Indoleamine 2,3-dioxygenase 2, a novel mediator of pathogenic autoantibodies in autoimmune arthritis (BA12P.110)

Abstract

Several autoimmune disorders, including rheumatoid arthritis (RA), are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. We examined the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of autoimmune arthritis by comparing the effects of both genetic knockout models and chemical inhibitors of IDO on joint inflammation. We find that IDO2, but not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Specifically, IDO2 knockout mice display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirmed that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Future work will define the relevant cell types for IDO2 activity. Our results provide the first insights into the previously unknown function of IDO2 by defining its pathogenic contributions to autoantibody-mediated autoimmunity.