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1.
The function of gammadelta T cells during ruminant paratuberculosis (Johne's disease) is presently unknown. An ex vivo system was used to test the hypothesis that gammadelta T cells are capable of activating Mycobacterium avium subsp. paratuberculosis-(M. paratuberculosis)-infected macrophages. Peripheral blood-derived macrophages were infected in vitro with live M. paratuberculosis, and autologous LN-derived gammadelta T cells or CD4+ T cells were co-cultured with infected macrophages for 48h, at which time bacterial survival as well as production of nitrites and IFN-gamma was evaluated. Incubation of M. paratuberculosis-infected macrophages with autologous gammadelta T cells did not result in reduced intracellular bacterial viability compared to infected macrophage cultures without added T cells. IFN-gamma production by-infected cultures containing added gammadelta T cells was not enhanced compared to that of infected macrophages alone. Although infection of macrophage cultures caused increased production of nitrites at both post-infection day (PID) 0 and PID 60, the addition of gammadelta T cells did not further increase nitrite production. In contrast, addition of PPD-stimulated CD4+ T cells obtained at PID 60 to M. paratuberculosis-infected macrophages resulted in significantly increased IFN-gamma production compared to cultures without added T cells or cultures containing unstimulated CD4+ T cells or unstimulated or antigen-stimulated gammadelta T cells. However, the increased production of IFN-gamma by co-cultures containing PPD-stimulated CD4+ T cells did not result in increased bacterial killing or increased production of nitrites compared to cultures without added T cells. In additional in vitro experiments, M. paratuberculosis-infected macrophages, but not uninfected macrophages, were unable to increase nitrite production when stimulated with recombinant IFN-gamma. Taken together, the data suggest that (1) gammadelta T cells do not produce significant IFN-gamma and do not significantly increase NO production from M. paratuberculosis-infected macrophages in vitro, (2) the production of significant IFN-gamma by antigen-stimulated CD4+ T cells from infected calves is insufficient to enhance mycobacterial killing or nitrite production by infected macrophages, and (3) macrophages may have an impaired NO response following intracellular M. paratuberculosis infection, even in the presence of significant concentrations of IFN-gamma. 相似文献
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Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's disease, a chronic granulomatous enteritis of wild and domestic ruminants. During a long subclinical period, the organism persists in the intestine despite systemic cellular and humoral immune responses. To explore the mucosal immune response in Johne's disease, we isolated mononuclear leukocytes from the ileum of cows naturally infected with M. avium subsp. paratuberculosis and from cows that were not infected. We evaluated the immunophenotype of these cells and the proliferative responses after the addition of M. avium subsp. paratuberculosis sonicate or B-cell or T-cell mitogens. Although the percentage of T cells was increased in infected cows, these cells consisted mostly of memory (CD2+CD62L-) and regulatory (CD4+CD25+) T cells. Further evidence of immune hyporesponsiveness included a decrease in the percentage of T cells with an activated phenotype and a decrease in cells expressing major histocompatibility factor class II (MHC class II). Unlike the spleen, ileal lymphocytes from infected cows failed to proliferate in response to M. avium subsp. paratuberculosis sonicate. Additionally, ileal lymphocytes from infected cows proliferated poorly in response to concanavalin A and pokeweed mitogen, suggesting generalized T cell and B cell hyporesponsiveness. These results indicate that a state of tolerance may exist in the intestine of cows subclinically infected with M. avium subsp. paratuberculosis organisms in subclinically infected cows. This effect may be induced, at least in part, by proliferation of regulatory T cells that nonspecifically suppress mucosal immune responsiveness. 相似文献
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Stabel JR 《Veterinary microbiology》2000,77(3-4):465-473
The host immune response to infection with Mycobacterium paratuberculosis is paradoxical, with strong cell-mediated immune responses during the early, subclinical stages of infection and strong humoral responses during the late clinical stages of the disease. Cell-mediated immune responses modulated by various T cell subsets are essential to provide protective immunity and prevent progression of the disease. Secretion of cytokines by T cell populations serves to activate macrophages to kill ingested M. paratuberculosis as well as activate other T cell subsets to contain the infection. This paper reviews the current knowledge of T cell immune responses in M. paratuberculosis infection based upon clinical studies and research using mouse models. 相似文献
