The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity

Abstract

Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B cells.

Ability of IDO To Attenuate Liver Injury in α-Galactosylceramide–Induced Hepatitis Model

“…In sharp contrast, IDO can act as a mediator of inflammatory disease, particularly in ischemia-reperfusion injury (20). Additionally, it was reported that administration of 1-MT to K/BxN mice reduced the level of inflammatory cytokines and autoantibodies, resulting in an attenuated course of arthritis (21). Thus, IDO has contrasting effects on several types of inflammation models.…”

B-Cell Depletion with CD20 Antibodies as New Approach in the Treatment of Inflammatory and Immunological Events Associated with Spinal Cord Injury

“…The role of B cells and autoimmunity as factors that contribute to neurological outcomes following SCI is poorly understood. The alteration of the local cytokine environment during SCI favors B-cell autoimmunity [57], and B cells produce pathogenic antibodies that impair lesion repair [58], resulting in worse neurological outcome. Therapies that target the B cell or obstruct the effects of pathogenic antibodies have demonstrated to be effective [20,59].…”

Oxidative Processes and Antioxidative Metaloenzymes

“…Firstly, part of O2 •-generated during mitochondrial electron transfer is vectorially released into the intermembrane space [78]. The mechanism underlying the release of O2 •-into the intermembrane space covers the formation of ubisemiquinone at two sites in the ubiquinone pool: the Q1 site that lies near the matrix, and the Qo site in the vicinity of the intermembrane space [154]. Autooxidation of ubisemiqiunone at the Qo site (UQo •-) results in the release of O2 •-through the cytosolic side of the mitochondrial inner membrane.…”