Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity - PubMed

Establishment of rheumatoid arthritis (RA): Mechanisms of disease initiation, development, and progression. (A) Multiple risk factors, including both genetic and non-genetic influences, are required to induce the development of RA in susceptible individuals. Years before first clinical symptoms of RA occur, autoimmunity against modified self-proteins is initiated, which results in the onset of a subclinical inflamed synovium (symptomatic autoimmunity) propagated by immune cell infiltration and pannus formation. Once established, RA can be classified according to the clinical symptoms. (B) Onset of autoimmunity is supposed to occur in the mucosa (e.g., mouth, lung, and gut) by the creation of neo-epitopes as a result of post-translational modifications, e.g., by citrullination. These neo-epitopes can be recognized by antigen-presenting cells (APCs) of the adaptive immune system and (C) are presented to adaptive immune cells in lymphoid tissues, activate an immune response, and induce autoantibody formation (e.g., ACPA and RF). (D) Activated immune cells and immune complexes can activate synovial cells, such as fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes of the intimal lining and APCs in the sublining area, to produce a range of inflammatory factors and expand and form the cartilage- and bone-invasive pannus. Autoimmune activation and immune cell infiltration (T cells, B cells, macrophages) of the sublining area further contribute to the excessive production of inflammatory factors, autoantibodies, and synovial vascular leakage, ultimately leading to articular cartilage and subchondral bone destruction as a result of matrix-degrading enzymes and a de-balanced bone homeostasis characterized by an imbalanced RANKL/RANK/OPG system and activated osteoclasts. ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; APCAs, anti-citrullinated protein antibodies; RF, rheumatoid factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NO, nitric oxide; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand; RANK, receptor activator of nuclear factor-κB; TCR, T cell receptor; TNF, tumor necrosis factor. Figure contains graphics from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License.

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