Identification of Immune Parameters To Differentiate Disease States among Sheep Infected with Mycobacterium avium subsp. paratuberculosis

Abstract

Johne's disease, a chronic enteritis of ruminants, is caused by infection with Mycobacterium avium subsp. paratuberculosis. Three distinct forms have been observed in sheep: paucibacillary disease (PB), multibacillary disease (MB), and asymptomatic infection (AS). In this study, immune parameters for animals naturally infected with M. avium subsp. paratuberculosis and identified postmortem as having PB, MB, or AS were compared to provide a further understanding of the immunological reactivity contributing to or resulting from these different disease states in sheep. PB was associated with strong ex vivo M. avium subsp. paratuberculosis antigen-stimulated gamma interferon responses, pronounced increases in CD25 ؉ T-cell frequencies in circulation, antibody production, and a B-cell population that expanded significantly upon ex vivo antigenic stimulation. The MB group featured the highest antibody levels and a lack of cellular immune responsiveness to the M. avium subsp. paratuberculosis antigen. The AS group expressed an immunological phenotype intermediate between that for noninfected control animals and that for the PB group. The relationship between immune responses and disease severity within the PB group was investigated more closely; significant positive correlations were observed between disease severity and both the CD8 ؉ population in the circulating blood and the expression of interleukin-4 mRNA in antigen-stimulated blood samples ex vivo.

Does a Th1 over Th2 dominancy really exist in the early stages of Mycobacterium avium subspecies paratuberculosis infections?

“…The observations on the production levels of IFN-␥ from animals with multibacillary or paucibacillary lesions correlated with previous findings, in which paucibacillary diseased animals had stronger Th1 type cytokine responses (Gillan et al 2010;Smeed et al 2007Smeed et al , 2010. These were characterised by stronger IFN-␥ and delayed type hypersensitivity responses compared to those seen in the multibacillary animals.…”

“…lary lesions tend to have a dominant Th2 type (antibody) response (Burrells et al 1998;Chiodini et al 1984;Clarke 1997;Clarke et al 1996;Gillan et al 2010;Perez et al 1999;Smeed et al 2007). Thus it has been assumed that Th1 responses to Map infection were the first to be activated with a later switch to a Th2 response as clinical disease developed; this is referred to as the classical switch profile (Chiodini et al 1984;Stabel, 2000bStabel, , 2006.…”

Histopathological Characterization of Cutaneous Delayed-type Hypersensitivity and Correlations with Intestinal Pathology and Systemic Immune Responses in Sheep with Paratuberculosis

“…Most studies have focused on the immunological differences between paucibacillary and multibacillary disease outcomes. The immune responses of animals with low-grade JD pathology are less well understood, with one study supporting the finding of reduced IFN-g responses by these animals (Gillan et al, 2010). These findings suggest that the immune mediators of the skin DTH histopathology in these animals may be more complex than IFN-g memory responses alone.…”

“…Studies of paratuberculosis have reported two distinct immunological profiles, in that sheep with paucibacillary lesions show a T helper (Th)1-dominant immunological profile with strong CMI and lower pathogen numbers, compared with sheep with multibacillary lesions that show a Th2-dominant immunological profile, characterized by high serum antibody (Ab) levels and high pathogen load (Clarke, 1997;Gillan et al, 2010). These contrasting profiles may overlap and represent a continuum, signifying a gradual decline in the functional capacity of the immune system, but the reason for this progression is unknown .…”

Induction of B Cell Responses upon Experimental Infection of Neonatal Calves with Mycobacterium avium subsp. paratuberculosis

“…However, B cells are antigen-presenting cells as well and play a role in the activation of CD4 ϩ Th2 cells. Although it has not been explored fully, the decrease in CD4 ϩ Th1-mediated function noted in the later stages of paratuberculosis may be associated closely with an increase in B cell activity (10).…”