RESEARCH - The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity

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J Immunol. 2009 Jun 15;182(12):7509-17.

The immunoregulatory enzyme IDO paradoxically drives B cell-mediated

autoimmunity.

GN, DuHadaway J, Pigott E, Ridge N, Prendergast GC, Muller AJ,

Mandik-Nayak L.

The Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.

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.

PMID: 19494274

http://www.ncbi.nlm.nih.gov/pubmed/19494274

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