Progressive Bovine Paratuberculosis Is Associated with Local Loss of CD4⁺T Cells, Increased Frequency of γδ T Cells, and Related Changes in T-Cell Function

Abstract

Bovine paratuberculosis is caused by the infection of young calves with Mycobacterium avium subsp. paratuberculosis, resulting in a chronic granulomatous infection of predominantly the ileum. After an incubation period of 2 to 5 years, the disease becomes progressive in some of the chronically infected, but asymptomatic cows. This results in a protein-losing enteropathy that will ultimately be fatal. A loss of cell-mediated immune responses in symptomatic animals has been described, but no information is available concerning immune reactivity in the intestine. We sought to investigate putative disease status-associated lymphocyte subset distributions and antigen-specific functional characteristics of mononuclear cells isolated from blood, gutassociated lymphoid tissue, and the intestinal walls of 22 cows in different stages of disease and in control animals. The results demonstrated a significant decrease in CD4 ؉ T-cell frequency and a significant increase in TcR1-N12؉ ␥␦ T-cell frequency in ileum lamina propria lymphocytes of symptomatic animals compared to the asymptomatic shedders. Immunohistology revealed that there was also an absolute decrease in the number of CD4 ؉ T cells in sections of the lesional ileum. Our findings also indicated that both peripheral and intestinal cell-mediated responses are decreased in symptomatic animals compared to asymptomatic animals. We conclude that the decrease in cell-mediated responses is likely related to a loss of antigen-specific CD4 ؉ T cells, which is most prominent in the lesional ileum from symptomatic animals, thus contributing to the progressive nature of bovine paratuberculosis.

Susceptibility to paratuberculosis infection in cattle is associated with single nucleotide polymorphisms in Toll-like receptor 2 which modulate immune responses against Mycobacterium avium subspecies paratuberculosis

“…The PMBC had been obtained from whole blood by density gradient centrifugation as published previously (Koets et al, 2002). The DNA from purified PBMC or whole blood was isolated using the DNAWizard-Kit (Promega, Madison, WI, USA) according to manufacturer's instructions and spectrophotometrically tested for yield and purity.…”

“…In these later phases, the Th1 CMI declines to an undetectable low level and the amount of apparently non-protective antibodies increases. The loss of protective CMI leads to a widely disseminated infection and uncontrolled growth of mycobacteria in macrophages, causing the clinical manifestation of paratuberculosis (Koets et al, 2002). Hence, following a prolonged period of chronic diarrhoea, weight loss and decreased milk production, cows become emaciated and may die from this protein-loosing enteropathy (Coussens, 2004).…”

Immunological characteristics of cattle with Mycobacterium avium subsp. paratuberculosis infection

“…The differences between normal and infected animals in responses to T lymphocytes were studied by Bassey and Collins (1997) who demonstrated that the major subpopulation producing IFN-γ are CD4 + lymphocytes, and that, in the animals affected by paratuberculosis, the effect of γδ T lymphocytes is not mediated through the production of IFN-γ. Koets et al (2002) demonstrated a significant decrease in CD4 + T-cell frequency and a significant increase in TcR-N12 + gamma delta T-cell frequency in illeum lamina propria lymphocytes of symptomatic animals compared to the asymptomatic shedders. These authors also demonstrated shi� of the immune reaction from Th1 type towards the Th2 type at the time of the development of clinical signs (Koets et al, 1999(Koets et al, , 2001.…”

Trends and advances in the diagnosis and control of paratuberculosis in domestic livestock

“…IFN-g production by TH1-cells are, therefore, major mediators of specific immunity during early infection (Stabel 2000). Peripheral and intestinal CMI responses are reduced in symptomatic compared to asymptomatic animals (Koets et al 2002). Disease development appears to be linked with local loss of CD4 C T-cells and gd T-cells (Chiodini 1996;Koets et al 2002).…”

“…Peripheral and intestinal CMI responses are reduced in symptomatic compared to asymptomatic animals (Koets et al 2002). Disease development appears to be linked with local loss of CD4 C T-cells and gd T-cells (Chiodini 1996;Koets et al 2002). The fundamental defect that could be connected with a reduction in CMI response is the deregulation in MAP-mediated macrophage function (Tooker et al 2002;Weiss et al 2002;Zur et al 2003).…”