- Email: [email protected]
Understanding immunology in disease development and control
Understanding Immunology in Disease Development and Control1 M. A. QURESHI,2 I. HUSSAIN, and C. L. HEGGEN Department of Poultry Science, North Carolina State University, Raleigh, North Carolina 27695-7608 cell activation, several cytokines and metabolites are also produced. The consequence of cytokine- and metabolitemediated microenvironments may be either beneficial or result in a noninfectious immunopathology. Nevertheless, the integrity of the immune system and its functional modulation by factors such as genetics, nutrition, and prophylactic approaches continue to be an important focus of attention in current poultry research and production efforts.
(Key words: immunosurveillance, cytokines, immunomodulation) 1998 Poultry Science 77:1126–1129
INTRODUCTION Lymphoid and nonlymphoid systems constitute two broad structural categories of the avian (and mammalian) immune system. Among lymphoid components, the bursa of Fabricius, a site of B-lymphocyte development and differentiation, and the thymus, a site of Tlymphocyte development and differentiation, are considered to be primary lymphoid organs, whereas the spleen is usually termed a secondary lymphoid organ. In addition, lymphoid structures distributed throughout the intestinal tract represent the “intestinal arm” of the immune system. Although not studied extensively, intestinal immune structures may in fact be the crucial barriers to external pathogens because many economically important pathogens replicate in the intestinal epithelium. The anatomical and functional complexities of lymphoid organs and their role in avian health and disease have recently been reviewed (Schat and Myers, 1991; Jeurissen et al., 1994; Glick, 1995). The nonlymphoid components of the immune system include cells that provide a nonspecific immunological defense to the host. Being the first line of immunological defense, the cells of the mononuclear phagocytic system are the primary players in this category. Blood monocytes and tissue macrophages are unique because of their wide
Received for publication August 3, 1997. Accepted for publication January 20, 1998. 1The use of trade names in this publication does not imply endorsement by the North Carolina Agricultural Research Service, nor criticism of similar products not mentioned. 2To whom correspondence should be addressed.
distribution throughout the body fluids, organs, and cavities. Being phagocytic in nature, macrophages bind, internalize, and degrade foreign antigens, such as bacteria, without any lag period after encounter. For example, chicken macrophages have been shown to kill greater than 80% of the internalized Salmonella in the first 15 min of engulfment (Qureshi et al., 1986). Additional nonlymphoid cells with phagocytic potential in aves include heterophils (counterparts of the mammalian neutrophils) and thrombocytes (Chang and Hamilton, 1979; Harmon et al., 1992). Functionally, the avian immune system, similar to that of mammals, mediates the so-called humoral and cell-mediated immunity. Humoral immunity is the adaptive function of the immune system through which antibodies are produced in response to an antigenic challenge. Cell-mediated immunity involves immune mechanism(s) by which cells infected with a foreign agent, such as a virus, are destroyed, and is accomplished via a direct effector (e.g., an activated T cell) and target cell contact (Weinstock et al., 1989).
IMMUNE SYSTEM AND DISEASE It is reasonable to assume that organisms that have direct tropism for any of the primary or secondary lymphoid organs would cause alterations in immune system functions. Insults by such infective organisms
Abbreviation Key: IBDV = infectious bursal disease virus; PEMS = poult enteritis and mortality syndrome; TGF-b = transforming growth factor-b; TNF = tumor necrosis factor.
1126
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
ABSTRACT Two functional aspects of the avian immune system, the humoral and the cell-mediated arms, provide the basis for the preventive and protective response against disease-causing microorganisms. On the other hand, certain avian diseases may induce a transient or permanent immunosuppressive state in one or both of these arms, leading to increased disease susceptibility. In addition to the classical immune response, manifested as antibody production or effector
SYMPOSIUM: INFECTIOUS POULTRY DISEASES
FIGURE 1. An example of enhanced production of immune-system mediated metabolites in avian diseases. As seen, nitrite levels in the culture supernatant fractions of macrophages increase significantly during the progression of both coccidial infection in chickens and poult enteritis and mortality syndrome (PEMS) in turkeys. The histograms represent the means and standard errors of nitrite in splenic (coccidial challenge) and abdominal (PEMS) macrophage culture supernatants at given days. The histograms within each disease with varying letters (a, b) indicate statistical significance at P < 0.05.
immune dysfunction, possibly based on these proinflammatory cytokines, may cause severe metabolic disorders like those seen associated with PEMS (Qureshi et al., 1997).
