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GENETIC CONTROL OF IMMUNE RESPONSIVENESS: A REVIEW OF ITS USE AS A TOOL FOR SELECTION FOR DISEASE RESISTANCE 1 C. M. Warner 2, D. L. Meeker a and M. F. Rothschild 4 Iowa State University Ames 50011 ABSTRACT Disease resistance and immune responsiveness have been traits generally ignored by animal breeders. Recent advances in immunology and molecular biology have opened new avenues towards our understanding of genetic control of these traits. The major histocompatibility gene complex (MHC) appears to play a central role in all immune functions and disease resistance. The need to understand the relationship between immune responsiveness, disease resistance and production traits is discussed in this review. Antagonistic relationships might prevent simultaneous improvement of all of these traits by conventional breeding methods. It is suggested that genetic engineering methods may allow the simultaneous improvement of disease resistance and production traits in domestic animals. Genes of the MHC will be especially good candidates for genetic engineering experiments to improve domestic species. (Key Words: Immune Response, Disease Resistance, Major Histocompatibility Complex.) I ntroduction Livestock disease costs producers and consumers millions of dollars every year. Medication, vaccination and isolation of animals from pathogens are effective for control of many diseases, but some diseases still have a devastating effect when outbreaks occur. Substantial losses are sustained from mortality, veterinary costs, product contamination and subclinical symptoms. Changes in drug-use regulations and the fact that some vaccines are only partly effective underscore the need for other approaches to disease control. Eradication programs, though successful for a few well-known diseases, are generally too costly. The chances of completely eliminating an organism are small, especially in cases of diseases like pseudorabies in swine where the epidemiology of the disease is not well under- Journal Paper No. J-12189 of the Iowa Agr. and Home Econ. Exp. Sta., Ames. Projects 2594 and 2609. The authors gratefully acknowledge partial financial support from the USDA, the Natl. Pork Producers Council and the NIH. uDept. of Biochem. and Biophy. aPresent address: Natl. Pork Producers Council, Des Moines, IA 50306. 4 Dept. of Anita. Sci. Received February 21, 1986. Accepted September 16, 1986. stood. Another problem with eradication is that depopulation of whole herds sacrifices not only the diseased animals, but also resistant members of the herd that could be used to breed for resistance. Present regulations may require slaughter of breeding stock that have positive serum titers to certain diseases. Eradication may eliminate the animals that can effectively respond to disease challenges, while multiplying animals that cannot effectively respond to the pathogen. Genetic disease resistance could be a useful tool in livestock production. Research of this nature has been limited in domestic species, but studies of mice and humans indicate that immune response, while subject to environmental influence, is under genetic control. Selection for improved immune response leading to increased numbers of resistant animals could enhance vaccination and medication programs through synergistic interactions. Genetic screening to identify predisposition for the more serious diseases also could become a major part of disease prevention. Biochemical or molecular identification of genetic markers (gene products) for disease resistance may be possible and would clearly enhance selection efforts. An understanding of the association of disease resistance and production traits is very important if future breeding efforts will be employed to improve both. Antagonistic correlations between some production traits 394 J. Anim. Sci. 1987.64:394-406 BREEDING FOR DISEASE RESISTANCE and disease resistance would make simultaneous improvement for both more difficult. The purpose of this paper is to review aspects of genetic control of immune response and its relationship to disease resistance and production traits and suggest possible avenues for future research. Disease Resistance and immune Response Disease Resistance. The development of a disease by an animal is the result of the interaction between the genotype of the individual and the environment. Disease occurs when environmental insult meets genetic predisposition. Historically, disease prevention has been through improvement of the environment, vaccination and drug use. These conditions allow animals with marginal natural resistance to remain viable for the breeding population. Selection for genetic disease resistance will require identification of specific resistance genes or identification of genetic markers linked to resistance. Genetic control of the resistance to disease is highly complex and involves many of the systems of the body