The Effect of Immunosuppressive Therapy on MAP Infection

Anti-inflammatory agents such as anti-TNF- α and corticosteroids are common effective treatments for Crohn's disease. These treat­ments are also recognized to have immunosup­pressive effects.

2012). Indeed, Crohn's disease patients treated with TNF-α inhibitors are at an increased risk of tuberculosis when compared with untreated individuals (Cao et al., 2018). The lack of re­ported disseminated MAP infection following immunosuppressive therapy has served as a strong argument against its potential link with Crohn's disease. However, there is evidence to suggest that MAP responses to immunosup­pressive therapy may not follow the established paradigm of other mycobacteria. Research us­ing calf infection models have suggested that prior depletion of CD4 cells has no effect on MAP disease progression (Allen et al., 2011); this stands in stark contrast to the expectation from the human literature on AIDS-associated CD4 depletion and M. avium disease. An addi­tional observation is that M. leprae, the cause of leprosy, has not been reported to cause dissemi­nated disease following anti-TNF-α and steroid treatments (Athreya, 2007); indeed, anti-TNF- α has been used as an adjunctive therapy to manage hyperinflammatory phenotypes of leprosy, albeit while also receiving antimicro­bial therapy. In this section we will review the recent research which has aimed to under­stand anti-TNF-α in MAP infection.

Several studies have suggested that Crohn's disease immunosuppressive therapies lead to a measurable decrease in MAP infection status. Bach et al. (2011) demonstrated that subjects with Crohn's disease had significantly higher ti­tres of antibodies against the MAP proteins PtpA and PknG when compared with controls and that these antibodies were decreased in those who were treated with infliximab (Bach et al., 2012).

In order to understand the effect of TNF-α inhibitors, more research is required to deline­ate the role of TNF-α in host responses to MAP. Recent studies have suggested that MAP infec­tion modulates TNF-α production to support its survival in the host, potentially explaining how anti-TNF-α treatments may negatively impact MAP. The gut culture supernatant TNF-α levels are increased in Crohn's disease patients positive for MAP when compared with MAP-negative patients (Clancy et al., 2007). Human macrophages have been shown to se­crete increased levels of TNF-α when infected with MAP, but not when infected with other mycobacteria such as M. avium (Nakase et al., 2011). Additionally, two SNPs in the TNF-α re­ceptor, which were previously associated with undesired outcomes of anti-TNF-α therapy, have been associated with increased suscep­tibility to infection with MAP (Qasem et al., 2019). In opposition to this argument how­ever, Campos et al. (2011) found that mac­rophages from Crohn's disease patients had a defective TNF-α response to MAP compared with healthy controls, although this effect was not specific to bacterial challenge with MAP.

Taken together, recent data suggest that a lack of observed MAP dissemination following immunosuppressive treatments neither proves nor disproves a potential role of MAP in Crohn’s disease. More research is required to elucidate the role of TNF-α in MAP pathogenesis and how this may further our understanding of patient responses to anti-TNF-α therapy.

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