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Impact of genetics on disease resistance
Impact of Genetics on Disease Resistance1 SUSAN J. LAMONT2 Department of Animal Science, Iowa State University, Ames, Iowa 50011-3150 ABSTRACT The genetics of a bird or flock has a profound impact on its ability to resist disease, because genetics define the maximum achievable performance level. Careful attention should be paid to genetics as an important component of a comprehensive disease management program including high-level biosecurity, sanitation, and appropriate vaccination programs. Some
specific genes (e.g., the MHC) are known to play a role in disease resistance, but resistance is generally a polygenic phenomenon. Future research directions will expand knowledge of the impact of genetics on disease resistance by identifying non-MHC genetic control of resistance and by further elucidating mechanisms regulating expression of genes related to immune response.
(Key words: genetics, disease, Major Histocompatibility Complex, immunoglobulins, Salmonella enteritidis)
INTRODUCTION A basic tenet in all considerations of disease in poultry is that the genetics of a bird or a flock defines the maximum disease-resistance potential available. One gene family, the MHC, has long been the subject of intense investigation for its role in disease resistance. Responses to a wide array of pathogens has been demonstrated to be associated, in part, with the major histocompatibility complex. Many other candidate genes with a proven or potential role in disease resistance can also be identified: cytokine genes, CD-encoding genes, T cell receptor genes, Nramp1, growth hormone, and the immunoglobulin genes. But resistance to most diseases is likely controlled by polygenes. Both physiological genetic and molecular genetic approaches can be used to investigate polygenic control of immune response and disease resistance. Divergent genetic selection for immunocompetence traits or disease resistance can produce genetic lines to study for correlated changes in their physiology and genetics. These divergent lines can also be crossed to generate populations suitable for mapping molecular markers for desirable performance. Genetic selection, aided by molecular markers, can be used to improve resistance to disease. But, ultimately, a detailed understanding of the genetic basis of immune response modulation will be needed to fully exploit the
Received for publication August 3, 1997. Accepted for publication February 21, 1998. 1Journal Paper Number J-17605 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa; Project Numbers 3290 and 3342 and supported by Hatch Act and State of Iowa funds. 2To whom correspondence should be addressed: [email protected]
discoveries of modern molecular genetics in improving poultry health.
MAJOR HISTOCOMPATIBILITY COMPLEX The best-characterized genetic control of disease resistance and immune response in the chicken is that associated with the MHC. The MHC genes have a profound effect on the ability of animals to respond to specific antigens. The MHC in the chicken was first discovered as a blood group locus and is also termed the B complex (Briles et al., 1950). Schierman and Nordskog (1961) demonstrated that the B blood group locus in chickens is linked to genes controlling histocompatibility. The MHC encodes for three classes of proteins named B-F, B-L, and B-G (reviews, Lamont and Dietert, 1990; Lamont, 1993; Kaufman and Lamont, 1996). At the molecular level, the chicken MHC has unique features that will enhance its value as a marker for disease resistance (Lamont, 1993, 1994; Kaufman and Lamont, 1996): the Class I and II genes overlap, therefore forming extremely tight linkage; introns are relatively small (10% of the size of most mammalian MHC); additional genes, including ones with homology to mammalian genes involved in lymphocyte activation and TAP2 (transporter associated with antigen processing) have been identified in the chicken MHC. Recently, a region similar in sequence but genetically unlinked to the
Abbreviation Key: DWR = delayed wattle reaction; LD50 = 50% lethal dose; REV = reticuloendotheliosis virus; RFLP = restriction fragment length polymorphisms; TAP2 = transporter associated with antigen processing.
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1998 Poultry Science 77:1111–1118
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lines divergently selected for an index of immunocompetence traits, including antibodies, inflammatory response, and reticuloendothelial activity, differences occurred in MHC genotype frequencies (Kean et al., 1994a). Genetic control of immunoresponsiveness can also be investigated by measuring cell-mediated immunity. The delayed wattle reaction (DWR) is commonly used as a measure of cell-mediated immunity in the chicken (Klesius et al., 1977). Both polyclonal inducers (e.g., phytohemagglutinin Taylor et al., 1987) and specific inducers (e.g., Staphylococcus aureus, Cotter et al., 1987) generate a cell-mediated immunity associated with the B complex. Qureshi and colleagues (Qureshi et al., 1986, 1988) showed that chemotactic activity of chicken blood mononuclear leukocytes, and activity and recruitment to the peritoneal cavity of macrophages differed among the 15I5-B-congenic lines. Allograft and antibody responses also varied by MHC in the same lines (Shen et al., 1984; Bacon et al., 1987). Lines of chicken congenic for the MHC were also used to demonstrate MHC associations with CD4 and CD8 lymphocyte percentages and ratios (Hala et al., 1991). The levels of total serum hemolytic complement have been associated with the MHC in chickens (Chanh et al., 1976) although specific components were not found to segregate with the MHC (Koch, 1986). Investigations of the fundamental biology of the chicken MHC have been motivated by the association of the chicken MHC with resistance to disease. Several reviews (Bacon, 1987; Lamont, 1989, 1991, 1993; Gavora, 1990; Stevens, 1991) have surveyed this subject. The best-characterized association of the MHC with disease resistance is to Marek’s disease, a herpes virus-induced lymphoma. This MHC influence has been mapped, using recombinants, to the B-F|B-L region (Briles et al., 1983; Hepkema et al., 1993). The MHC is associated with traits of tumor incidence, mortality, and transient paralysis induced by Marek’s disease virus. One specific haplotype, B21, seems to convey Marek’s resistance to many different genetic backgrounds. Variation in response to Marek’s disease virus by sublines that are identical at the B locus, however, illustrates the importance of non-MHC gene effects on Marek’s response (Bacon, 1987). Genetic complementation with MHC alleles of genes such as Ir-GAT or other genes affecting antibody response may affect the susceptibility to Marek’s disease (Steadham et al., 1987; Pinard et al., 1993). The MHC also influences the response to other virally induced diseases, including Rous sarcoma virus tumors (Schierman et al., 1987; White et al., 1994), v-src tumors (Taylor et al., 1992), and avian leukosis (Yoo and Sheldon, 1992). Resistance to diseases caused by nonviral pathogens also has been associated with the MHC (Gavora, 1990). These diseases include spontaneous autoimmune thyroiditis (Rose, 1994), and coccidiosis (Lillehoj et al., 1989; Caron et al., 1997). There is a relative paucity of
