The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity

The Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 182(12):7509-17. DOI: 10.4049/jimmunol.0804328
Source: PubMed


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.

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    • "Moreover, a lot of studies underline the neuroprotective properties of KYNA in animals with experimental brain injury (Darlington et al. 2007; Gellért et al. 2013; Sas et al. 2008). KYNA production is also elevated during a bacterial or viral inflammation, an autoimmune disease and after a severe trauma (Forrest et al. 2006; Hartai et al. 2007; Scott et al. 2009; Zeden et al. 2010). Increases in plasma tryptophan metabolites have also been observed in patients undergoing elective abdominal or cardiac surgery (Forrest et al. 2011; Marfella et al. 1999). "
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    • "In contrast to studies in CIA, studies in the K/BxN model of RA showed that administration of 1-MT resulted in amelioration of arthritis due to a reduced level of autoreactive B cell activity.26 Further analysis revealed that the principal effect of 1-MT was to inhibit the ability of autoreactive B cells to differentiate into autoantibody-secreting cells, but did not influence their initial activation or survival.27 "
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    Preview · Article · Jul 2013 · International Journal of Tryptophan Research
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    • "Although the immune suppressive role of IDO has been generally accepted, increasing amounts of data suggest that IDO serves more than one function in the immune system [34], [35]. Inhibition of IDO activity in the K/BxN murine rheumatoid arthritis model resulted in amelioration rather than exacerbation of the arthritic symptoms with decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course [36]. Specifically, IDO−/− mice and IDO inhibitor (1-methyl-tryptophan)-treated mice have decreased production of proinflammatory cytokines and increased survival from endotoxin shock [37], and IDO activity in bacteremic patients correlates with disease severity and case fatality [38]. "
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