Immunopathology

Granulomatous lesions in the intestine are a hallmark characteristic of MAP infection, and the composition of cell types within the lesions is correlated with stage of infection.

The localized immune response at the site of lesions changes in accordance with lesion severity. The progression of disease from asymptomatic to clinical has been associated with decreased CD4+ T-cell and increased γδ T-cell populations in the lamina propria of the ileum, with no differences in cell frequency noted between asymptomatic infected and non-infected cattle (Koets etal., 2002;Valheim etal., 2004). An increase in CD8+ T cells, concomitant with reduced numbers of CD4+ T cells, was also noted in goats with clinical paratuberculosis (Navarro et al., 1998). The pattern of cytokine expression in intestinal tissue is also influenced by the state of infection (Sweeney et al., 1998; Lee et al., 2001; Coussens et al., 2004; Khalifeh and Stabel, 2004b; Tanaka et al., 2005). Major findings include an upregulation of proinflammatory cytokines such as IFN-γ, IL-1, TNF-α, TGF-β, IL-5 and IL-8 in tissues from infected animals compared with non-infected controls. Studies contrasting cytokine expression in the asymptomatic and symptomatic stages of disease have demonstrated that subclinically infected animals generally have increased levels of IFN-γ and IL-18 in tissues compared with clinically infected cows (Sweeney et al., 1998; Khalifeh and Stabel, 2004b; Tanaka et al., 2005). In contrast, clinically infected animals have greater expression of proinflammatory cytokines, IL-1 and TNF-α; Th2 cytokines, IL-4 and IL-10; and Th3 cytokine, TGF-β (Alzuherri et al., 1996; Lee et al., 2001; Khalifeh and Stabel, 2004b; Tanaka et al., 2005). More recently a comprehensive evaluation of cytokine gene expression in the ileal tissues of sheep that were classified into one of three groups - paucibacillary, multibacillary or asymptomatic - was performed (Smeed et al., 2007).

Expression of many of the proinflamma- tory cytokines, such as IL-1β, IL-6, IL-8, TNF-α and IL-12, increased progressively according to stage of disease, from lowest for non-infected animals to highest for multibacillary sheep. Secretion of proinflammatory cytokines may trigger a sequence of events that contributes to the formation of lesions in the tissues. Although proinflammatory cytokines are critical for the recruitment of immune cells to fight infection, protracted activation may result in tissue damage and lesion formation (Clarke, 199 7). A linear increase in TGF-β expression was correlated with increased pathology in the intestinal tissue of infected sheep (Clarke, 199 7), suggesting that TGF-β was responding to the need to control tissue damage potentiated by the secretion of proinflammatory cytokines (Smeed et al., 2007). A study in red deer focusing also on Treg gene expression indicated that animals with clinical signs of disease and severe multibacil- lary infection showed reduced transcription of IL-4, FoxP3, GATA3 and TGF-β (Robinson et al., 2011). The pattern of cytokine expression in target tissues of infected animals may also reflect that increased proinflammatory gene expression driven by or combined with a loss of regulatory gene expression contributes to enhanced pathology and progressive disease in late stage disease rather than protection. The role of (local) macrophages in the outcome of mycobacterial infections has recently been studied in more detail. Immunohistochemical staining of mid-ileal tissues from cattle in various stages of disease demonstrated that subclinical cows had a nearly equal ratio of host defence (M1) and resolution and repair (M2) phenotype macrophages compared with dominant M1 and M2 macrophage phenotypes in control and clinical cows, respectively (Jenvey et al., 2019). Recent insights into tuberculosis granuloma pathophysiology also indicate that a delicate balance, rather than skewing in lymphocyte function and cytokine production, controls disease outcome and macrophages appear to play a critical role in maintaining the inflammatory balance (Flynn et al., 2011).

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Source: Behr Marcel A., Stevenson K., Kapur V. (eds.). Paratuberculosis: Organism, Disease, Control. 2nd edition. — CAB International,2020. — 439 p.. 2020

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