IMMUNE SURVEILLANCE The ultimate test of the immunocompetence of a flock is the ability of the birds to resist either a natural or an experimental disease challenge. Modern poultry health practices include vaccination programs that are designed to hyperimmunize hens to effectively transfer passive immunity to the progeny and initiate natural immunity from day of hatch. Obviously, such vaccination regimens are dependent upon the type of the bird as well as the disease under consideration. Furthermore, for the vaccines to be effective, it is important that they are delivered properly and effectively for maximum immunological benefit. Vaccines are currently available for immunizing birds against a variety of infectious diseases (Koch, 1994; Baxendale, 1996). The immunological response of birds to either vaccination or natural infection is quite diversified (Morrison, 1996). Innate immune responses mediated by cells of the mononuclear phagocytic system, such as monocyte and macrophages and natural killer cells, would either inhibit the growth and replication of the antigen source in question or they would initiate a cascade of events leading to an adaptive response. Adaptive immune response starts with the processing and presentation of the antigen. The host’s immune system then responds by mounting either humoral (e.g., antibody production) or cell-mediated
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
may result either in organ necrosis or atrophy or specific subpopulations of the lymphoid cellular components may be affected. For example, chicks infected with infectious bursal disease virus (IBDV) show bursal involvement (e.g., replication of the virus in bursa, bursal necrosis, and lymphoid depletion). Immunologically, infected chicks have lower serum IgM levels. However, Rodenberg et al. (1994) observed no drastic changes in CD4 and CD8 lymphocyte subpopulations in spleens of IBDV-infected chicks. Nevertheless, it is often observed that chickens infected with IBDV show increasing susceptibility to several diseases and respond poorly to vaccination (Saif, 1991). The point, therefore, is that a disease can lead to an immunologically dysfunctional state. On the other hand, it is also possible that immune dysregulation can cause alterations in normal physiological and metabolic processes with adverse consequences. The candidates for such immune system-mediated pathology are several cytokines such as transforming growth factor-b (TGF-b), interleukin-1, interleukin-6, and tumor necrosis factor (TNF) produced by macrophages in response to inflammatory challenge. Interleukin-1 or TNF produced after immune stimulation cause reduction in growth and feed utilization and rapid muscle protein degradation (Klasing and Johnston, 1991). Interleukin-6 and TGF-b are found elevated in ascites fluid of chickens suffering from ascites syndrome (Rath et al., 1995). The role of these cytokines may therefore be significant in noninfectious, metabolic diseases, such as the ascites syndrome in chickens. Recently, Jakowlew and co-workers (1997) have also shown enhanced expression of TGF-b during coccidial infection in chickens. The fact that some isoforms of TGF-b inhibit the proliferation of T-lymphocytes (Kehrl et al., 1986) suggests that TGF-b may interfere with the resolution of a disease such as coccidiosis. Also unclear is the role of arginine metabolites, such as nitric oxide, in avian diseases. Nitric oxide synthase, an enzyme that uses arginine as a substrate and converts it into bioactive metabolites, is inducible by lymphokines in chicken macrophages (Hussain and Qureshi, 1997). Therefore, it is possible that in diseases such as coccidiosis, the cytokine-metabolite milieu created within the intestinal microenvironment, may lead to physiological alterations such as vasodilation, resulting in increased hemorrhagic lesions as reported by Allen (1997). Indeed, our studies have shown that macrophages cultured from spleens of chickens challenged with Eimeria acervulina produced increasing levels of nitrite (an indicator of nitric oxide synthase activity) with the progression of clinical coccidiosis (Figure 1). Another example of heightened cytokine production in a disease situation is our recent observation that macrophages from poults infected with the poult enteritis and mortality syndrome (PEMS) agent(s) produce higher levels of several cytokines. The fact that interleukin-1, interleukin-6, and nitrite levels are increased in PEMS (unpublished observation, Figure 1) suggests that an
1127
1128
QURESHI ET AL.
IMMUNOMODULATION There is enough evidence both in the mammalian and avian literature that the immune system is capable of responding to numerous factors such as dietary, environmental, physiological, genetic, toxicological factors. In fact, it is reasonable to believe that immune evaluation can serve as a sensitive indicator of environmental stressors such as heat (Miller and Qureshi, 1992), mycotoxin exposure (Qureshi et al., 1998), and several other stressors. For example, broiler breeder hens fed a diet containing aflatoxin have been shown to transfer active aflatoxin metabolites into the eggs (Qureshi et al., 1998). Such maternal transfer of aflatoxin residues through natural exposure (i.e., resulting from consumption of aflatoxin by dams) results in embryonic mortality, reduced hatchability, and significant immune dysfunction in progeny chicks. The obvious implications of such exposure would be an increased susceptibility to diseases owing to suppression of humoral and cellular immunity. Significant progress is being made in developing recombinant vaccines; however, the efficacy of these vaccines relative to the classical live attenuated vaccines
is still not fully tested. Similarly, new adjuvants are being discovered and employed as enhancers of the vaccine response. One can also exploit the use of specific dietary supplements to boost the intrinsic potential of poultry to perform better immunologically. Possible candidates for such dietary supplements include several vitamins, especially vitamin E. For example, we have recently demonstrated that in ovo vitamin E inoculation enhances both humoral and cellular effector components of the avian immune system (Gore and Qureshi, 1997). From a practical standpoint, the in ovo route is currently being used for delivering biological materials such as Marek’s and infectious bursal disease vaccines in commercial poultry. Vitamin E delivery via this route may, therefore, provide immune-enhancing benefits immediately following hatch. Cook (1991) has written an excellent account of the effect of several dietary supplements on immune system functions. The role of immunogenetics in disease resistance is also well documented and is being presented separately. Despite the positive contribution of the bird’s genetic makeup, its innate resistance may be overwhelmed by the virulence of the infective agent. Therefore, while considering issues such as vaccinal immunity, both the nature of pathogen and the genetic background of the host must be considered. For example, Marek’s disease vaccine serotype 1 (R2/23) protected B15B15 chickens against a very virulent Marek’s disease virus strain, Md5, but not B5B5 chickens, whereas vaccination with serotype 2 (301/1) or 3 (HVT) protected B5B5 chickens equally well (Bacon and Witter, 1994a). Although protective response against Marek’s disease involves T cell components, this response seems to be dictated by the antigenic nature of the viral serotypes along with the antigen presentation in conjunction with major histocompatibility antigens. Therefore, in dealing with experimental (e.g., congenics) or commercial chicken stocks, protective synergism (Bacon and Witter, 1994b) or “designer vaccines” matched to defined B-haplotypes (Bacon and Witter, 1993) may be important aspects of future vaccination strategies or immunomodulation. In conclusion, although the avian immune system is both structurally and functionally unique, it is directly influenced by physiological, genetic, nutritional, and environmental factors. Therefore, the immune system can serve as a sensitive indicator of management and production influences on avian health. Based on current developments in genetics, nutrition, and biotechnology, the immune system is an ideal candidate for multidisciplinary efforts in improving avian health.