and their interactions. One of the most important of these systems is the immune system. This review will focus on the immune system, specifically genes of the major histocompatibility complex, and how they are involved in the genetic control of the immune response and disease resistance. Components of tbe Immune System. The first line of defense against disease-causing organisms is the skin and mucous membranes of an animal. If a pathogen invades these protective structures, the immune system of the animal has the opportunity to eliminate the pathogenic organism through the mobilization of cells and soluble substances produced in the primary (bone marrow and thymus) and secondary (spleen and lymph nodes) organs of the immune system. (For a review of basic principles of immunology see Hood et al., 1984.) There are two major categories of immune responses-those involving antibody, which are called humoral immune responses, and those that are independent of antibody, called cell-mediated immune responses. An understanding of these two universes of the immune response has been possible because of the pioneering work of Glick (Glick et al. 1956) and Claman (Claman et al. 1966), two of the first researchers to recognize the cellular basis for the dichotomy of the immune system. 395 The production of antibody in a humoral immune response depends on the interaction of T cells, B cells and macrophages (Bach et al., 1979; Unanue, 1984). Cellular immunity is a function of many types of leukocytes, including T cells (Nabholz and MacDonald, 1983), macrophages (Adams and Hamilton, 1984), NK cells (Herberman et al., 1986), LAK cells (Andriole et al., 1985), etc. As time goes on, the types of cells involved in both humoral and cellular immune responses have been defined better because of new reagents which distinguish cellular subsets. However, it will take many more years to define fully each subset and the complete array ot types of cells involved and their interactions in the immune response. In addition to the cells of the immune response, many soluble substances mediate immunity. First of all, are the antibody (immunoglobulin) molecules themselves, the products of the B cells. Other soluble molecules are the complement components (Reid and Porter, 1981), the interferons (Friedman and Vogel, 1983), the interleukins (Smith, 1984; Durum et al., 1985) and other lymphokines and monokines. Hormones, prostaglandins and leukotrienes are also intimately involved in the control of the immune response (Cupps and Fauci, 1982; Larsen and Hensen, 1983; Munck et al., 1984). Cell surface molecules play a crucial role in the regulation of the immune response. The antigen receptor on B cells is a membrane-bound immunoglobulin molecule (Vitetta et al., 1984). The antigen receptor on T cells, called the T cell receptor, is unique in that it not only recognizes antigens, but does so in the context of molecules encoded by genes of the major histocompatibility complex (MHC; Kronenberg, 1986). The MHC is so important in the control of the immune response (Dorf, 1981) that it will be elaborated on further in the next section. The immunoglobulins, the T cell receptor and the MHC molecules are related structurally and are thought to have arisen from a single primordial gene (Hood et al., 1985). The Major Histocompatibility Complex. All higher animals possess a major histocompatibility gene complex that codes for the predominant cell surface proteins on the cells and tissues of each individual of the species (Snell et al., 1976; Goetze, 1977). The proteins are markers of "self" and are essentially unique for all individuals, except identical twins. The structure and function of the human MHC, the HLA 396 WARNER ET AL. complex and the mouse MHC, the H-2 complex, have been extensively investigated (Matzinger and Zamoyska, 1982; Hood et al., 1983; Moeller, 1985a,b,c). The MHC encodes three classes of protein molecules-class I, class II and class III. Class I molecules consist of a membrane-bound glycoprotein heavy chain, molecular weight 40 to 50,000, and a non-membrane bound light chain, 32-microglobulin, molecular weight 12,000. Class II molecules are membrane-bound glycoproteins consisting of two non-covalently associated chains, a and 3, each with a molecular weight of about 30,000. Class III molecules are components of serum complement. The first MHC to be described was that of the mouse (Gorer, 1937; Gorer et al., 1948). The revolution in recombinant DNA methodology has allowed the structure of the mouse MHC genes and proteins to be described (Hood et al., 1983; Moeller, 1985a,b,c; Mellor, 1986). In fact, the mouse MHC in the best-defined segment of mammalian DNA to date. In the mouse, the class I gene products consist of three types of molecules, H-2, Q and TL antigens (Mellor, 1986). The H-2 antigens are highly polymorphic and are expressed on all ceils of the individual, with few exceptions (Klein, 1975; Klein and Figueroa, 