Available at www.veterinaryworld.org/Vol.6/Nov-2013/14.pdf REVIEW ARTICLE Open Access Overview of Johne's disease immunology

Johne's disease or paratuberculosis is one of the most economically important diseases of the livestock. Most of the economic losses associated with paratuberculosis are related to decreased milk production, reduced fertility and higher rates of culling. Understanding the immunology of the disease is very important for better understanding of the interplay between the host and the causative agent, Mycobacterium avium subsp. paratuberculosis (MAP). After uptake of MAP by macrophages residing in host's intestinal tissue, two possible scenarios may emerge; MAP may be destroyed or may establish persistent infection within the macrophages. If MAP persists in the infected macrophage, it continuously modulates adaptive immune responses of the animal. In this short review we describe the host-pathogen interactions in Johne's disease and highlights potential protective mechanisms in order for future design of more effective diagnostic method and vaccine.


Introduction
undeveloped immune system of young animals and higher level of exposure of MAP in these animals [14-Johne's disease (JD) is caused by Mycobacterium 15].avium subsp.paratuberculosis (MAP) [1].The disease is responsible for economic losses of approximately

Stages of JD
US$ 250 million to the US dairy industry [2][3].JD is a JD can be divided into mainly 3 stage -early chronic disease of mainly ruminants leading to granuinfection, subclinical infection and clinical infection.lomatous enteritis, persistent diarrhea, progressive wasting Here, we will discuss host-pathogen interactions in and finally death [4][5].The disease is distributed each stage of JD, especially focusing on immunologlobally among domestic ruminants (e.g.cattle, sheep gical responses.and goats) and wildlife species, such as white-tailed deer and bison [6][7].Understanding the pathogenesis Early infection: The early stage of MAP infection is and immunology of infectious diseases helps policy initiated by uptake of MAP by intestinal cells.Until makers define control strategies.These control plans recently, it was thought that MAP enters the subbecome more important in developing nations where epithelial tissue only through M-cells; however, control measures are not properly designed and Momotani et al [16] reported that other enterocytes also implemented [8][9][10].The objective of this review is to play role in the MAP entry.M-cells were discovered to provide an understanding of the pattern of the immune be the portal of entry by studying increase in the beta response of JD.
integrin molecules and other pattern recognition receptors molecules after infection with MAP.Also,