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MHC, termed Rfp-Y has been mapped to the MHCbearing chromosome (Miller et al., 1994, 1996). The chicken MHC antigens perform crucial functions in the regulation of cellular communication in the immune response. The cell surface antigens of the MHC are unique to each genetically unique individual. This allows immune reactions to occur against disease organisms of an almost infinite spectrum, while simultaneously preserving the organism from self-destruction. The control of the MHC over communication events occurs at two levels: molecular interactions at the cell surface and cellular cooperation in an immune response (Dietert, 1987). The MHC cell surface glycoproteins interact with both the antigen and with complementary structures of other immune cells, generating an immune response that is specific for the inducing antigen. For different cell types of the immune system to communicate effectively, they must share at least one MHC haplotype, a phenomenon known as MHC restriction (Vainio and Toivanen, 1987; Vainio et al., 1987). The MHC restricts T cell cytotoxic reactions with some virus-infected or transformed cells (Schat, 1994). When cytotoxic T cells are combined with reticuloendotheliosis virus (REV) infected cells, significant cytotoxicity occurs only with syngeneic effector and target cell combinations (MacCubbin and Schierman, 1986). A T cell with antigen-restricted cytotoxic properties was identified as the effector cell responsible for the MHCrestricted cell-mediated cytotoxicity (Weinstock and Schat, 1987). The MHC- and virus-restricted cytotoxic cells may be an important immune surveillance mechanism to stop proliferation of virally induced tumors (Schierman and Collins, 1987). Antibody production against a variety of antigens is linked to the chicken MHC. Immune responses to synthetic polypeptides such as (T, G)-A-L, GAT, and GT are linked to the MHC in the chicken (Gunther et al., 1974; Benedict et al., 1975; Pevzner et al., 1979). Antibody titers to other soluble antigens (e.g., bovine serum albumin) and to cellular antigens (e.g., Salmonella pullorum bacterin, SRBC) are also associated with the chicken MHC (Pevzner et al., 1975; Loudovaris et al., 1990). Total serum IgG levels are associated with the B complex (Rees and Nordskog, 1981; Pinard and van der Zijpp, 1993). In long-term selection experiments for antibody response to SRBC conducted independently by Siegel and colleagues and by van der Zijpp and colleagues, correlated changes in MHC allelic frequencies were detected (Dunnington et al., 1984; Pinard et al., 1993). The MHC genotype explains part of the total variation in the antibody levels, and the background genome also has a substantial effect. In meat-type lines divergently selected for early antibody response to Escherichia coli vaccination, differences occurred in frequency of MHC class IV restriction fragment-length polymorphisms (RFLP) bands (Uni et al., 1993). Recent studies with other probes showed the Tap2 and B-F regions to be associated with antibody production (Cahaner et al., 1997). In Leghorn
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The poultry breeding industry can currently apply MHC information to selectively alter MHC allelic frequencies for improvement of disease resistance and vaccine response. Certain MHC alleles are associated with Marek’s disease vaccination efficacy in commercial genetic backgrounds (Bacon and Witter, 1994). Beneficial MHC alleles can be increased in frequency or fixed within a parent line. The extreme polymorphism of the MHC (over 50 allelic forms) allows many options for choice of specific MHC alleles in parent lines and allelic combinations in commercial birds. New applications of MHC manipulation to improve avian health should incorporate new biotechnologies (Lamont, 1994). Because antigen-binding specificity is critical to effective poultry vaccine design, knowledge of specific MHC types in the flock could allow specific choices to optimize the vaccine-host MHC combination or allow design of targeted recombinant vaccines (Schat, 1994; Bacon and Witter, 1994; Pharr et al., 1993; Witter and Hunt, 1994). With the use of specific gene probes or primers, DNA can be directly examined for allelic forms of the MHC and MHC-linked genes and fine-mapping of the specific loci contributing to disease resistance can be conducted.
REGULATION OF GENES CONTROLLING IMMUNE RESPONSE Many studies of genetic control of disease resistance focus on structural variation. For example, are different alleles associated with differential response to pathogen challenge? But it is becoming increasingly evident that variation in structural genes and their encoded proteins are only one source of variation in biological traits. Variation in gene expression is another important source of differences in performance. Factors controlling gene expression must be understood in order to selectively enhance expression (Lamont, 1994). The regulation of expression of two genes of importance in disease resistance (MHC and immunoglobulin) has been studied in the author’s lab. A 0.7 kb DNA fragment from the 5′ flanking region of a chicken MHC class II B gene (the putative regulatory region) was cloned into chloramphenicol acetyltransferase reporter vectors and then transfected into a chicken macrophage cell line. Positive orientation-dependent promoter activity of the chicken DNA was detected in the reporter construct containing an SV40 enhancer (Chen et al., 1997). Deletion analysis revealed a short fragment in the 3′ end that was crucial for the promoter function and negative regulatory elements located further upstream. Sequence analysis of the chicken MHC class II 5′ region suggests possible involvement of interferon, E 26 specific (ETS)-related proteins, and other factors as candidates in regulating this promoter. An interferonrich chicken T cell line culture supernatant increased the cell-surface expression of MHC class II antigens, as well as class II promoter activity, in this macrophage cell line.
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information on the genetic control of bacterial disease in chickens. Lamont et al. (1987a) demonstrated that genetic control of resistance of a low dosage of Pasteurella multocida was linked with genes of the chicken MHC Class IV region. Cotter et al. (1992) reported MHC linkage of resistance to Staphylococcus aureus. Convincing evidence also exists for a genetic component to resistance to Salmonella enteritidis in chickens. Two groups have examined resistance to S. enteritidis in several genetic lines and have found variation in 50% lethal dose (LD 50) organ contamination, and bacterial burden (Bumstead and Barrow, 1993; Guillot et al., 1995; Protais et al., 1996). No evidence, however, was found for MHC effect on Salmonella response. In a recent report, several NRAMP1-linked markers were identified to be associated with splenic bacterial burden 3 d after intravenous inoculation of S. enteritidis (GirardSantosuosso et al., 1996). This generic association is an excellent example of the application of comparative genomics, in which a gene already defined in a mammalian species is found to have similar structure and function in the chicken (Hu et al., 1995, 1996). The range and variety of diseases influenced by the chicken MHC is, therefore, extensive. Additional factors, such as non-MHC genetic background and vaccination, have also been shown to interact with MHC genes in influencing immune response and disease resistance (Bacon and Witter, 1992; Dunnington et al., 1989, 1992). An important observation that emerges from studies on the MHC and disease, however, is that there is not a single haplotype (perhaps with the exception of B21 and Marek’s disease) that responds optimally in all genetic backgrounds to all disease challenges. Given the many different immune mechanisms involved in resistance to disease and the many levels at which the MHC exerts genetic control, this is not surprising. The repeated associations with the MHC suggest that there are genes for disease response within the MHC, but the lack of consistent association with specific haplotypes suggests that MHC-linked genes other than the classical MHC class I and II genes may have a major influence. Many diverse traits of economic importance such as fertilization rate, embryonic mortality, hatchability, juvenile and adult mortality, body weight, and egg production are also influenced by MHC genotype (Bacon, 1987; Dietert et al. 1991; Sander, 1993). In three independent studies it was shown that long-term selection for egg production traits and disease resistance significantly altered MHC allelic frequencies (Simonsen et al., 1982; Gavora et al., 1986; Lamont et al., 1987b). Although different combinations of B haplotypes were present in these selection studies, some general patterns emerge. The B2 and B21 haplotypes may show overall beneficial associations with economic traits in chickens. Other studies have demonstrated MHC associations with particular production traits, but not necessarily consistency of specific MHC haplotypes or associated traits (Dunnington et al., 1992; Kim et al., 1987, 1989; Abplanalp et al., 1992; Sato et al., 1992).
