The interdisciplinary subject of immunology and genetics, mainly studyingimmune systemThe genetic basis of its structure and function, such as immune response, antibody diversity, etc.In addition, immunological methods are also used to identify genetic differences between individuals (such as blood type, surface antigen, etc.) as indicators of genetic law analysis.Immunogenetics is one of the important theoretical bases of modern medical clinical practiceorgan transplantThe theoretical basis of fetal mother incompatibility and paternity test is also of great significance for clarifying the evolution of the immune system, ethnic differences and biological evolution.
1900-1902AustriaDr. K. Landsteiner and other scientists cross mixed the serum and red blood cells of different people, and detected two kinds of human red blood cell alloantigens A and B for the first time through the observation of cell agglutination reaction.F. Bernstein certification in 1924ABO blood groupThreeMultiple alleleControlled by, this is the first discovered human blood type genetic system.Since then, a variety of red cell antigens have been found in some animals and humans (seeBlood group heredity）And gradually clarified their genetic laws.1958FranceImmunologist J. Dorset discovered the first human leukocyte antigen.1959 Australian immunologist FM. Burnett proposedClonal selection theoryAnd explained the source of antibody diversity from the cell level.1970smolecular geneticsandSomatic cytogeneticsThe development of immunogenetics has further promoted the development of immunogenetics.For example, applying genetic engineering andMolecular hybridization technologyIt is proved that the heavy chain and light chain of antibody molecule are respectively encoded by several DNA sequences;applicationSomatic hybridizationA technique for preparing monoclonal antibodies was established.These new developments make the study of immunogenetics an important part of molecular genetics.
1936 PA. Goller used rabbit anti mouse red blood cell serum to detect four kinds of red blood cell antigens in mice.He hybridized the antigen II positive mouse strain with the antigen II negative mouse strain, and then backcrossed the offspring with the antigen II negative mouse strain.Transplanting tumor from antigen II positive mice to antigen II negative offspring will result in rejection of tumor;When transplanted to the positive offspring of antigen II, the tumor will not be rejected, which proves that antigen II is aHistocompatibility antigen(H-2), controlled by a single gene.Then we found that H-2 specificity canlymphocyteThe study of leukocyte antigen was initiated.It was later proved that the histocompatibility antigen of mice was not controlled by a single gene but by several closely linked genes.These many genes constituteMajor histocompatibility complex(MHC), located on mouse chromosome 17, is divided into K, I, S, G, D/L, and T6 regions.The main histocompatibility complex of human body is called human leukocyte antigen (HLA).It is determined that the complex seat of HLA is on the short arm of chromosome 6. There are known A, C, B and D/DR seats, and each seat has many codominantsMultiple allele。The corresponding gene complexes of monkeys and dogs are called RhLA and DLA respectively.
Antigen inheritance of other animals
Of various animal cellsproteinBothantigenThe differences of these proteins can be detected by immunological methods to reveal their genetic mechanism.For example, using rabbit antiserum against paramecium fragments, it is found that each strain of paramecium can synthesize about 10 different specific surface antigens.Paramecium binucleatumThree major genes, s, g and d, control its surface antigens, S, G and D. These genes are not linked.Although these surface antigens are controlled by nuclear genes, their expression is affected by temperature.S gene was expressed at 15~18 ℃, and g gene was expressed when s gene was turned off with the increase of temperature, and d gene was expressed when the temperature was about 30~32 ℃.The g gene of different strains with different geographical distribution, such as 156 and 168 strains, can encode different antigens 156G and 168GZygogenesisAfter the formation of heterozygotes, although their genotypes are the same (156g/168g) and the temperature conditions during culture are the same (30 ℃), the asexual reproduction line of the hybrid paramecium originally belonging to 156 strains expresses antigen G, while the asexual reproduction line of the hybrid paramecium originally belonging to 168 strains expresses antigen D.This heterozygote with the same genotype has different phenotypes under certain circumstances, and can beAsexual reproductionThe phenomenon of passing from generation to generation is called epigenetic phenomenon.The essence of epigenetics is not only a problem in genetics but also in immunology that has not been fully solved.