1981). The Q/TL antigens, identified as class I antigens in the past few years, are much less polymorpbic and have a more limited cell distribution than the H-2 antigens (Flaherty et al., 1985). The class II antigens (Ia antigens) are also less polymorphic than the H-2 antigens and show a much more limited cell distribution than the H-2 antigens (Klein, 1975). Class III molecules (complement components C2, C4, Bf) show some polymorphisms (Porter, 1983), but are not nearly as polymorphic as the H-2 antigens. For over 30 yr after its description, the function of the MHC remained a mystery. Then, in 1969, McDevitt and Benacerraf reported that the response of inbred strains of mice and guinea pigs to certain synthetic antigens depended on genes in the MHC (McDevitt and Benacerraf, 1969). These genes were called Ir (immune response) genes, and it is now known that the products of the Ir genes are the class II MHC proteins. The function of the class I genes was first elucidated by the studies of Zinkernagel and Doherty (1974, 1979). The class I genes act as restricting dements in T cell recognition of vitally infected target cells. Thus, the cell receptor recognizes both foreign antigen and self class I MHC antigens in order to generate an immune response. The function of the class II genes (Ir genes), as mentioned previously, is the genetic control of the immune response. The class II genes control the interaction of T cells, B ceils and macrophages in the generation of the humoral immune response, and participate in some aspects of cellular immunity as well. The function of class III genes is to be part of the complement cascade, which ends with the lysis of the cell or virus particle to which antibody has bound. There are still many unknown aspects of MHC structure and function. For instance, the reason for the location of the class III complement genes (C2, C4, Bf) in the MHC has remained an enigma. Likewise, the recent discovery of genes for the enzyme 21-hydroxylase within the MHC (White et al., 1984) has no known functional significance. However, because the location of complement and 21hydroxylase genes within the MHC has persisted through evolution, the consensus is that there must be some functional significance to this, but it is not yet understood. Although much more is known about the MHC of mouse and man compared with domestic species, the MHC of most domestic species has been identified (Goetze, 1977). For instance, the MHC of the bovine is the BoLA complex (identified by Amorena and Stone, 1978; Spooner et al., 1978; reviewed in Spooner, 1985); in the pig it is the SLA complex (identified by Valman et al., 1970; reviewed in Lunney et al., 1986); and in the chicken it is the B complex (identified by Schierman and Nordskog, 1961; reviewed in Briles et al., 1982). The structural data~ although limited, on the organization and function of genes of the MHC of domestic species, suggest that the structure and function of the MHC of all mammals is similar (Warner, 1986). Genetic Control of Immune Response and Disease Resistance-General Considerations. As mentioned previously, the development of the disease state has both genetic and environmental components. The genetic components include those that affect the immune system, as well as virtually every other system of the body. The most important environmental component is exposure to the pathogen. There are some diseases that are strictly genetic and do not involve the immune system or exposure to a pathogen. In humans, over BREEDING FOR DISEASE RESISTANCE 3,000 genetic defects ("diseases") have been described that show simple inheritance patterns (McKusick, 1986). Some of these genes have been mapped to particular chromosomes and some have had the exact genetic defect pinpointed at the molecular level. A few of the better known examples are sickle cell anemia, which is caused by a single amino acid substitution in the /3 chain of hemoglobin; LeschNyan syndrome, which is caused by the absence of the enzyme hypoxanthine-guanine phosphoribosyl transferase; and Tay-Sachs disease, which is caused by the deficiency of the enzyme hexosaminidase A. Some diseases classified as genetic diseases may, in fact, be the inheritance of the receptors for a specific pathogen. In these cases, if the individual is kept free of the pathogen, the disease will not develop. There are examples of resistance to disease in animals that are simply inherited and may be a reflection of a receptor mechanism. Crittenden (1974) found resistance to specific subgroups of leukosis virus in chickens to be simply inherited. It seems possible that resistance will be shown to be the lack of the receptor for this virus. Plant and Glynn (1976) documented the simple Mendelian dominant inheritance of resistance to Salmonella typhirmurium in mice, and here, too, a receptor mechanism seems possible. The resistance in sheep to the nematode Haemonthus contortus has also been shown