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SELECTION FOR ANTIBODY RESPONSE In instances in which candidate gene information is not readily available, the approach of selection for a trait of immunocompetence can be employed to enhance disease resistance. Antibody level is a popular choice, because of the ease of repeated measurements and generation of quantitative results. Also, antigens (such as vaccines) can be used that have direct relevance to specific diseases. Although the antibody-disease resistance associations are widely accepted as a general rule, the exact immune defense mechanism for most specific diseases are poorly understood. Many researchers have investigated the genetic control of humoral immune response in egg-type chickens. Siegel and Gross (1980) and Gross et al. (1980) selected egg-type chickens for antibody production to SRBC and tested the resistance of selected lines to infectious diseases. The high-antibody production line was more resistant to parasites and viruses, but not bacteria, than the low antibody line. Subsequent studies showed an interaction of antibody selection and MHC with disease response (Martin et al., 1989). van der Zijpp and coworkers (van der Zijpp and Leenstra, 1980; van der Zijpp et al., 1982; van der Zijpp, 1983) also studied humoral immune response of egg-type chickens to SRBC, with emphasis on dose, genetic origin, interaction, and correlation between primary and secondary immune responses and between humoral and cellmediated responses. Studies with these lines have
TABLE 1. Correlations of Salmonella enteritidis burden in liver, spleen, and cecal content and sibling vaccine antibody level
Spleen Liver Spleen Cecal content
0.98*
Cecal content –0.13 0.02
Antibody 0.00 –0.17 –0.87*
*P < 0.05.
elucidated a role for both antibody selection and MHC type in influencing Marek’s disease response (Pinard et al., 1993). Selection of egg-type chickens for antibody response to Salmonella pullorum antigen (Pevzner et al., 1981) was also successful. Selection for high and low antibody response in meat-type birds, as well as for early and late antibody production, has been successfully conducted (Pitcovski et al., 1987a,b; Leitner et al., 1992; Yonash et al., 1996). Cell-mediated immunity of chickens has also been examined and demonstrated to be under the influence of genetic origin (van der Zijpp, 1983; Lamont and Smyth, 1984). Multitrait immune response selection in egg-type chickens has also been successful (Cheng and Lamont, 1988; Cheng et al., 1991; Kean et al., 1994a,b). Thus, many studies have demonstrated the feasibility of altering immunophysiology by genetic selection. For antibody selection to be effective in a program of genetic selection for disease resistance, the variation in antibody levels must be associated with variation in response to disease. Fortunately, evidence is available for association of antibody and resistance, including examples of association of high antibody levels with resistance to important bacterial pathogens such as E. coli and Salmonella enteritidis. Lines selected for rapid, early antibody response to E. coli were more resistant to E. coli challenge (Leitner et al., 1990; Yonash et al., 1994). Heritability (0.25 and 0.26 in two different broiler breeder male lines) of antibody response to S. enteritidis vaccine established the feasibility of identifying the genetic basis of control of this response (Kaiser et al., 1997, 1998). But because many components of the immune response may be involved in resistance to any specific disease, it was important to investigate the relationship of S. enteritidis antibody and response to live S. enteritidis challenge. To accomplish this goal, the genetic relationship between S. enteritidis colonization and S. enteritidis vaccine antibody response was determined in broiler breeder chicks. Half-sib groups of chicks were either exposed to live S. enteritidis or vaccinated against S. enteritidis. Serum antibodies at 3 wk (10 d postvaccination) were determined by ELISA from the vaccinated chicks. The unvaccinated chicks exposed to S. enteritidis were euthanatized at 3 or 6 wk, and bacterial burden of selected sites was determined. Sire means were calculated for all traits and used for statistical analysis (Table 1). Antibody response to
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This functional characterization of a chicken MHC class II B gene promoter will aid in understanding the regulatory mechanisms that control the expression of these genes of importance in immune function (Chen et al., 1997). Another category of regulatory elements are the Oct transcription factors. The chicken immunoglobulin lambda light chain promoter contains an octamer motif. Two different lymphoid cell lines, DT40 (a B cell line) and MSB1 (a T cell line), were used to test the activity of the germline immunoglobulin promoter and the function of the octamer motif. The promoter was functional only in B cells and then only in the presence of an SV40 enhancer. Mutation of the octamer motif eliminated the transcriptional activity of the immunoglobulin promoter (Heltemes et al., 1997). These results demonstrate that the chicken immunoglobulin promoter functions similarly to mammalian immunoglobulin promoters, in that it plays a role in tissue specificity and requires both an enhancer and an intact octamer motif for activity (Heltemes et al., 1997). Full understanding of the mechanisms that regulate genes of the immune system pave the way toward targeted, specific gene expression and perhaps bypassing tissue specificity in expression of specific genes (e.g., MHC class II, immunoglobulins), thereby opening new avenues to enhance disease resistance.
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vaccination and number of S. enteritidis in cecal swab cultures were significantly negatively correlated (–0.87). Thus, the genetic potential for greater S. enteritidis vaccine antibody response was associated with lesser S. enteritidis cecal colonization in broiler breeder chicks exposed to S. enteritidis. This information demonstrates the feasibility of the goal of improving resistance to S. enteritidis colonization by selecting for increased S. enteritidis antibody response.
CONCLUSION
ACKNOWLEDGMENTS Recent research of the author’s laboratory was partly supported by grants from the USDA-National Research Initiative (95-372205-2245) and the BARD Foundation (US-2317-93), and by Hatch and state of Iowa funds.