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Stabel JR 《Animal health research reviews / Conference of Research Workers in Animal Diseases》2006,7(1-2):61-70
The immune system is not always successful in recognizing and destroying pathogens it may encounter. Host immunity to mycobacteria is characterized by a very complex series of events, designed to clear the infection. The first line of defense is uptake and processing of the pathogen by macrophages, followed by the initiation of cell-mediated immunity. The secretion of pro-inflammatory cytokines such as IFN-gamma is credited with containment of mycobacterial infections. Yet it is clear that activated T-cells may contain but fail to clear the infection in some hosts. Further, it is recognized that if infection progresses to a more clinical state, the production of pro-inflammatory cytokines is suppressed and expression of anti-inflammatory cytokines is increased. It is unclear what defines a host that can successfully contain the infection versus one that succumbs to severe immunopathologic disease. This review will address some of the key elements in host immunity to mycobacterial pathogens, with an emphasis on Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis), in an attempt to understand the dialogue between immune cells and their mediators during infection and what causes this discourse to go awry. 相似文献
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J A Navarro J Sanchez A Bernabe M A Gomez S Gomez J Seva 《Zentralblatt für Veterin?rmedizin. Reihe B. Journal of veterinary medicine. Series B》1992,39(6):421-427
The anti-Mycobacterium paratuberculosis polyclonal serum is proved useful for labelling Mycobacterium paratuberculosis in glutaraldehyde-osmium-fixed and epon-embedded intestinal samples from sheep with clinical symptoms of paratuberculosis. M. paratuberculosis marked with antibody-coated colloidal gold stain was seen in macrophages, epithelioid cells, giant cells and neutrophils throughout intestinal mucosa. In large macrophages with a low lysosomal content, a great number of intact mycobacteria was seen within phagosomes. In macrophages with average lysosomal content, very few intact mycobacteria or mycobacterial debris were present and lysosome-phagosome fusions were observed. Mycobacteria within neutrophils were scanty. These results show the usefulness of colloidal immunogold techniques for studies of the pathogenesis of paratuberculosis. 相似文献
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Coussens PM Sipkovsky S Murphy B Roussey J Colvin CJ 《Comparative immunology, microbiology and infectious diseases》2012,35(3):233-239
The intracellular bacterium Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease in wild and domestic ruminants. Johne's disease presents as a chronic enteritis with severe inflammation of intestinal tissues, characterized by widespread infiltration of macrophages, the target cell of MAP. Clinical signs of Johne's disease are typically accompanied by a loss of peripheral CD4+ T cell responses to MAP antigens and an increase in anti-MAP serum IgG levels. Recently, it was proposed that regulatory T cells might develop over the lengthy course of subclinical MAP infection. In the past five years, significant progress in defining bovine regulatory T cells has been made. These studies grew out of observations that IL-10 is produced by PBMCs in response to MAP antigen stimulation and that neutralization of this IL-10 could enhance IFN-γ production from MAP-antigen reactive effector T cells. Depletion studies revealed that MAP responsive cell populations producing IL-10 were largely CD4+ and CD25+, although monocytes have also been shown to produce IL-10 in response to MAP. In addition, evidence for a regulatory population of γδ T cells has also begun to accumulate. We summarize current thinking regarding regulatory T cells in MAP infection and provide data suggesting a potential link between regulatory T cells, bovine leukemia virus, and MAP. 相似文献
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Beard PM Rhind SM Sinclair MC Wildblood LA Stevenson K McKendrick IJ Sharp JM Jones DG 《Veterinary immunology and immunopathology》2000,77(3-4):311-319