REFERENCES Allen, P. C., 1997. Nitric oxide production during Eimeria tenella infections in chickens. Poultry Sci. 76:810–813. Andreasen, J. R., Jr., A. B. Andreasen, M. Anwar, and A. E. Sonn, 1993. Chicken heterophil chemotaxis using staphylococcus-generated chemoattractants. Avian Dis. 37: 835–838.
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
(activation of antiviral and antitumor mechanisms) responses. Characteristics of both of these responses include specificity and memory, which are absolutely essential and exploited for effective vaccination. In a recent review, Koch (1994) has presented an excellent account of several aspects of immune responses and mechanisms operative during infection and vaccination in poultry. For immunosurveillance at the flock or individual bird level, it is important to select appropriate immunological endpoints as a measure of immune competence. Comparable immune test panels have been described for mammals (Luster et al., 1992) and poultry (Bacon, 1992; Dietert et al., 1994; Qureshi, 1996). The immune test panels described for avian species take into account both the humoral and cell-mediated immune assessment needed for research as well as at the field level. Some of these immune endpoints include lymphoid organ integrity, antibody production, T-lymphocyte functions, and relative frequency of subpopulations, blood monocytes and heterophils chemotaxis, phagocytosis by macrophages, and tumoricidal activity by natural killer cells. Examples in the avian literature describing the usefulness of these immunological techniques include antibody responses to sheep red blood cells (Dix and Taylor, 1996) and bovine serum albumin (Parmentier et al., 1997); commercial enzyme-linked immunosorbent assay kits for Newcastle, infectious bronchitis, infectious bursal disease, and reovirus (Keck et al., 1993), quantification of lymphocyte subpopulations (Erf and Bottje, 1996), chemotaxis (Andreasen et al., 1993), toe-web assay (Bayyari et al., 1997), and phagocytosis assay (Qureshi and Miller, 1991).
SYMPOSIUM: INFECTIOUS POULTRY DISEASES
Kehrl, J. H., L. M. Wakefield, A. B. Roberts, S. B. Jakowlew, M. Alvarez-Mon, R. Derynck, M. B. Sporn, and A. S. Fauci, 1986. Production of transforming growth factor b3 by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med. 163:1037–1050. Klasing, K. C., and B. J. Johnston, 1991. Monokines in growth and development. Poultry Sci. 70:1781–1789. Koch, G., 1994. Immunological principles of vaccination of poultry: A lot to explore. Pages 197–206 in: Advances in Avian Immunology Research. T. F. Davison, N. Bumstead, and P. Kaiser, ed. Carfax Publishing Co., Oxfordshire, UK. Luster, M. I., C. Portier, D. G. Pait, K. L. White, Jr., C. Gennings, A. E. Munson, and G. J. Rosenthal, 1992. Risk assessment in immunotoxicology. Fundam. Appl. Toxicol. 18:200–210. Miller, L., and M. A. Qureshi, 1992. Induction of heat-shock proteins and phagocytic function of chicken macrophages following in vitro heat exposure. Vet. Immunol. Immunopathol. 30:179–191. Morrison, W. I., 1996. Future approaches to vaccine development. Pages 389–403 in: Poultry Immunology. T. F. Davison, T. R. Morris, and L. N. Payne, ed. Carfax Publishing Co., Oxfordshire, UK. Parmentier, H. K., M.G.B. Nieuwland, M. W. Barwegen, R. P. Kwakkel, and J. W. Schrama, 1997. Dietary unsaturated fatty acids affect antibody responses and growth of chickens divergently selected for humoral responses to sheep red blood cells. Poultry Sci. 76:1164–1171. Qureshi, M. A., 1996. Genetic basis of immune responses in chickens. Pages 1–23 in: Proceedings Watt Poultry Summit II, Breed X Nutrition, University of Georgia, Athens, GA. Qureshi, M. A., and L. Miller, 1991. Comparison of macrophage functions in several commercial broiler genetic lines. Poultry Sci. 70:2094–2101. Qureshi, M. A., R. R. Dietert, and L. D. Bacon, 1986. Genetic variation in the recruitment and activation of chicken peritoneal macrophages. Proc. Soc. Exp. Biol. Med. 181: 560–568. Qureshi, M. A., F. W. Edens, and G. B. Havenstein, 1997. Immune system dysfunction during exposure to poult enteritis and mortality