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LAMONT complex frequencies after multitrait, divergent selection for immunocompetence. Poultry Sci. 73:7–17. Kean, R. P., A. Cahaner, A. E. Freeman, and S. J. Lamont, 1994b. Direct and correlated responses to multitrait, divergent selection for immunocompetence. Poultry Sci. 73:18–32. Kim, C. D., S. J. Lamont, and M. F. Rothschild, 1987. Genetic associations of body weight and immune response with the major histocompatibility complex in White Leghorn chicks. Poultry Sci. 66:1258–1263. Kim, C. D., S. J. Lamont, and M. F. Rothschild, 1989. Associations of major histocompatibility complex haplotypes with body weight and egg production traits in S1 White Leghorn chickens. Poultry Sci. 68:464–469. Klesius, P., W. Johnson, and T. Kramer, 1977. Delayed wattle reaction as a measure of cell-mediated immunity in the chicken. Poultry Sci. 56:249–256. Koch, C., 1986. A genetic polymorphism of the complement component factor B in chickens is not linked to the major histocompatibility complex (MHC). Immunogenetics 23: 364–367. Lamont, S. J., 1989. The chicken major histocompatibility complex in disease resistance and poultry breeding. J. Dairy Sci. 72:1328–1333. Lamont, S. J., 1991. Immunogenetics and the major histocompatibility complex. Vet. Immunol. Immunopathol. 30: 121–127. Lamont, S. J., 1993. The major histocompatibility complex. Pages 185–203 in: Manipulation of the Avian Genome. R. J. Etches and A. M. Verrinder, ed. CRC Press, Boca Raton, FL. Lamont, S. J., 1994. Poultry immunogenetics: which way do we go? Poultry Sci. 73:1044–1048. Lamont, S. J., and R. R. Dietert, 1990. Immunogenetics. Chapter 22. Pages 497–541 in: Poultry Breeding and Genetics. R. Crawford, ed. Elsevier, Amsterdam, The Netherlands. Lamont, S. J., and J. R. Smyth, Jr., 1984. Effect of selection for delayed amelanosis on immune response in chickens. 2. Cell-mediated immunity. Poultry Sci. 63:440–442. Lamont, S. J., C. Bolin, and N. Cheville, 1987a. Genetic resistance to fowl cholera is linked to the major histocompatibility complex. Immunogenetics 25:284–289. Lamont, S. J., Y.-H. Hou, B. M. Young, and A. W. Nordskog, 1987b. Research note: Differences in major histocompatibility complex gene frequencies associated with feed efficiency and laying performance. Poultry Sci. 66: 1064–1066. Leitner, G., Z. Uni, A. Cahaner, M. Gutman, and E. D. Heller, 1992. Replicated divergent selection of broiler chickens for high or low early antibody response to Escherichia coli vaccination. Poultry Sci. 71:27–37. Leitner, G. D., D. Melamed, N. Drabkin, and E. D. Heller, 1990. An enzyme-linked immunosorbent assay for detection of antibodies against Escherichia coli: association between indirect hemagglutination test and survival. Avian Dis. 34: 58–62. Lillehoj, H. S., M. D. Ruff, L. D. Bacon, S. J. Lamont, and T. K. Jeffers, 1989. Genetic control of immunity to Eimeria tenella: interaction of MHC genes and genes within the genetic background influence levels of disease susceptibility. Vet. Immunol. Immunopathol. 20:135–148. Loudovaris, T., M. R. Brandon, and K. J. Fahey, 1990. The major histocompatibility complex and genetic control of
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Gavora, J. S., 1990. Disease genetics. Chapter 33. Pages 805–846 in: Poultry Breeding and Genetics. R. D. Crawford, ed. Elsevier, Amsterdam, The Netherlands. Gavora, J. S., M. Simonsen, J. F. Spencer, R. W. Fairful, and R. S. Gowe, 1986. Changes in the frequency of major histocompatibility haplotypes in chickens under selection for both high egg production and resistance to Marek’s disease. Z. Tierzucht Zuchtungsbiol. 103:218–226. Girard-Santosuosso, O., P. Menanteau, I. Lantier, P. Mariani, J. Protais, P. Colin, J. F. Guillot, N. Bumstead, P. Pardon, C. Beaumont, and F. Lantier, 1996. Genetic control of resistance to Salmonella enteritidis in chicken. Anim. Genet. 27(Suppl. 2)47. (Abstr.) Gross, W. G., P. B. Siegel, R. W. Hall, C. H. Domermuth, and R. T. DuBois, 1980. Production and persistence of antibodies in chickens to sheep erythrocytes. 2. Resistance to infectious diseases. Poultry Sci. 59:205–210. Guillot, J. F., C. Beaumont, F. Bellatif, C. Mouline, F. Lantier, P. Colin, and J. Protais, 1995. Comparison of resistance of various poultry lines to infection by Salmonella enteritidis. Vet. Res. 26:81–86. Gunther, E., J. Balcarova, K. Hala, E. Rude, and T. Hraba, 1974. Evidence for an association between immune responsiveness of chicken to (T, G)-A-L and the major histocompatibility system. Eur. J. Immunol. 4:548–553. Hala, K., O. Vainio, J. Plachy, and G. Bock, 1991. Chicken major histocompatibility complex congenic lines differ in the percentages of lymphocytes bearing CD4 and CD8 antigens. Anim. Genet. 22:279–284. Heltemes, L. M., C. K. Tuggle, and S. J. Lamont, 1997. Octamer function in the chicken lambda immunoglobulin light chain promotor. Immunogenetics 47:73–76. Hepkema, B. G., J. J. Blankert, G.A.A. Albers, M.G.J. Tilanus, M. E. Egberts, A. J. van der Zijpp, and E. J. Hensen, 1993. Mapping of susceptibility to Marek’s disease within the major histocompatibility (B) complex by refined typing of White Leghorn chickens. Anim. Genet. 24:283–287. Hu, J., N. Bumstead, D. Burka, F. A. Ponce de Leon, E. Skamene, P. Gros, and D. Malo, 1995. Genetic and physical mapping of the natural resistance-associated macrophage protein 1 (NRAMP1) in chicken. Mammal. Genome 67:809–815. Hu, J., N. Bumstead, E. Skamene, P. Gros, and D. Malo, 1996. Structural organization, sequence, and expression of the chicken NRAMP1 gene encoding the natural resistanceassociated macrophage protein 1. DNA and Cell Biol. 15(2):113–123. Kaiser, M. G., T. Wing, A. Cahaner, and S. J. Lamont. 1997. Line difference and heritability of early antibody response to Salmonella enteritidis vaccine in broiler breeder chicks. Pages 138–139 in: Proc. AVIAGEN, 12th International Symposium Current Problems in Avian Genetics. Prague, Czech Republic. Kaiser, M. G., T. Wing, and S. J. Lamont, 1998. Effects of genetics, vaccine dosage, and postvaccination sampling interval on early antibody response to Salmonella enteritidis vaccine in broiler breeder chicks. Poultry Sci. 77:271–275. Kaufman, J. F., and S. J. Lamont, 1996. The chicken major histocompatibility complex. Pages 35–64 in: The Major Histocompatibility Complex in Domestic Animal Species. S. J. Lamont and L. B. Schook, ed. CRC Press, Boca Raton, FL. Kean, R. P., W. E. Briles, A. Cahaner, A. E. Freeman, and S. J. Lamont, 1994a. Differences in major histocompatibility