Modes of transmission
since M-cells lack digestive enzymes, microvilli, and Major mode of MAP transmission in dairy cattle mucous, it provides an easier path for MAP to invade is ingestion of feces, milk and colostrum contaminated the intestinal tissue [17].M-cells then transfer MAP with MAP.In-utero transmission of MAP has also been into sub-epithelial tissue where the bacteria will be reported [11].Most of the previously published studies phagocytized by macrophages and dendritic cells.have reported that young animals (calves) are the most There are 2 types of infected macrophages-persistently susceptible for infection but recently it has been shown infected (PM) and activated macrophages (AM).MAP that MAP can also infect adult animals [12].Infectivity inside the PM survives by inhibiting the fusion of depends on many factors including dose of MAP phagosome-lysosome and also by increased levels of ingested, host susceptibility and environmental factors mitogen activated protein kinase (MAPK) [15].MAPK [13].The reason for age -dependent susceptibility is helps bacterial survival by decreasing expression of not well understood but it is mostly attributed to interleukin (IL)-10 (anti-inflammatory cytokine) and preventing fusion of phagosome-lysosome.Also, increased level of Toll-like receptors (TLR's)-TLR2 and TLR 4 occurs in cells infected with MAP.The AM cells produce pro-inflammatory cytokines (e.g.IL-1, TNF-α, and IL-12) which in turn increases IL-6, IL-8 Clinical infection: This stage is characterized clinically and IL-10.Increase in IL-1 causes activation of IL-2 by reduced weight loss and intermittent diarrhea.producing T cells and leads to clonal expansion of Histologically, there is extensive damage of the intestine CD4+ T helper cells and CD8+T cytolytic cells.
and presence of a large number of granulomas.There is CD4+T cells can differentiate into either Th1 or Th2 also a high level of shedding of MAP in feces, milk and cells.Th1 response causes release of IFN-γ, IL-2 and colostrum.This phase is often accompanied by a strong TNF-α.In calves (ruminants), γ δ T cells are the pre-Th2 response with release of IL-4 and IL-10 [19-20].dominant T cells before 6 months of age.Under the Also, the occurrence of Treg cells (CD4+CD25+) causes influence of IFN-γ, these cells release IFN-γ and TNFsecretion of IL-10 and TGF β which further suppresses α.However, the release of IFN-γ from both γ δ T cells CD4+T cell population.Due to the suppression of Th2 and CD4+T cells is not sufficient for macrophages to cells, there is a reduction in B-cell response.However, kill intracellular MAP.Destruction of intracellular the overall B cell response is still measurable and thus pathogens primarily relies on cytotoxic lymphocytes the IgG1 response can be found in this stage.Finally, in like natural killer (NK) cells and CD8+ cells.A CD8+T the last stage of the clinical disease, infected animals cell response has also been noticed in spite of its shows profuse diarrhea, weakness, emaciation, interrequirement of MHC-I presentation which has not been mandibular edema and finally death of the animal [21] .well understood in bacterial infections [18].Also, γ δ Diagnostics based on humoral immune response cytotoxic T cells have also been shown to be activated Three different tests are used to measure antibody at an early stage of infection.The reason for this response in JD: complement fixation, agar gel immunoactivation is not well understood and needs further diffusion, and ELISA.The complement fixation and investigation.In the early stage of MAP infection, a agar gel immunodiffusion tests both suffer poor sensitivity, role for B cells has also been suggested.Being in close and so a recent report has suggested that ELISAs are proximity of macrophages and T-cells, B cells can act the best of the three methods for controlling JD in dairy as antigen presenting cells for CD4+T cells and further increase the production of IFN-γ.IFN-γ is known to and beef herds [22].Diagnoses of JD using ELISA cause an antibody class switch from IgM to IgG .If all have been reported in many previous studies using 1 different antigens.The antigens used in these studies these cells and cytokines fail to remove PM the animal have used protoplasmic antigen (PPA) [23], lipoarabinoprogresses to subclinical infection [ have previously reported that the surface antigens of by macrophages, CD4+T cells and γ δ T cells.In this MAP are capable of detecting anti-MAP antibodies in stage, the most important cytokine is TNF-α, which is serum at early stages of JD [29][30][31][32][33].There has always secreted by γ δ T cells and CD4+T cells.TNF-α plays a been a need to understand the immunology of infectious role in recruitment of macrophages to help control the diseases to implement it for the development of vaccines infection but also causes tissue damage.A proportion and diagnostics. of PM secretes IL-10, which is classified as a Th2 cytokine along with IL-4 and IL-5, reduces production

Conclusion of IFN-γ through suppression of CD4+T cells. Due to
Understanding the pathogenesis becomes more the reduced level of IFN-γ, the newly recruited important for JD since there is no efficient vaccine macrophages become more prone to persistent available and the treatment is not practically possible.infection.The cytotoxic T cell population -CD8+ and Thus, better understanding of the pathogenesis for γ δ T cells --play different roles in this stage.The γ δ T development of more effective vaccine and diagnostic cells suppress proliferation response of CD4 + T cells tests will be the keys to control the disease, The present to MAP antigen while CD8+ T cells prevent this action.
pathogenesis describes a higher Th1 response initially There is likelihood that γ δ T cells causes formation of and a shift to Th2 response later in the course of the granulomas and limit further inflammatory responses.There is a limited amount of humoral immune response disease.It has been evident that for an early infection is in this stage of infection and is due to infrequent cell mediated dominated with a later switch to a Th2 shedding of MAP.The sub type of immunoglobulin is type response.This phenomenon has been referred to still IgG since the switch from the subtype to IgG as Th1-Th2 dominancy shift.Therefore, Th1-based test shift and induction of CD4+ T cell activity are the 18.Sohal, J.S., Singh, S.V., Tyagi, P., Subodh, S., Singh, P. K., influential events that leads to persistent MAP strain virulence and host genetic susceptibility needs to 19.Begg, D.J., de Silva, K., Carter, N., Plain, K. M., Purdie, A.
be studied in detail in future.the views of their institutions.
and Whittington, R. J. (2011) Does a Th1 over Th2 dominancy really exist in the early stages of Mycobacterium avium subspecies Disclaimer: The findings and conclusions in this report paratuberculosis infections?Immunobiology, 216(7): 840are those of the authors and do not necessarily represent 846.