to be inherited as a simple dominant characteristic (Wakelin, 1978). Gibbons et al. (1977) studied the inheritance of resistance to colibacillosis and found that resistance results from the lack of a simply inherited cell surface receptor for K88, a cell surface protein on some Escherichia coil Escherichia coli cannot attach if the receptor is not present. Maternal antibodies have allowed sustained frequencies of susceptible animals. The most susceptible offspring are produced by mating resistant dams to susceptible boars because the resistant dams do not produce maternal antibodies. In the immune system there are also diseases that are strictly genetic and not dependent on pathogens. In humans, there are many genetic deficiencies in the immune system, that are simply inherited (McKusick, 1986). These include deficiences in T cells, B cells, bone marrow stem cells, NK cells, thymus development, etc. All of these diseases occur in the absence of a pathogen. The devastating effects of these genetic diseases has made the observed incidence of these diseases rare in farm animals. 397 In the presence of a pathogen, the ability of an animal to respond immunologically resides in many genes that affect the integrity of the immune system. For instance, the repertoire of cells and antibodies that an individual develops during ontogeny is under genetic control. In adult animals, antibody-producing ability is controlled by multiple genes that have been postulated to correlate with resistance to disease. Biozzi et al. (1979, 1980), Buschmann (1982), Gavora and Spencer (1983) and Buschmann et al. (1985) have suggested that the immune response is an indicator of disease resistance. Balcarova et al. (1973), van der Zijpp (1978, 1983, 1984), van der Zijpp et al. (1982a,b, 1983) and Pevzner et al. (1973, 1975, 1981) have all detected genetic differences in immune responsiveness in poultry. Van der Zijpp (1983) detailed the genetic components involved in immune response and resistance to viruses causing Marek's disease, lymphoid leukosis and Newcastle disease. This work demonstrated that the many aspects of an immune response are so entangled for complex antigens that knowledge of all aspects of the immune system, including t h e MHC, will be necessary to understand fully the genetic control of disease resistance. Genetic Control of Immune Response --Breed Differences and Heritabilities. Quantitative geneticists have traditionally used estimates of heritabilities to describe the genetic control of the inheritance of a particular trait. The heritability of the humoral immune response has been calculated in many species. Biozzi et al. (1970) estimated the heritability of the antibody response to sheep red blood cells in mice to be .36, compared with an estimate of .43 for the primary response by Claringbold et al. (1957). Van der Zijpp (1984) estimated heritability of antibody production in response to inactivated Newcastle disease virus vaccine in chickens to be .42 from paternal half-sibs and .16 from maternal half-sibs. Peleg et al. (1976) and Soller et al. (1981), using chickens, calculated heritability estimates ranging from .31 to .60 for the same traits in similar studies. In pigs, breed differences were observed in the immune response to sheep red blood cells (SRBC) and to DNP-hapten by Buschmann et al. (1974, 1975) and Buschmann (1980). Huang (1977) calculated heritabilities of .51 for secondary response and .40 for peak response to bovine serum albumin (BSA) in swine. Heritability estimates by Rothschild et al. (1984a) for immune response after vaccination 398 WARNER ET AL. with B. bronchiseptica were .10 (half-sib)and .42 (full-sib). Interestingly, breeds with more turbinate damage (Straw et al., 1983) were the same breeds that had responded with low titers of antibodies against B. bronchiseptica bacterin (Rothschild et al., 1984a). Rothschild et al. (1984b) also reported breed differences in immune response to a modified live pseudorabies virus. The breed rankings differed in Rothschild et al. (1984a) and Rothschild et al. (1984b) using different antigens. Meeker et al. (1987b) estimated the heritability of response to pseudorabies vaccine to be .18 measured at 56 d of age, and the heritabilities of response to B. bronchiseptica vaccine to be .15 and .52 measured at 56 and 119 d of age, respectively. Meeker et al. (1987a) showed no evidence for nonadditive genetic control (heterosis) of immune response to pseudorabies or B. bronchiseptica vaccines, but did observe additive genetic control and breed differences similar to Rothschild et al. (1984a). Edfors-Lilja et al. (1984, 1985) showed significant sire effects on immune response, indicating genetic influence of immune response to E. coli antigens. It has been suggested (Gavora and Spencer, 1983) that the importance of these studies is that estimates of heritabilities of the humoral immune response correspond well to resistance to a disease caused