M.a. paratuberculosis is the causal agent of paratuberculosis (Johne's disease). Recent work has suggested that gammadelta T cells may play an important role in the early immunological response to mycobacterial diseases, and that CD1 may act as a non-classical MHC molecule in antigen presentation to these gammadelta T cells. Experimental infection of neonatal lambs with M.a. paratuberculosis was used to investigate the changes in gammadelta T cells and CD1 molecules in the gut associated lymphoid tissue 4 weeks after inoculation. Immunohistochemistry was used to label the gammadelta lymphocytes and CD1 molecules. An increase in the number of gammadelta T cells was noted in both the jejunal and ileal Peyer's patches in the gut of infected lambs, but no statistically significant change was found in the mesenteric lymph nodes. There were no obvious changes in the CD1 molecules in any tissue. This work suggests that gammadelta T cells may play a role in the initial immunological events of paratuberculosis infection. 相似文献
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Mycobacterium paratuberculosis is the causative agent of paratuberculosis (Johne's disease), a chronic inflammation of the terminal portion of the ileum in ruminants. The predominance of cell-mediated immunity in early stages of the disease suggests that T lymphocytes are essential to protect the host from infection with M. paratuberculosis. In this study, we investigated the role of alphabeta and gammadelta T cells in resistance to M. paratuberculosis infection using a T-cell receptor (TCR) knockout mouse model. Weanling TCR-alpha-deficient, TCR-delta-deficient, and C57BL/6 control mice (5-6 weeks of age) were acclimated for 2 weeks and then inoculated intraperitoneally with 10(8)CFU/ml of M. paratuberculosis (either strain 19698 or strain Ben). Groups of mice within each treatment group were euthanized at 1, 3 and 6 months post-inoculation. Sections of spleen, liver, ileum and mesenteric lymph node were prepared for bacterial culture and histologic examination. At all time points of infection and regardless of bacterial strain, TCR-alpha-deficient mice had higher levels of M. paratuberculosis colonization in their tissues compared to TCR-delta-deficient mice or C57BL/6 control mice. Lesions were located predominately in the liver and the ileum, depending upon period of infection, and lesion scores were higher for TCR-alpha-deficient mice compared to the other treatment groups. These results suggest that alphabeta T cells play a major role in resistance to infection with M. paratuberculosis and that gammadelta T cells may play a lesser role and potentially confound protective immune responses. 相似文献
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Allen AJ Park KT Barrington GM Lahmers KK Abdellrazeq GS Rihan HM Sreevatsan S Davies C Hamilton MJ Davis WC 《Veterinary immunology and immunopathology》2011,141(3-4):258-266
Mycobacterium avium subsp. paratuberculosis (Map), the etiologic agent of Johne's disease (JD) in ruminants, has been implicated in the pathogenesis of Crohn's disease (CD) in humans. We developed a bovine ileal cannulation model to facilitate comparison of the immune response to Map and the mechanisms of pathogenesis in cattle and humans. Initial studies showed a T cannula could be maintained for up to a year in calves without inducing inflammation or adversely affecting intestinal function. Map introduced through the cannula established a persistent low level of infection without inflammation. Infection elicited an immune response to Map antigens detectable by flow cytometry. Further studies now show the cannulation model can be used with cows during the later stage of infection, affording access to the target tissue at all stages of infection. The studies also revealed no difference in infectivity or immunogenicity of isolates of Map obtained from cattle or humans with CD. Comparison of the immune response to Map during the early and late stages of infection using PCR, flow cytometry and QRT-PCR, showed the immune response early in the disease process is dominated by CD4 T cells. A CD8 response is delayed but comparable at later stages of infection. Genes for pro-inflammatory cytokines IFN-γ and the recently identified genes encoding IL-17 and IL-22 are up regulated in infected animals. These findings reveal that both human and bovine isolates of Map can establish infection and induce similar immune responses in a bovine model. They also reveal the cytokine responses elicited in cattle are similar to those implicated in CD pathogenesis. 相似文献
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Johne's disease (paratuberculosis) was diagnosed as the cause of chronic weight loss and intermittent diarrhea in a five year old Saanen doe. Confirmatory necropsy findings included granulomatous enteritis, lymphadenitis, lymphangitis and the demonstration of abundant acid fast organisms within macrophages in impression smears of intestinal mucosa. Some of the difficulties encountered in diagnosing and controlling Johne's disease are discussed with emphasis given to the disease in small ruminants. 相似文献
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Whittington RJ Begg DJ de Silva K Plain KM Purdie AC 《Veterinary immunology and immunopathology》2012,148(1-2):29-47