Antibody heredity
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Antibody molecular composition
Antibody molecules areimmunoglobulin, consisting of two light chains and two heavy chains.Both light chain and heavy chain can be divided into variable region (V) and constant region (C) according to the degree of amino acid sequence variation.Higher animals and humans can produce extremely large amounts of immunoglobulins with different specificity.Does every individual have so many light chain genes and heavy chain genes?This has puzzled geneticists.Burnett'sClonal selection theoryIt answers this question at the cellular level.According to this theory, each plasma cell can only produce one or a few antibodies, and the innumerable plasma cells of an individual together can produce innumerable kinds of antibody molecules.
Chromosome combination
Immunogenetics
Various plasma cells are composed oflymphocyteDifferentiated.Using gene strain building, molecular hybridization and nucleotide sequence analysis techniques, it was found that the light and heavy chains of immunoglobulin molecules were encoded by several separated gene fragments or exons.There are four types of gene fragments, L, V, J and C, on the chromosome that determines the light chain.There are about 150 kinds of V segments (variable segments), 5 kinds of J segments (connecting segments), and one kind of L segments (guiding segments) and one kind of C segments (constant segments).In the process of lymphocyte differentiation, these gene fragments can be transcribed after being rearranged and connected together.The V/J connector is flexible during rearrangement, and it is estimated that there are 10 possibilities.The original transcript is processed and spliced to become L-V-J-C continuous mRNA.L segment is cut after translation, V-J segment is translated into variable region, and C segment is translated into constant region.The different combinations of rearrangements and the flexibility of V/J joints can lead to about 7500 light chain genes (150 × 5 × 10).There are five types of gene fragments, L, V, D, J and C, on the chromosome that determines the heavy chain.Among them, there are 1 L segment, 80 estimated V segments, 50 D segments (diversity segments), 6 J segments and 8 C segments.It is estimated that there are 10 possibilities for V/D and D/J joints respectively.Eight C fragments determine the type of immunoglobulin, namely lgM, lgD, lgG3, lgG1, lgG2b, lgG2a, lgE, or lgA. They target the sameAntigenic determinantThe same variable area exists.Through rearrangement and joint flexibility, 2.4 million heavy chain genes (80 × 50 × 6 × 10 × 10) can be generated.The combination of light and heavy chains can produce 18 billion kinds (750 × 2400000) of immunoglobulin molecules.If we add the possibleSomatic mutation(The estimated mutation rate is 1/10000 cells/generation), and the diversity of antibodies can also be expanded.
Although the source of antibody diversity has been explained at the cellular and molecular levels, there are still many problems to be solved.It is known that a plasma cell produces only one specific antibody molecule, and its allele is not expressed in the heterozygous state.The mechanism of this allelic repulsion phenomenon is still unknown.Little is known about the exact process of chromosome rearrangement.
Immune response genetics
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As early as 1938, PA. Goller and others found that different inbred lines of micePneumococcusThe ability of capsular polysaccharides to produce antibodies varies greatly.Later, some people used synthetic peptides as antigens and got the same results.This difference is hereditary.The immune response gene (Ir) controls the degree of immune response of an individual to the antigen.For example, when immunizing mice with a synthetic polypeptide, H-2 system q homozygous mice (Irq/Irq) are highly responsive strains and can produce more antibodies;The s homozygous mice (Irs/Irs) are low responsive strains and produce fewer antibodies.Their hybrid offspring (Irq/Irs) are the same as their qhomozygous parents, and they are also highly responsive.When the hybrid progeny is backcrossed with the s pure line parents, half of the backcross progeny are highly responsive and half are low responsive.This fact indicates that the immune response is controlled by a pair of genes. High response is dominant, while low response is recessive.Mice have several Ir genes, and sometimes the immune response to one antigen can be controlled by two Ir genes at the same time.The degree of human response to ragweed allergen producing lgE antibodies is also controlled by the Ig gene linked to HLA.Ir gene is also found in chickens, rats, dogs, monkeys and other animals.In addition to the above three aspects, the genetics of complement and interferon also belong to the scope of immune genetics research.