by a particular pathogen. Of course, estimates of heritability do not indicate which genes or how many genes are involved in the control of a particular trait. They do, however, show which diseases have a strong additive genetic component, and would therefore be most responsive to breeding for increased disease resistance. Genetic Control of Immune Response--the Major Histocompatibility Complex. It is clear from the previous discussion that the complexity of the immune response and its relationship to disease resistance is enormous. It was, therefore, a startling discovery that a single gene in the MHC could influence the magnitude of the immune response (McDevitt and Benacerraf, 1969; Benacerraf and McDevitt, 1972). For their contribution to the understanding of the role of the MHC in the immune response, Benacerraf, Snell and Dausset shared the Nobel Prize in 1980. In humans, the susceptibility to many diseases has been shown to be associated with the human MHC, the HLA complex (Braun, 1979, Tiwari and Terisaki, 1985). Associations of disease states with class I, class II and class Ill MHC molecules have been documented. Diseases involving both humoral and(or) cellular immunity have been shown to be associated with the HLA complex. Because genes in the HLA complex show linkage disequilibrium (i.e., crossing-over is suppressed and they tend to be inherited as a group), it has not often been possible to show exactly which gene(s) in the MHC are involved in the control of the susceptibility to a particular disease. Thus, for many diseases in humans, HLA type serves as a marker gene for disease susceptibility. Calculations of relative risk (see review by Thomson, 1981) are made that compare the risk of an individual of a particular HLA haplotype (a " h a p l o t y p e " is the collection of all genes in the MHC on a single chromosome of an individual) developing a particular disease, compared with the population at large. In mice, where many inbred, congenic and recombinant strains are available, it has been possible to describe more fully the genes involved in the control of the immune response and disease resistance. Domestic species, however, are much more similar to the human population in that they are generally outbred. For this reason, research on the role of the MHC in disease resistance in domestic species has been quite limited. One of the best-studied domestic species with respect to the role of the MHC in disease resistance is the chicken. The B complex, the MHC of the chicken, has been shown to be associated with many immune phenomena, including the humoral immune response to synthetic antigens (Gunther et al., 1974; Benedict et al., 1975; Gebriel et al., 1979; Pevzner et al., 1981), the level o f serum complement (Chanh et al., 1976), and resistance to Marek's disease, Rous sarcoma, and lymphoid leukosis viruses (Schierman et al., 1977; Briles et al., 1977, 1983; Pevzner et al., 1981). The humoral immune response to Salmonella pullorum (Pevzner et al., 1973, 1975) and to the tuberculin bacillus (Karakoz et al., 1974) have also been shown to be controlled by genes linked to the B complex. It is, of course, appealing to speculate that, as in mice, the viral associations with the B complex are due to class I MHC genes, the response to the synthetic antigens and bacteria due to class II MHC genes (Ir genes), and the complement levels due to class III MHC genes. In swine, the best-studied mammalian domestic species, with respect to the MHC and BREEDING FOR DISEASE RESISTANCE disease resistance, several studies have been undertaken to show a relationship of the immune response to the swine MHC, the SLA complex. The humoral immune response to hen egg-white lysozyme was shown by Vaiman et al. (1978b) to be linked to the SLA complex. Lunney et al. (1984) have shown that humoral and cellular responses to this same antigen and the synthetic polypeptide antigen (T, G)-A--L are under the control of class II SLA genes. Rothschild et al. (1984a) and Meeker (1985) reported an association of the immune response to B. bronchiseptica vaccination and the SLA complex. Quantitative differences in levels of class III molecules have been linked to the SLA complex (Vaiman et al., 1978a). Kerzenbaum et al. (1985) have reported evidence for mapping C4 complement genes within the SLA complex. In other species, there have been only a few reports of the relationship of the MHC to the immune response and disease resistance. For instance, in cattle, intestinal parasites, tick susceptibility, mastitis and squamous cell carcinoma of the eye, have been shown to be associated with the BoLA complex, the MHC in cattle (reviewed in Spooner, 1985). In horses, Lazary et al. (1985), found an association between the ELA complex (horse MHC) and susceptibility to equine sarcoid tumors. In sheep, resistance to scrapie (Cullen et al., 1984; Millot et al., 1985) and response to vaccination against trichostronglylus