Abstract
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.
Highlights
In contrast to Godin-Ethier et al [222], Nouël and coworkers [65] reveal a novel regulatory pathway in B cells, mediated by the TGF-β/IDO1 axis in a CTLA-4 dependent manner. They showed for the first time that CTLA-4 induced B-cells can produce IDO1 and become effective induced regulatory B cells, which were able to generate T regulatory cells (Tregs), Tr1, and Th3 cells when were cocultured with T cells, whereas they suppress the induction of Th1 cells
Tregs, which have an important role in repressing these autoreactive T cells in healthy conditions, show a reduced suppressive capacity in patients with type 1 diabetes mellitus (T1DM) [238], suggesting that insufficient immune regulation can be the reason for an intensified autoimmune response exerted by autoreactive T cells
Autoimmune diseases typically result from the loss of self-tolerance, which leads to the generation of self-reactive lymphocytes and the production of autoantibodies that cause tissue damage
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. T1DM is characterized by aberrant immune responses to specific β-cell autoantigens, resulting in insulin deficiency and hyperglycemia, which develops through the interplay of genetic susceptibilities and environmental factors. AAD is the major cause of primary adrenal insufficiency, which is diagnosed with low basal serum cortisol, high plasma adrenocorticotropic hormone (ACTH) concentrations, and impaired cortisol secretion after ACTH stimulation test. Another essential condition for the diagnosis is the presence of autoantibodies to 21hydroxylase (21-OHAbs); adrenal cortex autoantibodies may be detected in 40–80% of patients with ADD. Special attention was paid to the role played by IDO1 and KP metabolites in the onset and progression of autoimmune endocrinopathies
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