from macrophages. These C3-enriched EVs were taken up by γδT cells and stimulated intracellular C3a receptor to drive IL-17A production in γδT cells. Our findings revealed an previously unrecognized immunological mechanism linking periodontitis to RA through the accumulation and migration of oral γδT17 cells.
Project description:Lymph node stromal cells (LNSCs) are an important lymphoid tissue cellular type that regulates the immune response and maintain peripheral tolerance. In rheumatoid arthritis, break of tolerance and formation of autoantibodies occurs years before arthritis. Studies in mice have shown lymph nodes activation before the onset of arthritis. We hypothesize that malfunctioning of LNSCs leads to a microenvironment where immune responses are not properly controlled leading to activation of (autoreactive) lymphocytes and the production of autoantibodies. Here we studied human LNSCs and search for differentially methylated genes between RA versus healthy using Illumina human methylation arrays in order to identify new epigenetic targets.
Project description:Lymph node stromal cells (LNSCs) are an important lymphoid tissue cellular type that regulates the immune response and maintain peripheral tolerance. In rheumatoid arthritis, break of tolerance and formation of autoantibodies occurs years before arthritis. Studies in mice have shown lymph nodes activation before the onset of arthritis. We hypothesize that malfunctioning of LNSCs leads to a microenvironment where immune responses are not properly controlled leading to activation of (autoreactive) lymphocytes and the production of autoantibodies. Here we studied human LNSCs and search for differentially expressed genes between RA at risk or RA versus healthy using RNA sequencing in order to identify new therapeutic targets.