colubriformis (Outeridge et al., 1985) have been shown to be associated with the sheep MHC (OLA). As research in the different species increases, more such associations or linkages will undoubtedly be found. In summary, the MHC of domestic animals, like the MHC of mice and humans, seems to be involved in all aspects of the immune response, including humoral and cellular responses. There is mounting evidence that class I, class II and class lII genes of the MHC are important in disease resistance in animals. However, due to limited knowledge on the structure of the MHC of domestic species, the class I gene products are not only important because they have a direct role in immune responsiveness and disease resistance, but also because they serve as a set of marker genes. Both these characteristics suggest that MHC typing will be important in future selection programs. Selection for Immune Responsiveness and its Relationship to Disease Resistance. Domestic animals vary in genetic susceptibility to 399 disease, which points the way to effective control of some diseases through the development of genetically resistant stock (Hutt, 1958). Biozzi et al. (1970) selected for high and low antibody synthesis in mice, and suggested that the number of generations needed for selection is directly proportional to the number of genes involved. The populations were completely genetically separated by the ninth generation. Buschmann and Meyer (1981) successfully selected mice for high and low phagocytic activity. Siegel and Gross (1980) demonstrated response to divergent selection for high and low antibody titers in chickens and mice. Chickens were separated into susceptible and resistant lines to Marek's disease after only three generations (Cole, 1968). Divergent selection for seven generations in Japanese quail divided high and low antibody-producing lines in response to inactivated Newcastle disease virus antigen (Takahashi et al., 1984). Scheibel (1943) separated lines of guinea pigs into good and poor diptheria-antitoxin-producing lines in six generations. Selection for immune response to three antigens has been applied to goats (Almlid et al., 1980). Significant differences were found between the high and low lines after two generations. Windon and Dineen (1984) divided sheep infected with irradiated T. colubriformis into high- and low-responding lines after two generations. Early selection for disease resistance in swine by using immune response was practiced by Cameron et al. (1942). Two weeks after inoculation with live Brucella suis, animals testing positive by agglutination were discarded. Animals without agglutinins against brucellosis were considered to be resistant. German veterinarians were reported to have developed a strain of swine resistant to erysipelas in the late 1940s (Hutt, 1958). Buschmann (1980) selected swine for antibody-forming capacity to DNP-hapten. After four generations, the high line had a significantly higher antibody response than the low line, whereas cell-mediated response was not affected by selection. Li (1985) calculated a realized heritability of .62 of immune response to B. bronchiseptica vaccine in Chester White swine after one generation of selection. In retrospect, it can be hypothesized that many of these selections have probably selected indirectly for particular MHC genes. This is certainly the case with Biozzi's mice (Biozzi et al., 1980). As better MHC-typing reagents become 400 WARNER ET AL. available for domestic species, it should be possible to MHC-type many of these interesting selected lines to determine disease associations, and to create other lines with particular MHC types that confer disease resistance. Difficulties in Using I m m u n e Response as a Selection Tool. The complexity of the immune response and the many genes involved make it difficult to use immune response as a selection tool. A good response to one antigen does not necessarily predict a good response to another antigen (Benacerraf and McDevitt, 1972; Gavora and Spencer, 1978, 1983). However, heterozygosity for genes controlling the immune response, especially those of the MHC, is particularly advantageous in mice (Doherty and Zinkernagel, 1975), in man (Hendrick and Thomson, 1983) and in domestic animals (Antczak, 1982). The polymorphism of the MHC loci probably provides species with strategies to survive by making it unlikely that a large portion of a species would be susceptible to a given pathogen because of immune response deficiencies. The greater the polymorphism of a species at the MHC loci, the greater the number of responder genes available. This leads to a greater number of pathogens to which the species can respond. An animal would have less chance of being a nonresponder to a pathogen if it displayed as many different MHC alleles as possible. One problem with heterozygosity at the MHC is that each animal possesses only two alleles (one paternal, one maternal) at each