Paratuberculosis or Johne's disease of livestock, which is caused by Mycobacterium avium subsp. paratuberculosis (MAP), has increased in prevalence and expanded in geographic and host ranges over about 100 years. The slow and progressive spread of MAP reflects its substantial adaptation to its hosts, the technical limitations of diagnosis, the lack of practical therapeutic approaches, the lack of a vaccine that prevents transmission and the complexity and difficulty of the on-farm control strategies needed to prevent infection. More recently evidence has accumulated for an association of MAP with Crohn's disease in humans, adding to the pressure on animal health authorities to take precautions by controlling paratuberculosis. Mycobacterial infections invoke complex immune responses but the essential determinants of virulence and pathogenesis are far from clear. In this review we compare the features of major diseases in humans and animals that are caused by the pathogenic mycobacteria M. ulcerans, M. avium subsp. avium, M. leprae, M. tuberculosis and MAP. We seek to answer key questions: are the common mycobacterial infections of humans and animals useful "models" for each other, or are the differences between them too great to enable meaningful extrapolation? To simplify this, the immunopathogenesis of mycobacterial infections will be defined at cellular, tissue, animal and population levels and the key events at each level will be discussed. Many pathogenic processes are similar between divergent mycobacterial diseases, and at variance between virulent and avirulent isolates of mycobacteria, suggesting that the research on the pathogenesis of one mycobacterial disease will be informative for the others. 相似文献
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The histopathologic diagnosis of subclinical Johne's disease in North American bison (Bison bison) 总被引：1，自引：0，他引：1
The morphologic changes of subclinical Johne's disease in North American Bison (Bison bison) are characterized by microgranulomas composed of epithelioid macrophages and individual multinucleate giant cells of Langhans'-type occasionally containing individual cytoplasmic acid-fast bacilli compatible with Mycobacterium avium paratuberculosis. The microgranulomas are best visualized in the mesenteric lymph nodes of infected subclinical animals. Macrophages that can be confused with infection-associated epithelioid macrophages in the mesenteric lymph nodes are pigment-carrying cells from the intestinal tract. Mesenteric lymph node biopsy may be a useful diagnostic tool for detection of mild subclinical infection in individual ruminants from herds of unknown infection status. The biopsy may also be useful for Johne's disease surveillance during test-and-cull programs. 相似文献
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Paratuberculosis is a chronic, progressive disease of mainly ruminants caused by the facultative intracellular bacterium, Mycobacterium avium subsp. paratuberculosis. Infection usually occurs in young animals through oral uptake of food contaminated with the organisms. The ingested bacteria are transcytosed through M-cells overlying the Peyer's patches and are released in the stroma, where they are taken up by macrophages. Inside the macrophage, the mycobacteria resist enzymatic and toxic degradation and multiply until the infected macrophage ruptures. The thick, lipid-rich cell envelope is mainly responsible for micobacterial resistance. In addition to its barrier effect, which provides protections, the mycobacterial cell wall also contains several biologically active components that down-regulate the bactericidal function of macrophages. The basic survival strategy of pathogenic mycobacteria can be viewed at three levels: selective use of relatively safe entry pathways that do not trigger oxidative attack, modification of the intracellular trafficking of mycobacteria-containing phagosomes, and modulation of the cooperation between the innate and specific immunity. In doing so, pathogenic mycobacteria are successful intracellular organisms that survive and multiply inside macrophages. Current understanding about the survival strategies of M. a. paratuberculosis and its implications in the epidemiology, diagnosis, and control of the disease are discussed. 相似文献
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Polymerase chain reaction analysis of TNF-alpha and IL-6 mRNA levels in whole blood from cattle naturally or experimentally infected with Mycobacterium paratuberculosis. 总被引：1，自引：1，他引：0 