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Qureshi, M. A., R. R. Dietert, and L. D. Bacon, 1988. Chemotactic activity of chicken blood mononuclear leukocytes from 15I5-B-congenic lines to bacterially-derived chemoattractants. Vet. Immunol. Immunopathol. 19: 351–360. Rees, M. J., and A. W. Nordskog, 1981. Genetic control of serum immunoglobulin G levels in the chicken. J. Immunogenet. 8:425–431. Rose, N. R., 1994. Avian models of autoimmune disease: lessons from the birds. Poultry Sci. 73:984–990. Sander, J. F., 1993. The major histocompatibility complex and its role in poultry production. World’s Poult. Sci. J. 49: 132–138. Sato, K., H. Abplanalp, D. Napolitano, and J. Reid, 1992. Effects of heterozygosity of major histocompatibility complex haplotypes on reproduction and viability of Leghorn hens sharing a common inbred population. Poultry Sci. 71:18–26. Schat, K. A., 1994. Cell-mediated immune effector functions in chickens. Poultry Sci. 73:1077–1081. Schierman, L. W., and A. W. Nordskog, 1961. Relationship of blood type to histocompatibility in chickens. Science 134: 1008–1009. Schierman, L. W., and W. M. Collins, 1987. Influence of the major histocompatibility complex on tumor regression and immunity in chickens. Poultry Sci. 66:812–818. Shen, P. F., E. J. Smith, and L. D. Bacon, 1984. The ontogeny of blood cells, complement, and immunoglobulins in 3- to 12-week-old 15I5-B congenic White Leghorn chickens. Poultry Sci. 63:1083–1093. Siegel, P. B., and W. B. Gross, 1980. Production and persistence of antibodies in chickens to sheep erythrocytes. 1. Directional selection. Poultry Sci. 59:1–5. Simonsen, M., N. Kolstad, I. Edfors-Lilja, L. E. Liledahl, and P. Sorensen, 1982. Major histocompatibility genes in egglaying hens. Am. J. Reprod. Immunol. 2:148–152. Steadham, E. M., S. J. Lamont, I. Kujdych, and A. W. Nordskog, 1987. Association of Marek’s disease with Ea-B and immune response genes in subline and F2 populations of the Iowa State S1 Leghorn line. Poultry Sci. 66:571–575. Stevens, L., 1991. Genetics and Evolution of the Domestic Fowl. Cambridge University Press, Cambridge, UK. Taylor, R. L., Jr., P. F. Cotter, T. L. Wing, and W. E. Briles, 1987. Major histocompatibility (B) complex and sex effects on the phytohemagglutinin wattle response. Anim. Genet. 18:343–350. Taylor, R. L., Jr., D. L. Ewert, J. M. England, and M. S. Halpern, 1992. Major histocompatibility (B) complex control of the growth pattern of v-src DNA-induced primary tumors. Virology 191:477–479. Uni, Z., M. Gutman, G. Leitner, E. Landesman, D. Heller, and A. Cahaner, 1993. Major histocompatibility complex class IV restriction fragment length polymorphism markers in replicated meat-type chicken lines divergently selected for high or low early immune response. Poultry Sci. 72: 1823–1831. Vainio, O., and A. Toivanen, 1987. Cellular cooperation in immunity. Pages 1–12 in: Avian Immunology: Basis and Practice. Vol. 2. A. Toivanen, and P. Toivanen, ed. CRC Press, Boca Raton, FL. Vainio, O., P. Toivanen, and A. Toivanen, 1987. Major histocompatibility complex and cell cooperation. Poultry Sci. 66:795–801.
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antibody response to sheep red blood cells in chickens. Avian Pathol. 19:89–99. MacCubbin, D. L., and L. W. Schierman, 1986. MHC-restricted cytotoxic response of chicken T cells: expression, augmentation, and clonal characterization. J. Immunol. 136:12–16. Martin, A., E. A. Dunnington, W. E. Briles, R. W. Briles, and P. B. Siegel, 1989. Marek’s disease and major histocompatibility complex haplotypes in chickens selected for high or low antibody response, Anim. Genet. 20:407–414. Miller, M. M., R. Goto, A. Bernot, R. Zoorob, C. Auffray, N. Bumstead, and W. E. Briles, 1994. Two MHC class I and MHC class II genes map to the Rfp-Y system outside the Bcomplex. Proc. Natl. Acad. Sci. USA 91:4397–4401. Miller, M. M., R. Goto, R. L. Taylor, Jr., R. Zoorob, C. Auffry, R. W. Briles, W. E. Briles, and S. E. Bloom, 1996. Assignment of Rfp-Y to the chicken microchromosomes and evidence for high frequency recombination associated with nucleolar organizer region. Proc. Natl. Acad. Sci. USA 93:3958–3962. Pevzner, I. V., A. W. Nordskog, and M. L. Kaeberle, 1975. Immune response and the B blood group locus in chickens. Genetics 80:753–759. Pevzner, I. V., C. L. Trowbridge, and A. W. Nordskog, 1979. Bcomplex genetic control of immune response to GAT, (T, G)-A-L, GT and other substances in chickens. J. Immunogenetics 6:453–460. Pevzner, I. Y., H. A. Stone, and A. W. Nordskog, 1981. Immune response disease resistance in chickens. 1. Selection for high and low titer to Salmonella pullorum antigen. Poultry Sci. 60:920–926. Pharr, G. T., L. D. Bacon, and J. B. Dodgson, 1993. Analysis of B-LB chain gene expression in two chicken cDNA libraries. Immunogenetics 37:381–385. Pinard, M.-H., and A. J. van der Zijpp, 1993. Effects of major histocompatibility complex on antibody response in F1 and F2 cross of chicken lines. Genet. Sel. Evol. 25:283–296. Pinard, M.-H., L.L.G. Janss, R. Maatman, J.P.T.M. Noordhuizen, and A. J. van der Zijpp, 1993. Effect of divergent selection for immune responsiveness and of major histocompatibility complex on resistance to Marek’s disease in chickens. Poultry Sci. 72:391–402. Pinard, M.-H., J.A.M. van Arendonk, M.G.B. Nieuwland, and A. J. van der Zijpp, 1993. Divergent selection for humoral immune responsiveness in chickens: distribution and effects of major histocompatibility complex types. Genet. Sel. Evol. 25:191–203. Pitcovski, J., D. E. Heller, A. Cahaner, and B. A. Peleg, 1987a. Selection for early responsiveness of chicks to Escherichia coli and Newcastle disease virus. Poultry Sci. 66:1276–1282. Pitcovski, J., E. D. Heller, A. Cahaner, B. A. Peleg, and N. Drabkin, 1987b. Immunological traits of chicks selected for early and late immune response to E. coli and Newcastle disease virus. Pages 295–305 in: Progress in Clinical and Biological Research, Avian Immunology. Vol. 238. Weber, W. T., and D. L. Ewert, ed. Alan R. Liss, Inc., New York, NY. Protais, J., P. Colin, C. Beaumont, J. F. Guillot, F. Lantier, P. Pardon, and G. Bennejean, 1996. Line differences in resistance to Salmonella enteritidis PT4 infection. Br. Poult. Sci. 37:329–339. 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.
