The Central Role of the Tryptophan Metabolic Pathway in Tolerance and Immunity to Fungi

The inflammatory/anti-inflammatory state of DC is strictly controlled by the metabolic pathway involved in tryptophan catabolism and mediated by the enzyme IDO. IDO has a complex role in immunoregulation in infection, pregnancy, autoimmunity, transplantation, and neoplasia (Mellor & Munn, 2004). IDO-expressing DC are regarded as regulatory DC specialized to cause antigen-specific deletional tolerance or otherwise negatively regulating responding T cells. In experimental fungal infections IDO blockade greatly exacerbated infections, the associated inflammatory pathology and swept away resistance to reinfection, as a result of deregulated innate and adaptive immune responses caused by the impaired activation and functioning of suppressor CD4+ CD25+ Treg cells producing IL-10 (Bozza et al., 2005; Montagnoli et al., 2006). The results provide novel mechanistic insights into complex events that, occurring at the fungus-pathogen interface, relate to the dynamics of host adaptation by fungi. The production of IFN-y may be squarely placed at this interface, where IDO activation likely exerts a fine control over inflammatory and adaptive antifungal responses.

The implication for IDO in immunoregulation in candidiasis may help to accommodate several, as yet unexplained findings. As C. albicans is a commensal of the human gastrointestinal and genitourinary tracts and IFN-y is an important mediator of protective immunity to the fungus, the IFN-y/IDO axis may accommodate fungal persistence in a host environment rich in IFN-y. In its ability to downregulate anti-fungal Th1 response in the gastrointestinal tract, IDO behaves in a fashion similar to that described in mice with colitis where IDO expression correlates with the occurrence of local tolerogenic responses. Alternatively, the high levels of IL-10 production, such as those seen in patients with CMC, may be a consequence of IDO activation by the fungus, impairing antifungal Th1 immunity and thus favoring persistent infection (Romani & Puccetti, 2006b). In aspergillosis, the level of inflammation and IFN-y in the early stage set the subsequent adaptive stage by conditioning the IDO-dependent tolerogenic program of DC and the subsequent activation and expansion of tolerogenic Treg cells preventing allergy to the fungus. Therefore, regulatory mechanisms operating in the control of inflammation and allergy to the fungus are different but interdependent as the level of the inflammatory response early in infection may impact on susceptibility to allergy, in conditions of continuous exposure to the fungus. Early Treg cells, by affecting IFN-y-production, indirectly exert a fine control over the induction of late tolerogenic Treg cells. Thus, a unifying mechanism linking natural Treg cells to tolerogenic respiratory Treg cells in response to the fungus is consistent with the revisited 'hygiene hypothesis' of allergy in infections, and may provide at the same time mechanistic explanations for the significance of the variable level of IFN-y seen in allergic diseases and asthma and for the paradoxical worsening effect on allergy of Th1 cells. IDO has a unique and central role in this process as it may participate in the effector and inductive phases of anti-inflammatory and tolerogenic Treg cells.

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Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

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