Download GENETIC CONTROL OF IMMUNE RESPONSIVENESS: A REVIEW

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
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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.
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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
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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.
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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
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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. If a n y a n t a g o n i s t i c relat i o n s h i p s exist d u e to linkage, it will b e especially v a l u a b l e t o e m p l o y g e n e t i c e n g i n e e r i n g m e t h o d s to i n t r o d u c e i n d i v i d u a l l y t h e desired genes
into the germplasm.
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