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下载免费PDF全文 Johne's disease is characterized by a chronic enteritis that results in granulomatous inflammation, cachexia, and eventual death of cattle infected with Mycobacterium paratuberculosis. The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been associated with granuloma formation and wasting in other disease syndromes. The potential role of these cytokines in the development and progression of Johne's disease has not been investigated. Using the polymerase chain reaction (PCR) and specific bovine oligonucleotide cytokine primers and probes, we examined the expression of messenger RNA for these cytokines in whole blood from M. paratuberculosis infected and uninfected cattle. Cytokine mRNA levels were examined before and after in vitro incubation with E.coli lipopolysaccharide (LPS) and lipoarabinomannan (LAM) purified from M. paratuberculosis. Uninfected calves, experimentally infected calves, and naturally infected cattle all displayed similar cytokine mRNA expression patterns. However, individual animals demonstrated variability in the levels of IL-6 and TNF-alpha mRNA expression as determined by a semiquantitative PCR method using 32P-labelled oligonucleotide probes. 相似文献
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A study was conducted to determine whether trichostrongylid nematode larvae become contaminated with Mycobacterium avium subsp. paratuberculosis when they develop in the faeces of sheep with Johne's disease. Nematode larvae were hatched from ova in the faecal samples of affected sheep. Larval sheaths were removed and these as well as exsheathed larvae were subjected to radiometric culture for M. paratuberculosis. The organism was recovered from washing water used to prepare the larvae, third stage larvae and larval sheaths, but not from exsheathed larvae. The recovery of M. paratuberculosis from larvae was associated with the severity of the histological lesions in affected sheep and with the results of culture of the organism from intestinal tissues and faeces. Nematode parasites of sheep might be able to act as mechanical vectors for M. paratuberculosis as the organism associates with infective third stage larvae when these develop in the faeces of sheep with Johne's disease. 相似文献
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Disseminated Mycobacterium paratuberculosis infection in a cow 总被引：7，自引：0，他引：7
S A Hines C D Buergelt J H Wilson E L Bliss 《Journal of the American Veterinary Medical Association》1987,190(6):681-683
A cow with chronic diarrhea and weight loss caused by localization of Mycobacterium paratuberculosis in the intestinal tract (Johne's disease) had gross and microscopic changes indicative of a disseminated infection. A direct association between the remote lesions and the intestinal infection was shown by isolation of M paratuberculosis from renal tissue, detection of intracellular M paratuberculosis antigen(s), using an indirect immunoperoxidase method, and by the characteristic granulomatous nature of the lesions. This case illustrates the potential for extra-intestinal lesions in M paratuberculosis infection of cattle and should cause veterinarians to consider mycobacterial disease when confronted with multinodular lesions of the bovine kidney. The immunoperoxidase method was useful in determining the cause of the inflammatory lesion in which intact organisms were not evident. 相似文献
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Glass EJ 《Research in veterinary science》2001,70(1):71-75
The tick-borne protozoan parasite, Theileria annulata, causes an overwhelming disease in Friesian cattle, imported to improve productivity, in a large area of the world. The parasite invades bovine macrophages and induces aberrant changes which seem pivotal in triggering disease in na?ve susceptible animals: parasite infected cells acquire dendritic cell features and over-activate CD4+ and CD8+ T cells. Elevated levels of interferon-gamma (IFN-gamma) are induced and B cells are developmentally arrested in the light zone of germinal centres. Infected macrophages are refractory to the effects of IFN-gamma and indeed flourish in its presence. High levels of pro-inflammatory cytokines, as evinced by high acute phase protein responses, probably also play a role in pathology. However, animals can become immune to further challenge. Cellular immune responses involving macrophages, natural killer cells and CD8+ T cells play a major role in recovery and subsequent maintenance of immunity. The main target for immunity appears to be the parasite infected macrophage, as attenuated cell lines can protect and are used as vaccines. Cloned lines selected for low cytokine production protect with no associated pathological reactions. Theileria annulata causes a relatively mild disease in an indigenous breed of cattle, which is associated with lower acute phase protein responses (controlled by macrophage cytokines). Thus the initial host-parasite interactions must determine the balance between immunity and pathogenesis. New generation vaccines to T. annulata should both induce active immunity and suppress pathology. 相似文献