IDO2 drives autoantibody production and joint inflammation by repressing Runx1 function in B cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B597
Abstract ID: 4339

Presenting Author:
Laura Mandik-Nayak , Associate Professor at Lankenau Inst. for Med. Res., Maine Line Hlth.

Abstract:

The immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) is an essential mediator of autoantibody production and joint inflammation in preclinical models of autoimmune arthritis. Although originally identified as a tryptophan catabolizing enzyme, we recently discovered a previously unknown non-enzymatic pathway is essential for IDO2’s pro-arthritic function. Using a two-hybrid screen, we identified the runt-related transcription factor Runx1 as a potential component of the non-enzymatic pathway IDO2 uses to drive arthritis. To directly test if Runx1 mediated the downstream pathway driving B cell activation in arthritis, we bred B cell conditional Runx1 deficient (CD19^creRunx1^flox/flox) mice onto the KRN.g7 arthritis model in the presence or absence of IDO2. Runx1 ko KRN.g7 mice developed robust arthritis and autoantibody levels, with similar timing and overall severity to that seen in KRN.g7 mice expressing Runx1. Importantly, whereas arthritis and autoantibody levels in IDO2 ko KRN.g7 mice are delayed in time of onset and reduced in overall severity, arthritis and autoantibody levels are not reduced in IDO2 ko KRN.g7 mice that also lack Runx1. These data demonstrate that IDO2 is able to drive arthritis in the absence of Runx1 and deleting Runx1 in B cells reverses the anti-arthritic effect of IDO2 loss in this model. Taken together, these data suggest that IDO2 mediates autoantibody production and joint inflammation by acting as a repressor of Runx1 function.