syndrome agents. Poultry Sci. 76: 564–569. Qureshi, M. A., J. Brake, P. B. Hamilton, W. M. Hagler, Jr., and S. Nesheim 1998. Dietary exposure of broiler breeders to aflatoxin results in immune function in progeny chicks. Poultry Sci. 77:812–819. Rath, N. C., W. E. Huff, G. R. Bayyari, and J. M. Balog, 1995. Identification of transforming growth factor-b and interleukin-6 in chicken ascites fluid. Avian Dis. 39: 382–389. Rodenberg, J., J. M. Sharma, S. W. Belzer, R. M. Nordgren, and S. Naqi, 1994. Flow cytometric analysis of B cell and T cell subpopulations in specific-pathogen-free chickens infected with infectious bursal disease virus. Avian Dis. 38:16–21. Saif, Y. M., 1991. Immunosuppression induced by infectious bursal disease virus. Vet. Immunol. Immunopathol. 30: 45–50. Schat, K. A., and T. J. Myers, 1991. Avian intestinal immunity. Crit. Rev. Poult. Biol. 3:19–34. Weinstock, D., K. A. Schat, and B. W. Calnek, 1989. Cytotoxic T lymphocytes in reticuloendotheliosis virus-infected chickens. Eur. J. Immunol. 19:267–272.
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
Bacon, L. D., 1992. Measurement of immune competence in chickens. Poult. Sci. Rev. 4:187–195. Bacon, L. D., and R. L. Witter, 1993. Influence of B-haplotype on the relative efficacy of Marek’s disease vaccines of different serotypes. Avian Dis. 37:53–59. Bacon, L. D., and R. L. Witter, 1994a. Serotype specificity of Bhaplotype influence on the relative efficacy of Marek’s disease vaccines. Avian Dis. 38:65–71. Bacon, L. D., and R. L. Witter, 1994b. B-haplotype influence on the relative efficacy of Marek’s disease vaccine in commercial chickens. Poultry Sci. 73:481–487. Baxendale, W., 1996. Current methods of delivery of poultry vaccines. Pages 375–387 in: Poultry Immunology. T. F. Davison, T. R. Morris, and L. N. Payne, ed. Carfax Publishing Company, Oxfordshire, UK. Bayyari, G. R., W. E. Huff, J. M. Balog, and N. C. Rath, 1997. Variation in toe-web response of turkey poults to phytohemagglutinin-P and the resistance to Escherichia coli challenge. Poultry Sci. 76:791–797. Chang, C. F., and P. B. Hamilton, 1979. The thrombocyte as the primary circulating phagocyte in chickens. J. Reticuloendothelial Soc. 25:585–590. Cook, M. E., 1991. Nutrition and the immune response of domestic fowl. Crit. Rev. Poult. Biol. 3:167–189. Dietert, R. R., K. A. Golemboski, and R. E. Austic, 1994. Environment-immune interactions. Poultry Sci. 73: 1062–1076. Dix, M. C., and R. L. Taylor, Jr., 1996. Differential antibody responses in 6.B major histocompatibility (B) complex congenic chickens. Poultry Sci. 75:203–207. Erf, G. F., and W. G. Bottje, 1996. Nutrition and immune function in chickens: benefits of dietary vitamin E supplementation. Pages 113–130 in: Proceedings Arkansas Nutrition Conference, University of Arkansas, Fayetteville, AR. Glick, B., 1995. The Immune System of Poultry. Pages 483–524 in: World Animal Science C9: Poultry Production. Vol. 32, P. Huton, ed. Elsevier, New York, NY. Gore, A. B., and M. A. Qureshi, 1997. Enhancement of humoral and cellular immunity by vitamin E after embryonic exposure. Poultry Sci. 76:984–991. Harmon, B. G., J. R. Glisson, and J. C. Nunnally, 1992. Turkey macrophage and heterophil bactericidal activity against Pasteurella multocida. Avian Dis. 36:986–991. Hussain, I., and M. A. Qureshi, 1997. Nitric oxide synthase activity and mRNA expression in chicken macrophages. Poultry Sci. 76:1524–1530. Jakowlew, S. B., A. Mathias, and H. S. Lillehoj, 1997. Transforming growth factor-b isoforms in the developing chicken intestine and spleen: increase in transforming growth factor-b4 with coccidia infection. Vet. Immunol. Immunopathol. 55:321–339. Jeurissen, S. H. M., L. Vervelde, and E. M. Janse, 1994. Structure and function of lymphoid tissues of the chicken. Crit. Rev. Poult. Biol. 6:183–207. Keck, L. D., J. K. Skeeles, and R. W. McNew, 1993. Antibody detection in matched chicken sera and egg-yolk samples by commercial enzyme-linked immunosorbant assay kits for Newcastle disease virus, infectious bronchitis virus, infectious bursal disease virus, and avian reovirus. Avian Dis. 37:825–828.