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van der Zijpp, A. J., 1983. The effect of genetic origin, source of antigen, and dose of antigen on the immune response of cockerels. Poultry Sci. 62:205–211. van der Zijpp, A. J., and F. R. Leenstra, 1980. Genetic analysis of the humoral immune response of White Leghorn chicks. Poultry Sci. 59:1363–1369. van der Zijpp, A. J., J. M. Rooijakkers, and B. Kouwenhoven, 1982. The immune response of chick following viral vaccinations and immunization with sheep red blood cells. Avian Dis. 26:97–106. Weinstock, D., and K. A. Schat, 1987. Virus specific syngeneic killing of reticuloendotheliosis virus transformed cell line target cells by spleen cells. Pages 258–263 in: Progress in Clinical and Biological Research, Avian Immunology. Vol. 238. W. T. Weber, and D. L. Ewert, ed. Alan R. Liss, New York, NY. White, E. C., W. E. Briles, R. W. Briles, and R. L. Taylor, Jr., 1994. Response of six major histocompatibility (B) complex
recombinant haplotypes to rous sarcomas. Poultry Sci. 73: 836–842. Witter, R. L., and H. D. Hunt, 1994. Poultry vaccines of the future. Poultry Sci. 73:1087–1093. Yonash, N., M. Chaffer, E. D. Heller, and A. Cahaner, 1994. Effects of RFLP-defined haplotypes of the major histocompatibility complex on immune response and resistance to E. coli of meat-type chickens. Pages 242–245 in: Proceedings of the 5th World Congress on Genetics Applied to Livestock Production, Guelph, ON, Canada. Yonash, N., G. Leitner, R. Waiman, E. D. Heller, and A. Cahaner, 1996. Genetic differences and heritability of antibody response to Escherichia coli vaccination in young meat-type chicks. Poultry Sci. 75:683–690. Yoo, B.H.K., and B. L. Sheldon, 1992. Association of the major histocompatibility complex with avian leukosis virus infection in chickens. Br. Poult. Sci. 33:613–620.
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specific genes (e.g., the MHC) are known to play a role in disease resistance, but resistance is generally a polygenic phenomenon. Future research directions will expand knowledge of the impact of genetics on disease resistance by identifying non-MHC genetic control of resistance and by further elucidating mechanisms regulating expression of genes related to immune response.
(Key words: genetics, disease, Major Histocompatibility Complex, immunoglobulins, Salmonella enteritidis)
INTRODUCTION A basic tenet in all considerations of disease in poultry is that the genetics of a bird or a flock defines the maximum disease-resistance potential available. One gene family, the MHC, has long been the subject of intense investigation for its role in disease resistance. Responses to a wide array of pathogens has been demonstrated to be associated, in part, with the major histocompatibility complex. Many other candidate genes with a proven or potential role in disease resistance can also be identified: cytokine genes, CD-encoding genes, T cell receptor genes, Nramp1, growth hormone, and the immunoglobulin genes. But resistance to most diseases is likely controlled by polygenes. Both physiological genetic and molecular genetic approaches can be used to investigate polygenic control of immune response and disease resistance. Divergent genetic selection for immunocompetence traits or disease resistance can produce genetic lines to study for correlated changes in their physiology and genetics. These divergent lines can also be crossed to generate populations suitable for mapping molecular markers for desirable performance. Genetic selection, aided by molecular markers, can be used to improve resistance to disease. But, ultimately, a detailed understanding of the genetic basis of immune response modulation will be needed to fully exploit the
Received for publication August 3, 1997. Accepted for publication February 21, 1998. 1Journal Paper Number J-17605 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa; Project Numbers 3290 and 3342 and supported by Hatch Act and State of Iowa funds. 2To whom correspondence should be addressed: [email protected]
discoveries of modern molecular genetics in improving poultry health.
MAJOR HISTOCOMPATIBILITY COMPLEX The best-characterized genetic control of disease resistance and immune response in the chicken is that associated with the MHC. The MHC genes have a profound effect on the ability of animals to respond to specific antigens. The MHC in the chicken was first discovered as a blood group locus and is also termed the B complex (Briles et al., 1950). Schierman and Nordskog (1961) demonstrated that the B blood group locus in chickens is linked to genes controlling histocompatibility. The MHC encodes for three classes of proteins named B-F, B-L, and B-G (reviews, Lamont and Dietert, 1990; Lamont, 1993; Kaufman and Lamont, 1996). At the molecular level, the chicken MHC has unique features that will enhance its value as a marker for disease resistance (Lamont, 1993, 1994; Kaufman and Lamont, 1996): the Class I and II genes overlap, therefore forming extremely tight linkage; introns are relatively small (10% of the size of most mammalian MHC); additional genes, including ones with homology to mammalian genes involved in lymphocyte activation and TAP2 (transporter associated with antigen processing) have been identified in the chicken MHC. Recently, a region similar in sequence but genetically unlinked to the
Abbreviation Key: DWR = delayed wattle reaction; LD50 = 50% lethal dose; REV = reticuloendotheliosis virus; RFLP = restriction fragment length polymorphisms; TAP2 = transporter associated with antigen processing.
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1998 Poultry Science 77:1111–1118
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lines divergently selected for an index of immunocompetence traits, including antibodies, inflammatory response, and reticuloendothelial activity, differences occurred in MHC genotype frequencies (Kean et al., 1994a). Genetic control of immunoresponsiveness can also be investigated by measuring cell-mediated immunity. The delayed wattle reaction (DWR) is commonly used as a measure of cell-mediated immunity in the chicken (Klesius et al., 1977). Both polyclonal inducers (e.g., phytohemagglutinin Taylor et al., 1987) and specific inducers (e.g., Staphylococcus aureus, Cotter et al., 1987) generate a cell-mediated immunity associated with the B complex. Qureshi and colleagues (Qureshi et al., 1986, 1988) showed that chemotactic activity of chicken blood mononuclear leukocytes, and activity and recruitment to the peritoneal cavity of macrophages differed among the 15I5-B-congenic lines. Allograft and antibody responses also varied by MHC in the same lines (Shen et al., 1984; Bacon et al., 1987). Lines of chicken congenic for the MHC were also used to demonstrate MHC associations with CD4 and CD8 lymphocyte percentages and ratios (Hala et al., 1991). The levels of total serum hemolytic complement have been associated with the MHC in chickens (Chanh et al., 1976) although specific components were not found to segregate with the MHC (Koch, 1986). Investigations of the fundamental biology of the chicken MHC have been motivated by the association of the chicken MHC with resistance to disease. Several reviews (Bacon, 1987; Lamont, 1989, 1991, 1993; Gavora, 1990; Stevens, 1991) have surveyed this subject. The best-characterized association of the MHC with