MAP Immune Responses in Crohn’s Disease Patients
Immune responses that might be detectable in Crohn's disease include humoral and cell-mediated responses. In serological studies, Verdier et al. (2013) found significantly increased IgG against four MAP antigens (glycosyl-transferase-d, Johnin-purified protein derivative (PPD), heparin-binding haemagglutinin, L5P) in gut lavage fluids.
Another study also found a positive association in antibody titres against two MAP antigens (MAP3865C133141 and MAP3 8 6 5125 133) (Zamani et al., 2017). Lefranqois et al. (2011) described a MAP laminin-binding/histone-like protein (Lbp/Hlp) that is bound by serum antibodies of patients with Crohn's disease. In addition, Xia et al. (2014) found that anti-PtpA antibodies were significantly increased in Crohn's disease patients compared with healthy controls. However, many of these antigens are also found in other mycobacterial species. Therefore, seropositivity may not indicate reactivity to MAP but rather crossreactivity due to previous exposure with another mycobacteria. These studies are also limited by the fact that detection of MAP-reactive antibodies indicates prior exposure to the bacteria but does not specify ongoing infection. In animals with paratuberculosis, detection of MAP antibodies is often a lagging indicator, where culture positivity precedes seropositivity (Li et al., 2017). When considered with the above culture data, it does raise the possibility of some Crohn’s disease occurring as a post-infectious pathology, given that the prevalence of antibodies to MAP is generally much greater than the prevalence of a live MAP culture. To our knowledge, only one study has looked at serology and culture in the same matched subjects, so this hypothesis is difficult to explore from the published literature. Zamani et al. (2017) found that 13/28 (46%) and 11/28 (39%) of Crohn’s disease patients were seropositive for MAP3865c133141 and MAP3865c125133 peptides, respectively. MAP was cultured from two of these patients.Crohn’s disease lesions typically have an abundance of CD4+ T cells that will produce inflammatory cytokines including IL-17 and IFN-γ, which are characteristic of a Th1/Th17 immune response. In contrast to the expanding literature on a humoral immune response to MAP in Crohn’s disease, there is a relative paucity of evidence for MAP-reactive T cells present in patients with Crohn’s disease. Sibartie et al. (2010) found that PBMCs co-incubated with MAP produced significantly more T cells in patients with Crohn’s disease compared with ulcerative colitis or controls. Similarly, T-cell lines were shown to proliferate more in response to MAP when isolated from Crohn’s disease patients compared with ulcerative colitis. These T cells produced both IL-17 and IFN-γ, supporting the presence of a Th1∕Th17 immune response (Olsen et al., 2009). In intestinal biopsies of Crohn’s disease patients, the frequency of T cells reactive to mycobacteria was found to be significantly higher than those reactive against Escherichia coli. These T-cell lines were also shown to produce both IL-17 and IFN-γ (Olsen et al., 2013). In contrast however, Nakase et al. (2011) compared the cytokine production of monocytes from Crohn’s disease patients in response to MAP and M. avium. Although significantly more tumour necrosis factor α (TNF-α) was produced by monocytes infected with MAP, both IL-12p40 and IL-6 were not produced, arguing against the induction of a Th1/Th17 response.
A key component of the rationale linking MAP to Crohn’s disease concerns the gene mutations associated with an increased risk of disease. Many of these genes are involved in innate immune recognition of intracellular bacteria, suggesting that those who develop Crohn’s disease are at an increased risk of certain types of infection. Loss of function mutations in NOD2, an intracellular pathogen recognition receptor, are significantly associated with Crohn’s disease (Ogura et al., 2001; Hugot etal., 2001).
The NOD2 receptor will bind to bacterial mu- ramyl dipeptide (MDP). Mycobacteria are known to produce a glycolylated form of MDP, which is a more potent and efficacious activator of NOD2 (Coulombe et al., 2009; Vinh and Behr, 2013). Other genes include IRGM1, which encodes a GTPase involved in resistance to intracellular pathogens (Singh et al., 2006; Parkes et al., 2007) including mycobacteria (MacMicking et al., 2003; Feng et al., 2004), and ATG16L1, which is involved in induction of autophagy and the formation of the autophagosome (Cooney et al., 2010; Travassos et al., 2010). Taken together, one interpretation of the genomic data suggests that Crohn’s disease occurs in individuals with a genetically determined susceptibility to infection with an intracellular bacterium that produces glycolyl-MDP, such as MAP. However, several studies aimed at determining the relationship between MAP infection status and Crohn’s disease susceptibility genes including NOD2 have not found a positive association between them (Bernstein et al., 2007; Mendoza et al., 2010). An alternative interpretation of the data is that the genetic predisposition to Crohn’s disease overlaps not with the risk of developing a persistent infection, but rather with the risk of developing an inflammatory reaction to that intracellular pathogen. Research conducted by Fava et al. (2016) has shown that the predisposition to leprae reactions, which are inflammatory reactions during or after treatment of leprosy, have a remarkably similar genetic profile to Crohn’s disease. Supporting this paradigm, Wagner et al. (2013) found that susceptibility gene mutations in TLR4, which promotes proinflammatory responses in the gut (Lu et al., 2018), and IL-10Ra, the receptor for an immunoregulatory cytokine (Nunberg et al., 2018), were significantly associated with MAP-positive Crohn's disease patients.Overall, recent research has provided more evidence of antibodies to MAP antigens in Crohn's disease along with more limited evidence of a potential induction of a Th1/Th17 immune response against MAP infection in Crohn's disease patients. More data are required concerning host immune responses to MAP in order to gain a clearer picture of how MAP could contribute to the development of Crohn's disease.
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