1129
(Key words: immunosurveillance, cytokines, immunomodulation) 1998 Poultry Science 77:1126–1129
INTRODUCTION Lymphoid and nonlymphoid systems constitute two broad structural categories of the avian (and mammalian) immune system. Among lymphoid components, the bursa of Fabricius, a site of B-lymphocyte development and differentiation, and the thymus, a site of Tlymphocyte development and differentiation, are considered to be primary lymphoid organs, whereas the spleen is usually termed a secondary lymphoid organ. In addition, lymphoid structures distributed throughout the intestinal tract represent the “intestinal arm” of the immune system. Although not studied extensively, intestinal immune structures may in fact be the crucial barriers to external pathogens because many economically important pathogens replicate in the intestinal epithelium. The anatomical and functional complexities of lymphoid organs and their role in avian health and disease have recently been reviewed (Schat and Myers, 1991; Jeurissen et al., 1994; Glick, 1995). The nonlymphoid components of the immune system include cells that provide a nonspecific immunological defense to the host. Being the first line of immunological defense, the cells of the mononuclear phagocytic system are the primary players in this category. Blood monocytes and tissue macrophages are unique because of their wide
Received for publication August 3, 1997. Accepted for publication January 20, 1998. 1The use of trade names in this publication does not imply endorsement by the North Carolina Agricultural Research Service, nor criticism of similar products not mentioned. 2To whom correspondence should be addressed.
distribution throughout the body fluids, organs, and cavities. Being phagocytic in nature, macrophages bind, internalize, and degrade foreign antigens, such as bacteria, without any lag period after encounter. For example, chicken macrophages have been shown to kill greater than 80% of the internalized Salmonella in the first 15 min of engulfment (Qureshi et al., 1986). Additional nonlymphoid cells with phagocytic potential in aves include heterophils (counterparts of the mammalian neutrophils) and thrombocytes (Chang and Hamilton, 1979; Harmon et al., 1992). Functionally, the avian immune system, similar to that of mammals, mediates the so-called humoral and cell-mediated immunity. Humoral immunity is the adaptive function of the immune system through which antibodies are produced in response to an antigenic challenge. Cell-mediated immunity involves immune mechanism(s) by which cells infected with a foreign agent, such as a virus, are destroyed, and is accomplished via a direct effector (e.g., an activated T cell) and target cell contact (Weinstock et al., 1989).
IMMUNE SYSTEM AND DISEASE It is reasonable to assume that organisms that have direct tropism for any of the primary or secondary lymphoid organs would cause alterations in immune system functions. Insults by such infective organisms
Abbreviation Key: IBDV = infectious bursal disease virus; PEMS = poult enteritis and mortality syndrome; TGF-b = transforming growth factor-b; TNF = tumor necrosis factor.
1126
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
ABSTRACT Two functional aspects of the avian immune system, the humoral and the cell-mediated arms, provide the basis for the preventive and protective response against disease-causing microorganisms. On the other hand, certain avian diseases may induce a transient or permanent immunosuppressive state in one or both of these arms, leading to increased disease susceptibility. In addition to the classical immune response, manifested as antibody production or effector
SYMPOSIUM: INFECTIOUS POULTRY DISEASES
FIGURE 1. An example of enhanced production of immune-system mediated metabolites in avian diseases. As seen, nitrite levels in the culture supernatant fractions of macrophages increase significantly during the progression of both coccidial infection in chickens and poult enteritis and mortality syndrome (PEMS) in turkeys. The histograms represent the means and standard errors of nitrite in splenic (coccidial challenge) and abdominal (PEMS) macrophage culture supernatants at given days. The histograms within each disease with varying letters (a, b) indicate statistical significance at P < 0.05.
immune dysfunction, possibly based on these proinflammatory cytokines, may cause severe metabolic disorders like those seen associated with PEMS (Qureshi et al., 1997).