disease resistance is to Marek’s disease, a herpes virus-induced lymphoma. This MHC influence has been mapped, using recombinants, to the B-F|B-L region (Briles et al., 1983; Hepkema et al., 1993). The MHC is associated with traits of tumor incidence, mortality, and transient paralysis induced by Marek’s disease virus. One specific haplotype, B21, seems to convey Marek’s resistance to many different genetic backgrounds. Variation in response to Marek’s disease virus by sublines that are identical at the B locus, however, illustrates the importance of non-MHC gene effects on Marek’s response (Bacon, 1987). Genetic complementation with MHC alleles of genes such as Ir-GAT or other genes affecting antibody response may affect the susceptibility to Marek’s disease (Steadham et al., 1987; Pinard et al., 1993). The MHC also influences the response to other virally induced diseases, including Rous sarcoma virus tumors (Schierman et al., 1987; White et al., 1994), v-src tumors (Taylor et al., 1992), and avian leukosis (Yoo and Sheldon, 1992). Resistance to diseases caused by nonviral pathogens also has been associated with the MHC (Gavora, 1990). These diseases include spontaneous autoimmune thyroiditis (Rose, 1994), and coccidiosis (Lillehoj et al., 1989; Caron et al., 1997). There is a relative paucity of
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MHC, termed Rfp-Y has been mapped to the MHCbearing chromosome (Miller et al., 1994, 1996). The chicken MHC antigens perform crucial functions in the regulation of cellular communication in the immune response. The cell surface antigens of the MHC are unique to each genetically unique individual. This allows immune reactions to occur against disease organisms of an almost infinite spectrum, while simultaneously preserving the organism from self-destruction. The control of the MHC over communication events occurs at two levels: molecular interactions at the cell surface and cellular cooperation in an immune response (Dietert, 1987). The MHC cell surface glycoproteins interact with both the antigen and with complementary structures of other immune cells, generating an immune response that is specific for the inducing antigen. For different cell types of the immune system to communicate effectively, they must share at least one MHC haplotype, a phenomenon known as MHC restriction (Vainio and Toivanen, 1987; Vainio et al., 1987). The MHC restricts T cell cytotoxic reactions with some virus-infected or transformed cells (Schat, 1994). When cytotoxic T cells are combined with reticuloendotheliosis virus (REV) infected cells, significant cytotoxicity occurs only with syngeneic effector and target cell combinations (MacCubbin and Schierman, 1986). A T cell with antigen-restricted cytotoxic properties was identified as the effector cell responsible for the MHCrestricted cell-mediated cytotoxicity (Weinstock and Schat, 1987). The MHC- and virus-restricted cytotoxic cells may be an important immune surveillance mechanism to stop proliferation of virally induced tumors (Schierman and Collins, 1987). Antibody production against a variety of antigens is linked to the chicken MHC. Immune responses to synthetic polypeptides such as (T, G)-A-L, GAT, and GT are linked to the MHC in the chicken (Gunther et al., 1974; Benedict et al., 1975; Pevzner et al., 1979). Antibody titers to other soluble antigens (e.g., bovine serum albumin) and to cellular antigens (e.g., Salmonella pullorum bacterin, SRBC) are also associated with the chicken MHC (Pevzner et al., 1975; Loudovaris et al., 1990). Total serum IgG levels are associated with the B complex (Rees and Nordskog, 1981; Pinard and van der Zijpp, 1993). In long-term selection experiments for antibody response to SRBC conducted independently by Siegel and colleagues and by van der Zijpp and colleagues, correlated changes in MHC allelic frequencies were detected (Dunnington et al., 1984; Pinard et al., 1993). The MHC genotype explains part of the total variation in the antibody levels, and the background genome also has a substantial effect. In meat-type lines divergently selected for early antibody response to Escherichia coli vaccination, differences occurred in frequency of MHC class IV restriction fragment-length polymorphisms (RFLP) bands (Uni et al., 1993). Recent studies with other probes showed the Tap2 and B-F regions to be associated with antibody production (Cahaner et al., 1997). In Leghorn
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The poultry breeding industry can currently apply MHC information to selectively alter MHC allelic frequencies for improvement of disease resistance and vaccine response. Certain MHC alleles are associated with Marek’s disease vaccination efficacy in commercial genetic backgrounds (Bacon and Witter, 1994). Beneficial MHC alleles can be increased in frequency or fixed within a parent line. The extreme polymorphism of the MHC (over 50 allelic forms) allows many options for choice of specific MHC alleles in parent lines and allelic combinations in commercial birds. New applications of MHC manipulation to improve avian health should incorporate new biotechnologies (Lamont, 1994). Because antigen-binding specificity is critical to effective poultry vaccine design, knowledge of specific MHC types in the flock could allow specific choices to optimize the vaccine-host MHC combination or allow design of targeted recombinant vaccines (Schat, 1994; Bacon and Witter, 1994; Pharr et al., 1993; Witter and Hunt, 1994). With the use of specific gene probes or primers, DNA can be directly examined for allelic forms of the MHC and MHC-linked genes and fine-mapping of the specific loci contributing to disease resistance can be conducted.
REGULATION OF GENES CONTROLLING IMMUNE RESPONSE Many studies of genetic control of disease resistance focus on structural variation. For example, are different alleles associated with differential response to pathogen challenge? But it is becoming increasingly evident that variation in structural genes and their encoded proteins are only one source of variation in biological traits. Variation in gene expression is another important source of differences in performance. Factors controlling gene expression must be understood in order to selectively enhance expression (Lamont, 1994). The regulation of expression of two genes of importance in disease resistance (MHC and immunoglobulin) has been studied in the author’s lab. A 0.7 kb DNA fragment from the 5′ flanking region of a chicken MHC class II B gene (the putative regulatory region) was cloned into chloramphenicol acetyltransferase reporter vectors and then transfected into a chicken macrophage cell line. Positive orientation-dependent promoter activity of the chicken DNA was detected in the reporter construct containing an SV40 enhancer (Chen et al., 1997). Deletion analysis revealed a short fragment in the 3′ end that was crucial for the promoter function and negative regulatory elements located further upstream. Sequence analysis of the chicken MHC class II 5′ region suggests possible involvement of interferon, E 26 specific (ETS)-related proteins, and other factors as candidates in regulating this promoter. An interferonrich chicken T cell line culture supernatant increased the cell-surface expression of MHC class II antigens, as well as class II promoter activity, in this macrophage cell line.