locus. One of the promises of gene injection and genetic engineering is that heterozygosity for MHC alleles may be increased, with the ultimate goal of producing animals that would respond well to almost any pathogen. This goal, however, awaits many years of research on the identification and cloning of the MHC genes of domestic species. There are other problems in using the immune response as a selection tool. For instance, there are many known maternal effects on the immune response. Huang (1977) and Takahashi et al. (1984) indicate that larger than trace amounts of specific maternal antibody interfere with active immunity. Immune colostrum interference with active antibody production in pigs for about the first 3 wk reduces the importance of the genetics of a pig in the early stage of immunity development (Hoerlein, 1957; Segre and Kaeberle, 1962a,b; Perry and Watson, 1967; Rothschild et al., 1984a,b; Meeker et al., 1987b). Antigen presentation, site of entry, response of antigen-binding ceils and regulation of response affect the immune response in birds (Tizard, 1979). Environmental stress can be immunosuppressive in rats (Solomon, 1969; Keller et al., 1983), whereas socialization results in increased antibody response in most lines of chickens (Gross and Siegel, 1983). A review of the effects of environmental stressors on immune functions has been presented by Kelley (1980). Protein malnutrition impairs the humoral immune response (Kenney et al., 1970; Mathews et al., 1972; Ben-Nathan et al., 1981). The cell-mediated immune response is also reduced by protein or calorie malnutrition (Arbeter et al., 1971; Smythe et al., 1971; McFarlane, 1971). Parasitic infections have immunosuppressive effects on the host (Hudson, 1973), as do viruses (Dent, 1972) and mycoplasms (Roberts, 1972). Low-level consumption of naturally occurring toxicants, such as aflatoxins or other mycotoxins, can cause decreased disease resistance and vaccine failure (Peir and Heddleston, 1970; Peir et al., 1977). The decline in antibody production with advanced age has been studied in mice (Makinodan et al., 1972; Nordin and Makinodan, 1974) rats (Kunz et aI., 1974) and man (Nagel et al., 1985). These studies indicate that the stage of life cycle is important in quantity of antibody produced in response to antigens. Thus, a complex interaction of genotype and environment affect the immune response and disease resistance. It will be exciting to circumvent some of these problems in the breeding and genetic engineering of disease resistant animals. I m m u n e Response, Disease Resistance and Production Traits. With the previously presented evidence of genetic control of immune responsiveness and the obvious natural selective advantage of resistant animals, it would seem inevitable that selective breeding for improved production traits would have improved resistance in animals. This has not been the case. One reason might be that modern management, which includes vaccination, preventive medication and separation of animals from pathogens, masks the genetic capacity of the animals to resist disease. In addition, some genes may have pleiotropic effects antagonistic to improving both production traits and resistance. Adverse BREEDING FOR DISEASE RESISTANCE effects of selection for production traits on disease resistance occur if there are antagonistic correlations between the two (Gavora and Spencer, 1978, 1983; van der Zijpp, 1983, 1984). Information on genetic correlations among disease resistance, immune response parameters and production traits are scarce. Gavora and Spencer (1978) explain that it is impossible to distinguish between effects due to disease and those due to genetic potential when estimating genetic correlations in populations where disease is present. Dam variance components of egg production traits were found by Gavora et al. (1983) to be 30% higher in a population of chickens containing both positive and negative birds with regard to lymphoid leukosis virus than in a population of negative birds. Thus, disease agents may have an effect on genetic variability, heritability estimates and response to selection. Han and Smyth (1972) reported that selection for higher growth rate resulted in increased susceptibility to Marek's disease in poultry. Gavora et al. (1974) showed that chickens resistant to Marek's disease had lower adult body weight and produced smaller eggs. Spencer et al. (1979) selected strains for high egg production, and observed a decrease in presence of lymphoid leukosis virus. High immune response to sheep red blood cells is negatively correlated with body weight in chickens (Siegel and Gross, 1980; Siegel et al., 1982; van der Zijpp, 1983), but no correlation was shown to other production traits (van der Zijpp, 1983). Van der Zijpp (1984) reported a small positive correlation between immune response to Newcastle disease vaccine and body weight, but small negative correlations between Newcastle