IMMUNE SURVEILLANCE The ultimate test of the immunocompetence of a flock is the ability of the birds to resist either a natural or an experimental disease challenge. Modern poultry health practices include vaccination programs that are designed to hyperimmunize hens to effectively transfer passive immunity to the progeny and initiate natural immunity from day of hatch. Obviously, such vaccination regimens are dependent upon the type of the bird as well as the disease under consideration. Furthermore, for the vaccines to be effective, it is important that they are delivered properly and effectively for maximum immunological benefit. Vaccines are currently available for immunizing birds against a variety of infectious diseases (Koch, 1994; Baxendale, 1996). The immunological response of birds to either vaccination or natural infection is quite diversified (Morrison, 1996). Innate immune responses mediated by cells of the mononuclear phagocytic system, such as monocyte and macrophages and natural killer cells, would either inhibit the growth and replication of the antigen source in question or they would initiate a cascade of events leading to an adaptive response. Adaptive immune response starts with the processing and presentation of the antigen. The host’s immune system then responds by mounting either humoral (e.g., antibody production) or cell-mediated
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
may result either in organ necrosis or atrophy or specific subpopulations of the lymphoid cellular components may be affected. For example, chicks infected with infectious bursal disease virus (IBDV) show bursal involvement (e.g., replication of the virus in bursa, bursal necrosis, and lymphoid depletion). Immunologically, infected chicks have lower serum IgM levels. However, Rodenberg et al. (1994) observed no drastic changes in CD4 and CD8 lymphocyte subpopulations in spleens of IBDV-infected chicks. Nevertheless, it is often observed that chickens infected with IBDV show increasing susceptibility to several diseases and respond poorly to vaccination (Saif, 1991). The point, therefore, is that a disease can lead to an immunologically dysfunctional state. On the other hand, it is also possible that immune dysregulation can cause alterations in normal physiological and metabolic processes with adverse consequences. The candidates for such immune system-mediated pathology are several cytokines such as transforming growth factor-b (TGF-b), interleukin-1, interleukin-6, and tumor necrosis factor (TNF) produced by macrophages in response to inflammatory challenge. Interleukin-1 or TNF produced after immune stimulation cause reduction in growth and feed utilization and rapid muscle protein degradation (Klasing and Johnston, 1991). Interleukin-6 and TGF-b are found elevated in ascites fluid of chickens suffering from ascites syndrome (Rath et al., 1995). The role of these cytokines may therefore be significant in noninfectious, metabolic diseases, such as the ascites syndrome in chickens. Recently, Jakowlew and co-workers (1997) have also shown enhanced expression of TGF-b during coccidial infection in chickens. The fact that some isoforms of TGF-b inhibit the proliferation of T-lymphocytes (Kehrl et al., 1986) suggests that TGF-b may interfere with the resolution of a disease such as coccidiosis. Also unclear is the role of arginine metabolites, such as nitric oxide, in avian diseases. Nitric oxide synthase, an enzyme that uses arginine as a substrate and converts it into bioactive metabolites, is inducible by lymphokines in chicken macrophages (Hussain and Qureshi, 1997). Therefore, it is possible that in diseases such as coccidiosis, the cytokine-metabolite milieu created within the intestinal microenvironment, may lead to physiological alterations such as vasodilation, resulting in increased hemorrhagic lesions as reported by Allen (1997). Indeed, our studies have shown that macrophages cultured from spleens of chickens challenged with Eimeria acervulina produced increasing levels of nitrite (an indicator of nitric oxide synthase activity) with the progression of clinical coccidiosis (Figure 1). Another example of heightened cytokine production in a disease situation is our recent observation that macrophages from poults infected with the poult enteritis and mortality syndrome (PEMS) agent(s) produce higher levels of several cytokines. The fact that interleukin-1, interleukin-6, and nitrite levels are increased in PEMS (unpublished observation, Figure 1) suggests that an
1127
1128
QURESHI ET AL.
IMMUNOMODULATION There is enough evidence both in the mammalian and avian literature that the immune system is capable of responding to numerous factors such as dietary, environmental, physiological, genetic, toxicological factors. In fact, it is reasonable to believe that immune evaluation can serve as a sensitive indicator of environmental stressors such as heat (Miller and Qureshi, 1992), mycotoxin exposure (Qureshi et al., 1998), and several other stressors. For example, broiler breeder hens fed a diet containing aflatoxin have been shown to transfer active aflatoxin metabolites into the eggs (Qureshi et al., 1998). Such maternal transfer of aflatoxin residues through natural exposure (i.e., resulting from consumption of aflatoxin by dams) results in embryonic mortality, reduced hatchability, and significant immune dysfunction in progeny chicks. The obvious implications of such exposure would be an increased susceptibility to diseases owing to suppression of humoral and cellular immunity. Significant progress is being made in developing recombinant vaccines; however, the efficacy of these vaccines relative to the classical live attenuated vaccines
is still not fully tested. Similarly, new adjuvants are being discovered and employed as enhancers of the vaccine response. One can also exploit the use of specific dietary supplements to boost the intrinsic potential of poultry to perform better immunologically. Possible candidates for such dietary supplements include several vitamins, especially vitamin E. For example, we have recently demonstrated that in ovo vitamin E inoculation enhances both humoral and cellular effector components of the avian immune system (Gore and Qureshi, 1997). From a practical standpoint, the in ovo route is currently being used for delivering biological materials such as Marek’s and infectious bursal disease vaccines in commercial poultry. Vitamin E delivery via this route may, therefore, provide immune-enhancing benefits immediately following hatch. Cook (1991) has written an excellent account of the effect of several dietary supplements on immune system functions. The role of immunogenetics in disease resistance is also well documented and is being presented separately. Despite the positive contribution of the bird’s genetic makeup, its innate resistance may be overwhelmed by the virulence of the infective agent. Therefore, while considering issues such as vaccinal immunity, both the nature of pathogen and the genetic background of the host must be considered. For example, Marek’s disease vaccine serotype 1 (R2/23) protected B15B15 chickens against a very virulent Marek’s disease virus strain, Md5, but not B5B5 chickens, whereas vaccination with serotype 2 (301/1) or 3 (HVT) protected B5B5 chickens equally well (Bacon and Witter, 1994a). Although protective response against Marek’s disease involves T cell components, this response seems to be dictated by the antigenic nature of the viral serotypes along with the antigen presentation in conjunction with major histocompatibility antigens. Therefore, in dealing with experimental (e.g., congenics) or commercial chicken stocks, protective synergism (Bacon and Witter, 1994b) or “designer vaccines” matched to defined B-haplotypes (Bacon and Witter, 1993) may be important aspects of future vaccination strategies or immunomodulation. In conclusion, although the avian immune system is both structurally and functionally unique, it is directly influenced by physiological, genetic, nutritional, and environmental factors. Therefore, the immune system can serve as a sensitive indicator of management and production influences on avian health. Based on current developments in genetics, nutrition, and biotechnology, the immune system is an ideal candidate for multidisciplinary efforts in improving avian health.
