Immunogenetics


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Immunogenetics

A scientific discipline that uses immunological methods to study the inheritance of traits. Traditionally, immunogenetics has been concerned with moieties that elicit immune response, that is, with antigens (antigenic determinants). It has now broadened its scope to study also the genetic control of the individual's ability to respond to an antigen. See Antigen

The immunological methods used in immunogenetics are of two principal kinds, serological and histogenetical. In serological methods, antibodies are used to detect antigens, either in solution or on a cell surface. In histogenetical methods, immune cells (lymphocytes) are used to detect antigens on the surface of other cells. In modern immunogenetics research, the serological and histogenetical methods are combined with molecular methods in which the researcher isolates and works with the genes that code for the traits. This approach of going back and forth from classical to molecular methods has proved to be very successful and has led to the elucidation of several complex genetic systems. See Antibody

Animal immunogenetics relies heavily on the use of inbred, congenic, and recombinant inbred strains. Inbred lines result when individuals that are more closely related to each other than randomly chosen individuals mate together, for many generations. The advantage in working with inbred strains rather than outbred animals is that inbred strains restrict the variability of the conditions of an experiment. However, when two strains are compared and it is found that they respond differently to a treatment, it is not known to what gene this difference should be attributed. The strains may differ at as many genetic loci as two unrelated individuals in an outbred population do. To study the effect of single, defined genes, immunogeneticists have developed congenic lines. These lines always come in groups, the smallest group being a pair, which consists of a congenic line and its inbred partner strain. The two are homozygous at more than 97% of their loci (that is, they are inbred) and are identical except, ideally, at one locus—the locus that is to be studied. To find out whether two loci are on the same or on different chromosomes, two individuals that differ in the traits controlled by these loci are mated and then the F1 hybrids are intercrossed. In the F2, generation that results from this intercross, the genes assort either independently, if they are on different chromosomes, or nonrandomly, if they are the same chromosome—that is, when they are linked. Each time the strains are tested for linkage, this laborious procedure must be repeated. To avoid this repetition, immunogeneticists have prepared a “frozen” F2 generation by establishing separate inbred lines from the different F2 individuals. Such lines are called the recombinant inbred strains.

Contemporary immunogenetic research concentrates on two main categories of antigenic substances—those present in body fluids, primarily blood serum or plasma, and those expressed on surfaces of various cells. In the body-fluid antigens category, a prominent position is occupied by immunoglobulins. Although antibodies are usually used to detect antigens, they themselves may also serve as antigens, and antibodies can be produced against them. These antibodies against antibodies detect three principal kinds of antigenic determinants: isotypic, allotypic, and idiotypic. The main categories of cell-surface molecules studied by immunogenetical methods are blood-group antigens, histocompatibility antigens, tissue-restricted antigens, and receptors. Blood-group antigens are alloantigens found on erythrocytes. Histocompatibility antigens are antigens capable of inducing cellular immune responses and hence are detectable by histogenetical methods. Tissue-restricted antigens are expressed on some tissues but not on others and therefore serve as markers for cell sorting. Receptors are molecules that are capable of specifically interacting with certain other molecules. The interaction often leads to activation or inhibition of the receptor-bearing cell. See Blood groups, Genetics, Histocompatibility, Immunoglobulin, Immunology

Immunogenetics

 

a scientific discipline that combines the methods of immunology, molecular biology, and genetics to study the hereditary factors affecting immunity, intraspecific diversity, the inheritance of tissue antigens, the genetic and populational aspects of the interrelations between host and microorganism, and tissue incompatibility. Immunogenetics was initiated by the work of the German scientists P. Ehrlich and J. Morgenroth, who discovered blood groups in goats in the early 20th century, and by K. Landsteiner’s discovery of blood groups in man. The term “immunogenetics” was suggested by the American scientist M. Irwin in 1930.

The individual and species resistance of plants and animals to bacterial and viral infections is ensured by a complex multistage system of defenses. In the struggle between defenses and infectious agents, the “advantage” often rests with the latter, since microorganisms reproduce quickly and form populations in the millions in which, sooner or later, mutant forms arise that possess more aggressive properties than does the original strain. The system of adaptive immunity (antibody formation), the most powerful line of defense of the body, especially after repeated contact with infectious agents, probably arose at some stage in the evolution of vertebrates as a protective response. The ability or inability to produce antibodies is a hereditary character.

The genetic regulation of the biosynthesis of antibodies has certain characteristic features. For example, the formation of one polypeptide chain of an antibody molecule is controlled by two different genes. One of them controls the formation of the part of the chain that participates in the construction of the active center; the structure of this part varies in antibodies with different specificities. The other gene controls the formation of the part of the chain whose structure is the same in all antibodies of that class of immunoglobulins.

