Fig 1.
Loss of immune tolerance compromises immune homeostasis and results in the onset of autoimmune disorders. Host invasion by pathogens or trauma initially stimulate prostaglandins (PGs) and initiate early events in acute inflammation. Inflammatory leucocytes migrate to the inflamed site or area of tissue damage, with neutrophils being the first cell types at the scene (A). Secretion of leucotrienes (LTB4) and chemokines promotes the recruitment of more phagocytes. Once pathogens are killed or phagocytosed, neutrophils are cleared from the inflamed site by returning to the circulation or suffering apoptosis and subsequent phagocytosis by newly migrated macrophages, following an active program of resolution, where lipoxins (LXA4) and other lipid mediators play a major role (B). If inflammation is not maintained under control or complete resolution fails, acute inflammation can lead to chronic inflammation, scarring and eventual loss of tissue function. A further damage arises from potential autoimmune responses occurring during the chronic inflammatory response, in which the antigen presenting cells (APC) and molecules that respond to pathogen-derived antigens can also cross-react to self-antigens (C). Progression of the autoimmune response (multiple sclerosis is shown as example) involves the development of self-reactive T helper 1 (Th1) cells (D), their entry into the central nervous system (or target tissue), release of proinflammatory cytokines (tumour-necrosis factor-α (TNFα) and interferon-γ (IFNγ/)) and chemokines and subsequent recruitment and activation of inflammatory cells (macrophages and neutrophils), which produce cytotoxic factors, such as cytokines, nitric oxide and free radicals (E). Finally, regulatory T (Treg) cells are key players in maintaining tolerance by their suppression of self-reactive Th1 cells (F). Unbalance of Treg versus Th1 cells, and/or of anti-inflammatory cytokines versus proinflammatory factors, is the cause of autoimmune disorders. Therapeutic opportunities to manage inflammatory and autoimmune disorders should be found in agents that regulate inflammation resolution, control Th1 expansion, inhibit inflammatory mediators and/or induced Treg cell generation. Interleukin-10, IL-10; transforming growth factor-β, TGFβ; cytotoxic T lymphocyte associated antigen 4, CTLA4; T cell receptor, TCR.