REFERENCES Allen, P. C., 1997. Nitric oxide production during Eimeria tenella infections in chickens. Poultry Sci. 76:810–813. Andreasen, J. R., Jr., A. B. Andreasen, M. Anwar, and A. E. Sonn, 1993. Chicken heterophil chemotaxis using staphylococcus-generated chemoattractants. Avian Dis. 37: 835–838.
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
(activation of antiviral and antitumor mechanisms) responses. Characteristics of both of these responses include specificity and memory, which are absolutely essential and exploited for effective vaccination. In a recent review, Koch (1994) has presented an excellent account of several aspects of immune responses and mechanisms operative during infection and vaccination in poultry. For immunosurveillance at the flock or individual bird level, it is important to select appropriate immunological endpoints as a measure of immune competence. Comparable immune test panels have been described for mammals (Luster et al., 1992) and poultry (Bacon, 1992; Dietert et al., 1994; Qureshi, 1996). The immune test panels described for avian species take into account both the humoral and cell-mediated immune assessment needed for research as well as at the field level. Some of these immune endpoints include lymphoid organ integrity, antibody production, T-lymphocyte functions, and relative frequency of subpopulations, blood monocytes and heterophils chemotaxis, phagocytosis by macrophages, and tumoricidal activity by natural killer cells. Examples in the avian literature describing the usefulness of these immunological techniques include antibody responses to sheep red blood cells (Dix and Taylor, 1996) and bovine serum albumin (Parmentier et al., 1997); commercial enzyme-linked immunosorbent assay kits for Newcastle, infectious bronchitis, infectious bursal disease, and reovirus (Keck et al., 1993), quantification of lymphocyte subpopulations (Erf and Bottje, 1996), chemotaxis (Andreasen et al., 1993), toe-web assay (Bayyari et al., 1997), and phagocytosis assay (Qureshi and Miller, 1991).
SYMPOSIUM: INFECTIOUS POULTRY DISEASES
Kehrl, J. H., L. M. Wakefield, A. B. Roberts, S. B. Jakowlew, M. Alvarez-Mon, R. Derynck, M. B. Sporn, and A. S. Fauci, 1986. Production of transforming growth factor b3 by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med. 163:1037–1050. Klasing, K. C., and B. J. Johnston, 1991. Monokines in growth and development. Poultry Sci. 70:1781–1789. Koch, G., 1994. Immunological principles of vaccination of poultry: A lot to explore. Pages 197–206 in: Advances in Avian Immunology Research. T. F. Davison, N. Bumstead, and P. Kaiser, ed. Carfax Publishing Co., Oxfordshire, UK. Luster, M. I., C. Portier, D. G. Pait, K. L. White, Jr., C. Gennings, A. E. Munson, and G. J. Rosenthal, 1992. Risk assessment in immunotoxicology. Fundam. Appl. Toxicol. 18:200–210. Miller, L., and M. A. Qureshi, 1992. Induction of heat-shock proteins and phagocytic function of chicken macrophages following in vitro heat exposure. Vet. Immunol. Immunopathol. 30:179–191. Morrison, W. I., 1996. Future approaches to vaccine development. Pages 389–403 in: Poultry Immunology. T. F. Davison, T. R. Morris, and L. N. Payne, ed. Carfax Publishing Co., Oxfordshire, UK. Parmentier, H. K., M.G.B. Nieuwland, M. W. Barwegen, R. P. Kwakkel, and J. W. Schrama, 1997. Dietary unsaturated fatty acids affect antibody responses and growth of chickens divergently selected for humoral responses to sheep red blood cells. Poultry Sci. 76:1164–1171. Qureshi, M. A., 1996. Genetic basis of immune responses in chickens. Pages 1–23 in: Proceedings Watt Poultry Summit II, Breed X Nutrition, University of Georgia, Athens, GA. Qureshi, M. A., and L. Miller, 1991. Comparison of macrophage functions in several commercial broiler genetic lines. Poultry Sci. 70:2094–2101. Qureshi, M. A., R. R. Dietert, and L. D. Bacon, 1986. Genetic variation in the recruitment and activation of chicken peritoneal macrophages. Proc. Soc. Exp. Biol. Med. 181: 560–568. Qureshi, M. A., F. W. Edens, and G. B. Havenstein, 1997. Immune system dysfunction during exposure to poult enteritis and mortality syndrome agents. Poultry Sci. 76: 564–569. Qureshi, M. A., J. Brake, P. B. Hamilton, W. M. Hagler, Jr., and S. Nesheim 1998. Dietary exposure of broiler breeders to aflatoxin results in immune function in progeny chicks. Poultry Sci. 77:812–819. Rath, N. C., W. E. Huff, G. R. Bayyari, and J. M. Balog, 1995. Identification of transforming growth factor-b and interleukin-6 in chicken ascites fluid. Avian Dis. 39: 382–389. Rodenberg, J., J. M. Sharma, S. W. Belzer, R. M. Nordgren, and S. Naqi, 1994. Flow cytometric analysis of B cell and T cell subpopulations in specific-pathogen-free chickens infected with infectious bursal disease virus. Avian Dis. 38:16–21. Saif, Y. M., 1991. Immunosuppression induced by infectious bursal disease virus. Vet. Immunol. Immunopathol. 30: 45–50. Schat, K. A., and T. J. Myers, 1991. Avian intestinal immunity. Crit. Rev. Poult. Biol. 3:19–34. Weinstock, D., K. A. Schat, and B. W. Calnek, 1989. Cytotoxic T lymphocytes in reticuloendotheliosis virus-infected chickens. Eur. J. Immunol. 19:267–272.