disease response and egg production. Takahashi et al. (1984) showed that a line of Japanese quail selected for high response to Newcastle disease vaccine showed a decrease in hatchability. Data on immune response and performance traits in cattle are scanty. Oosterlee (1981) reported research that shows that resistance to the parasite Coopera oncophora in calves may be negatively correlated with performance. Results in swine concerning immune response and production traits are of interest. Huang (1977) showed no evidence of an association between early growth in pigs and ability to develop immune response. The presence of the intestinal receptor for K88 E. coli in swine was 401 related to higher average daily gain and better feed conversion, while allowing a higher frequency of enteric colibaccillosis (Edfors-Lilja et al., 1986). Meeker (1985) and Meeker et al. (1987a) showed an antagonistic relationship between immune response to pseudorabies and B. bronchiseptica vaccines and growth traits, probably due to maternal repression of immune response in young pigs. However, there was no relationship shown between immune response to these same two antigens and backfat thickness. Production traits related to growth and reproduction have been found to be associated with the MHC. For instance, in chickens, higher egg production is associated with the chicken MHC (B complex) (Simonsen et al., 1982); in rats, a "growth and reproduction complex" that influences body size and fertility is linked to the rat MHC (RT-1 complex; Kunz et al., 1980); in mice, mating preference (Yamasaki et al., 1976), fetal loss and fetal weight (Melnick et al., 1981) and rate of early embryonic development (Verbanac and Warner, 1981) have all been found to be associated with the mouse MHC (H-2 complex); and in humans, recurrent spontaneous abortion has been shown by some workers (Scott, 1982; Singh and Gambel, 1982), although not by others (Caudle et al., 1983), to be associated with the human MHC (HLA complex). Recent studies on pigs have also shown an association of the pig MHC (SLA complex) with reproductive performance. Vaiman and Renard (1980) and Philipsen and Kristensen (1985) have suggested that pre-implantation mortality may be associated with SLA haplotype, because embryos that are homozygous for certain SLA antigens are not born with the predicted theoretical frequency. Capy et al. (1981) found some association between the SLA gene complex and growth and carcass traits. Kristensen et al. (1982) found one SLA haplotype to be associated with early growth. The number of pigs born alive (Chen, 1983), the number of eggs ovulated (Rothschild et al., 1984c) and testicular size (Rothschild et al., 1986b) have also been found to be associated with SLA haplotype. Finally, birth weight and weaning weight have been shown to be associated with one particular SLA haplotype (Rothschild et al., 1986a). Thus, two extremely important sets of phenomena, immune responsiveness and production traits, have been found to be associated 402 WARNER ET AL. w i t h t h e MHC. As m e n t i o n e d previously, t h e g e n e t i c c o n t r o l of i m m u n e responsiveness resides in all t h r e e classes o f M H C genes. O n t h e o t h e r h a n d , individual genes c o n t r o l l i n g p r o d u c t i o n traits have n o t b e e n well-defined. It is possible t h a t s o m e o f t h e g r o w t h a n d r e p r o d u c t i o n genes m a y b e t i g h t l y linked to t h e M H C a n d n o t M H C genes per se, w h e r e a s o t h e r s m a y b e M H C genes w h i c h as y e t have n o k n o w n f u n c t i o n . It has b e e n h y p o t h e s i z e d t h a t in t h e m o u s e , Class I genes e n c o d e d in t h e Q / T L region o f t h e MHC m a y affect r e p r o d u c t i o n a n d d e v e l o p m e n t (Boyse, 1985). It is as y e t u n k n o w n w h e t h e r a set o f genes h o m o l o g o u s t o t h e Q / T L g e n e s o f t h e m o u s e exist in d o m e s t i c species. Conclusions T h e long-range goals o f a n i m a l b r e e d e r s are to c o m b i n e t h e b e s t set o f g e n e s in i n d i v i d u a l a n i m a l s a n d to preserve a n d e n h a n c e h e t e r o g e n e ity in t h e g e r m p l a s m o f t h e species. This p a p e r h a s reviewed e v i d e n c e t h a t disease resistance a n d t h e i m m u n e r e s p o n s e are u n d e r g e n e t i c c o n t r o l , a n d has f o c u s e d o n o n e p a r t i c u l a r set o f genes, t h o s e o f t h e m a j o r h i s t o c o m p a t i b i l i t y c o m p l e x (MHC), as t a r g e t s for use in f u t u r e a n i m a l b r e e d i n g programs. D a t a o n t h e associa t i o n o f p r o d u c t i o n traits w i t h disease resistance, i m m u n e r e s p o n s e a n d t h e MHC are i m p o r t a n t f o r b r e e d i n g p r o g r a m s , b u t are still n o t a d e q u a t e f o r d o m e s t i c species. 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