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information on the genetic control of bacterial disease in chickens. Lamont et al. (1987a) demonstrated that genetic control of resistance of a low dosage of Pasteurella multocida was linked with genes of the chicken MHC Class IV region. Cotter et al. (1992) reported MHC linkage of resistance to Staphylococcus aureus. Convincing evidence also exists for a genetic component to resistance to Salmonella enteritidis in chickens. Two groups have examined resistance to S. enteritidis in several genetic lines and have found variation in 50% lethal dose (LD 50) organ contamination, and bacterial burden (Bumstead and Barrow, 1993; Guillot et al., 1995; Protais et al., 1996). No evidence, however, was found for MHC effect on Salmonella response. In a recent report, several NRAMP1-linked markers were identified to be associated with splenic bacterial burden 3 d after intravenous inoculation of S. enteritidis (GirardSantosuosso et al., 1996). This generic association is an excellent example of the application of comparative genomics, in which a gene already defined in a mammalian species is found to have similar structure and function in the chicken (Hu et al., 1995, 1996). The range and variety of diseases influenced by the chicken MHC is, therefore, extensive. Additional factors, such as non-MHC genetic background and vaccination, have also been shown to interact with MHC genes in influencing immune response and disease resistance (Bacon and Witter, 1992; Dunnington et al., 1989, 1992). An important observation that emerges from studies on the MHC and disease, however, is that there is not a single haplotype (perhaps with the exception of B21 and Marek’s disease) that responds optimally in all genetic backgrounds to all disease challenges. Given the many different immune mechanisms involved in resistance to disease and the many levels at which the MHC exerts genetic control, this is not surprising. The repeated associations with the MHC suggest that there are genes for disease response within the MHC, but the lack of consistent association with specific haplotypes suggests that MHC-linked genes other than the classical MHC class I and II genes may have a major influence. Many diverse traits of economic importance such as fertilization rate, embryonic mortality, hatchability, juvenile and adult mortality, body weight, and egg production are also influenced by MHC genotype (Bacon, 1987; Dietert et al. 1991; Sander, 1993). In three independent studies it was shown that long-term selection for egg production traits and disease resistance significantly altered MHC allelic frequencies (Simonsen et al., 1982; Gavora et al., 1986; Lamont et al., 1987b). Although different combinations of B haplotypes were present in these selection studies, some general patterns emerge. The B2 and B21 haplotypes may show overall beneficial associations with economic traits in chickens. Other studies have demonstrated MHC associations with particular production traits, but not necessarily consistency of specific MHC haplotypes or associated traits (Dunnington et al., 1992; Kim et al., 1987, 1989; Abplanalp et al., 1992; Sato et al., 1992).
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SELECTION FOR ANTIBODY RESPONSE In instances in which candidate gene information is not readily available, the approach of selection for a trait of immunocompetence can be employed to enhance disease resistance. Antibody level is a popular choice, because of the ease of repeated measurements and generation of quantitative results. Also, antigens (such as vaccines) can be used that have direct relevance to specific diseases. Although the antibody-disease resistance associations are widely accepted as a general rule, the exact immune defense mechanism for most specific diseases are poorly understood. Many researchers have investigated the genetic control of humoral immune response in egg-type chickens. Siegel and Gross (1980) and Gross et al. (1980) selected egg-type chickens for antibody production to SRBC and tested the resistance of selected lines to infectious diseases. The high-antibody production line was more resistant to parasites and viruses, but not bacteria, than the low antibody line. Subsequent studies showed an interaction of antibody selection and MHC with disease response (Martin et al., 1989). van der Zijpp and coworkers (van der Zijpp and Leenstra, 1980; van der Zijpp et al., 1982; van der Zijpp, 1983) also studied humoral immune response of egg-type chickens to SRBC, with emphasis on dose, genetic origin, interaction, and correlation between primary and secondary immune responses and between humoral and cellmediated responses. Studies with these lines have
TABLE 1. Correlations of Salmonella enteritidis burden in liver, spleen, and cecal content and sibling vaccine antibody level
Spleen Liver Spleen Cecal content
0.98*
Cecal content –0.13 0.02
Antibody 0.00 –0.17 –0.87*
*P < 0.05.
elucidated a role for both antibody selection and MHC type in influencing Marek’s disease response (Pinard et al., 1993). Selection of egg-type chickens for antibody response to Salmonella pullorum antigen (Pevzner et al., 1981) was also successful. Selection for high and low antibody response in meat-type birds, as well as for early and late antibody production, has been successfully conducted (Pitcovski et al., 1987a,b; Leitner et al., 1992; Yonash et al., 1996). Cell-mediated immunity of chickens has also been examined and demonstrated to be under the influence of genetic origin (van der Zijpp, 1983; Lamont and Smyth, 1984). Multitrait immune response selection in egg-type chickens has also been successful (Cheng and Lamont, 1988; Cheng et al., 1991; Kean et al., 1994a,b). Thus, many studies have demonstrated the feasibility of altering immunophysiology by genetic selection. For antibody selection to be effective in a program of genetic selection for disease resistance, the variation in antibody levels must be associated with variation in response to disease. Fortunately, evidence is available for association of antibody and resistance, including examples of association of high antibody levels with resistance to important bacterial pathogens such as E. coli and Salmonella enteritidis. Lines selected for rapid, early antibody response to E. coli were more resistant to E. coli challenge (Leitner et al., 1990; Yonash et al., 1994). Heritability (0.25 and 0.26 in two different broiler breeder male lines) of antibody response to S. enteritidis vaccine established the feasibility of identifying the genetic basis of control of this response (Kaiser et al., 1997, 1998). But because many components of the immune response may be involved in resistance to any specific disease, it was important to investigate the relationship of S. enteritidis antibody and response to live S. enteritidis challenge. To accomplish this goal, the genetic relationship between S. enteritidis colonization and S. enteritidis vaccine antibody response was determined in broiler breeder chicks. Half-sib groups of chicks were either exposed to live S. enteritidis or vaccinated against S. enteritidis. Serum antibodies at 3 wk (10 d postvaccination) were determined by ELISA from the vaccinated chicks. The unvaccinated chicks exposed to S. enteritidis were euthanatized at 3 or 6 wk, and bacterial burden of selected sites was determined. Sire means were calculated for all traits and used for statistical analysis (Table 1). Antibody response to
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This functional characterization of a chicken MHC class II B gene promoter will aid in understanding the regulatory mechanisms that control the expression of these genes of importance in immune function (Chen et al., 1997). Another category of regulatory elements are the Oct transcription factors. The chicken immunoglobulin lambda light chain promoter contains an octamer motif. Two different lymphoid cell lines, DT40 (a B cell line) and MSB1 (a T cell line), were used to test the activity of the germline immunoglobulin promoter and the function of the octamer motif. The promoter was functional only in B cells and then only in the presence of an SV40 enhancer. Mutation of the octamer motif eliminated the transcriptional activity of the immunoglobulin promoter (Heltemes et al., 1997). These results demonstrate that the chicken immunoglobulin promoter functions similarly to mammalian immunoglobulin promoters, in that it plays a role in tissue specificity and requires both an enhancer and an intact octamer motif for activity (Heltemes et al., 1997). Full understanding of the mechanisms that regulate genes of the immune system pave the way toward targeted, specific gene expression and perhaps bypassing tissue specificity in expression of specific genes (e.g., MHC class II, immunoglobulins), thereby opening new avenues to enhance disease resistance.
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vaccination and number of S. enteritidis in cecal swab cultures were significantly negatively correlated (–0.87). Thus, the genetic potential for greater S. enteritidis vaccine antibody response was associated with lesser S. enteritidis cecal colonization in broiler breeder chicks exposed to S. enteritidis. This information demonstrates the feasibility of the goal of improving resistance to S. enteritidis colonization by selecting for increased S. enteritidis antibody response.
CONCLUSION
ACKNOWLEDGMENTS Recent research of the author’s laboratory was partly supported by grants from the USDA-National Research Initiative (95-372205-2245) and the BARD Foundation (US-2317-93), and by Hatch and state of Iowa funds.
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