The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis through a Nonenzymatic Mechanism.

IDO2 is one of two closely related tryptophan catabolizing enzymes induced under inflammatory conditions. In contrast to the immunoregulatory role defined for IDO1 in cancer models, IDO2 has a proinflammatory function in models of autoimmunity and contact hypersensitivity. In humans, two common single-nucleotide polymorphisms have been identified that severely impair IDO2 enzymatic function, such that <25% of individuals express IDO2 with full catalytic potential. This, together with IDO2's relatively weak enzymatic activity, suggests that IDO2 may have a role outside of its function in tryptophan catabolism. To determine whether the enzymatic activity of IDO2 is required for its proinflammatory function, we used newly generated catalytically inactive IDO2 knock-in mice together with established models of contact hypersensitivity and autoimmune arthritis. Contact hypersensitivity was attenuated in catalytically inactive IDO2 knock-in mice. In contrast, induction of autoimmune arthritis was unaffected by the absence of IDO2 enzymatic activity. In pursuing this nonenzymatic IDO2 function, we identified GAPDH, Runx1, RANbp10, and Mgea5 as IDO2-binding proteins that do not interact with IDO1, implicating them as potential mediators of IDO2-specific function. Taken together, our findings identify a novel function for IDO2, independent of its tryptophan catabolizing activity, and suggest that this nonenzymatic function could involve multiple signaling pathways. These data show that the enzymatic activity of IDO2 is required only for some inflammatory immune responses and provide, to our knowledge, the first evidence of a nonenzymatic role for IDO2 in mediating autoimmune disease.

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses.

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function. Indeed, IDO2, like IDO1, is necessary for the differentiation of regulatory T cells in vitro. However, compared to IDO1, in vivo studies demonstrated a contrasting role for IDO2, with experiments in preclinical models of autoimmune arthritis establishing a proinflammatory role for IDO2 in mediating B and T cell activation driving autoimmune disease. Given their potentially opposing roles in inflammatory responses, interpretation of results obtained using IDO1 or IDO2 single knockout mice could be complicated by the expression of the other enzyme. Here we use IDO1 and IDO2 single and double knockout (dko) mice to define the differential roles of IDO1 and IDO2 in B cell-mediated immune responses. Autoreactive T and B cell responses and severity of joint inflammation were decreased in IDO2 ko, but not IDO1 ko arthritic mice. Dko mice had a reduction in the number of autoantibody secreting cells and severity of arthritis: however, percentages of differentiated T cells and their associated cytokines were not reduced compared to IDO1 ko or wild-type mice. These data suggest that autoreactive B cell responses are mediated by IDO2, while autoreactive T cell responses are indirectly affected by IDO1 expression in the IDO2 ko mice. IDO2 also influenced antibody responses in models of influenza infection and immunization with T cell-independent type II antigens. Taken together, these studies provide evidence for the contrasting roles IDO1 and IDO2 play in immune responses, with IDO1 mediating T cell suppressive effects and IDO2 working directly in B cells as a proinflammatory mediator of B cell responses.

The population dynamics of black-white-mulatto racial systems.

Building on Preston and Campbell's two-sex model of intergenerational transmission, this article provides a theoretical analysis of the dynamics of the racial distribution in black-white-mulatto systems. The author shows that "bounded" patterns of racial classification and switching imply long-run racial homogeneity in the absence of differential reproduction. Beyond the theoretical analysis, the author attempts to account for the dramatic growth of the white population share in Puerto Rico in the early 20th century. Because the effects of racial classification and differential reproduction were roughly offsetting, the observed growth of the white share can be attributed almost entirely to racial switching.