Downloaded from http://ps.oxfordjournals.org/ at Purdue University Libraries ADMN on June 25, 2015
Bacon, L. D., 1992. Measurement of immune competence in chickens. Poult. Sci. Rev. 4:187–195. Bacon, L. D., and R. L. Witter, 1993. Influence of B-haplotype on the relative efficacy of Marek’s disease vaccines of different serotypes. Avian Dis. 37:53–59. Bacon, L. D., and R. L. Witter, 1994a. Serotype specificity of Bhaplotype influence on the relative efficacy of Marek’s disease vaccines. Avian Dis. 38:65–71. Bacon, L. D., and R. L. Witter, 1994b. B-haplotype influence on the relative efficacy of Marek’s disease vaccine in commercial chickens. Poultry Sci. 73:481–487. Baxendale, W., 1996. Current methods of delivery of poultry vaccines. Pages 375–387 in: Poultry Immunology. T. F. Davison, T. R. Morris, and L. N. Payne, ed. Carfax Publishing Company, Oxfordshire, UK. Bayyari, G. R., W. E. Huff, J. M. Balog, and N. C. Rath, 1997. Variation in toe-web response of turkey poults to phytohemagglutinin-P and the resistance to Escherichia coli challenge. Poultry Sci. 76:791–797. Chang, C. F., and P. B. Hamilton, 1979. The thrombocyte as the primary circulating phagocyte in chickens. J. Reticuloendothelial Soc. 25:585–590. Cook, M. E., 1991. Nutrition and the immune response of domestic fowl. Crit. Rev. Poult. Biol. 3:167–189. Dietert, R. R., K. A. Golemboski, and R. E. Austic, 1994. Environment-immune interactions. Poultry Sci. 73: 1062–1076. Dix, M. C., and R. L. Taylor, Jr., 1996. Differential antibody responses in 6.B major histocompatibility (B) complex congenic chickens. Poultry Sci. 75:203–207. Erf, G. F., and W. G. Bottje, 1996. Nutrition and immune function in chickens: benefits of dietary vitamin E supplementation. Pages 113–130 in: Proceedings Arkansas Nutrition Conference, University of Arkansas, Fayetteville, AR. Glick, B., 1995. The Immune System of Poultry. Pages 483–524 in: World Animal Science C9: Poultry Production. Vol. 32, P. Huton, ed. Elsevier, New York, NY. Gore, A. B., and M. A. Qureshi, 1997. Enhancement of humoral and cellular immunity by vitamin E after embryonic exposure. Poultry Sci. 76:984–991. Harmon, B. G., J. R. Glisson, and J. C. Nunnally, 1992. Turkey macrophage and heterophil bactericidal activity against Pasteurella multocida. Avian Dis. 36:986–991. Hussain, I., and M. A. Qureshi, 1997. Nitric oxide synthase activity and mRNA expression in chicken macrophages. Poultry Sci. 76:1524–1530. Jakowlew, S. B., A. Mathias, and H. S. Lillehoj, 1997. Transforming growth factor-b isoforms in the developing chicken intestine and spleen: increase in transforming growth factor-b4 with coccidia infection. Vet. Immunol. Immunopathol. 55:321–339. Jeurissen, S. H. M., L. Vervelde, and E. M. Janse, 1994. Structure and function of lymphoid tissues of the chicken. Crit. Rev. Poult. Biol. 6:183–207. Keck, L. D., J. K. Skeeles, and R. W. McNew, 1993. Antibody detection in matched chicken sera and egg-yolk samples by commercial enzyme-linked immunosorbant assay kits for Newcastle disease virus, infectious bronchitis virus, infectious bursal disease virus, and avian reovirus. Avian Dis. 37:825–828.
1129