In addition to group antigens there are heritable variants specific to particular types of cells (for example, to leukocytes). The structural differences between donor and recipient in leukocytic antigens is one of the reasons for incompatibility in organ and tissue transplants. The hereditary intraspecific structural differences between many serum proteins (albumins, transferrins, and so forth) are controlled, as a rule, by allelic genes; in this case the frequency of each allele in a population is high (20 percent or more), which points to the “pressure” of natural selection. One of the most important objectives of immunogenetics is to determine the factors responsible for the spread of new alleles in populations. One such factor may be the resemblance in the antigen structure of the pathogenic microorganisms and the host. Animals do not normally produce antibodies to their own antigens. Hence, resemblance in antigen structure between some constituent of the microbial cell and a particular molecule of the host prevents the latter from synthesizing antibodies that will render the given microbial species harmless. The host’s defenses are thereby weakened; selection will then seize upon the appearance of altered protein (or polysaccharide) molecules, increasing immune resistance. The spread of new alleles in a population may occur even when, as a result of a mutation in the corresponding gene, a molecule of the host organism changes in such a way that the enzyme systems of the microbe are no longer able to use it as a substrate. Sometimes the substitution of a single amino acid in a polypeptide chain is sufficient for this purpose. This occurs in certain mutant forms of hemoglobin, which are common in those parts of the world where the incidence of malaria is high: carriers of the mutant hemoglobin do not contract malaria because the malarial plasmodium cannot use this hemoglobin as a substrate. Mutations sometimes spread that alter the biochemistry of the cells or of an organ as a whole, thereby preventing the parasite from adapting. There are apparently additional mechanisms of hereditary immunity that contribute to the hereditary heterogeneity of the host species, interfering with the spread of the parasitic strain of a microorganism.

Thus, the degree of natural resistance to disease in animals of a given species is determined by many factors which, in the aggregate, reflect the constitutional features of both the animal and the causative agent of a disease. A three-dimensional model of these interrelations is presented in Figure 1, which shows that the number of individuals surviving an infection varies both with the hereditary resistance of the organism to the causative agent of the disease and with the virulence of the causative agent.

Hereditary resistance to disease is usually specific, since the physiological basis of resistance to different diseases is usually different.

Figure 1. Three-dimensional representation of the viability of a host as a function of resistance to pathogenic agents and virulence of the causative agent

For example, the African zebu is very tolerant of heat and resistant to tuberculosis but highly sensitive to trypanosomiasis. A strain of white leghorns that is resistant to monocytosis of chickens is sensitive to avian leukosis. Mouse strains resistant to murine typhus are extremely susceptible to pseudorabies virus. Since ancient times the genetic resistance to diseases of individuals, breeds, and races has served as a basis for selection. It was on this basis, for example, that breeders produced the Romney Marsh sheep, which is resistant to tricho-strongyloses, a race of rabbits that is resistant to myxomatosis, and honeybees that are resistant to American foul brood. Natural selection for resistance also exists in man. For example, after the discovery of the New World, it was found that North American Indians were more sensitive to measles and chickenpox than Europeans, for whom these diseases were ordinary and easily tolerated.

Genetic resistance to disease is based on a variety of mechanisms, including nonimmunological ones. White leghorns, for example, are resistant to pullorum disease because of fairly complete thermoregulation. The resistance of the zebu to tick-borne diseases is due to their rather thick hide and to cutaneous excretions that repel ticks. The sensitivity of individuals with A and AB blood to smallpox is due to the similarity between antigen A in man and the smallpox virus antigens. Therefore, individuals with B and O(H) blood tolerate smallpox more easily.

The transfer of genetic concepts to immunology enabled the Soviet scientist V. P. Efroimson to formulate his evolutionary-genetic concept of immunogenesis, which explains intraspecific antigenic diversity and the heterogeneity of antibodies with respect to specificity. Every healthy, immunologically mature individual is capable of an immune response to the tissue antigens of an individual with another genotype. Thus, tissue incompatibility is a universal biological phenomenon. Only identical twins and animals of a single pure line are not separated by the barrier of tissue incompatibility, the strength of which depends upon the extent of the dissimilarity between the genotypes of donor and recipient. It is very important to reduce to a minimum this degree of dissimilarity, by choosing a compatible donor, if organ and tissue transplants and blood and bone marrow transfusions are to be successful. The study of cellular antigens and their heredity, variety, and detection (typing) are the branches of immunogenetics of particular importance in transplantation, transfusion, immunohematology, and clinical immunology.

REFERENCES

Medvedev, N. N. Lineinye myshi. Leningrad, 1964.
Hutt, F. Genetika zhivotnykh. Moscow, 1969. (Translated from English.)
Efroimson, V. P. Immunogenetika. Moscow, 1971.
Hildemann, W. H. Immunogenetics. San Francisco, 1970.

A. N. MATS and O. V. ROKHLJN

immunogenetics

[¦im·yə·nō·jə′ned·iks]
(medicine)
A branch of immunology dealing with the relationships between immunity and genetic factors in disease.
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