Biomedical subjects
Publications and source records attributed to I I Fomicheva.
Reduced expressivity and penetrance of allotypes H2-H4 and the regulation of allotype H6 expression by regulatory gene concealed the linkage of mink C genes in statistical analyses. Their linkage was demonstrated by di- and polyhybrid test crosses with 3, 4 and more generations.
The results of a quantitative study of the expression of mink C gamma-allotypes (H3, H4, H6, and H8) in sera are presented. H6 and H8 were found to be stably expressed, and the individual concentrations of the allotypes varied within one order of magnitude. Gene dosage effects were observed for H6 and H8: average sera allotype concentrations in homozygotes were twice those in heterozygotes. In contrast, the serum concentrations of H3 and H4 varied by three orders of magnitude, ranging from minor (2-200 micrograms/ml) to high (1-10 mg/ml). No gene dosage effects were observed for the expression of H3 and H4. Histograms for the population of H3 concentrations showed three peaks, sharply differing from those of H4, H6, and H8. There was no association between the minor expression of H3 and H4. The data obtained indicate that the expression of mink C gamma-allotypes is regulated by different allotype-specific mechanisms.
The Aleutian disease (AD), i.e., viral plasmocytosis in mink can be used as a model of the natural development of immune complex pathology in man. The immunogenetic aspect of AD was studied with the help of genetic markers of the constant region of the mink immunoglobulin gamma-heavy chain (the C gamma allotypes H2, H3, H4, H6, H7 and H8). The frequencies of 2 of the 6 allotypes, H3 and H4, were significantly higher in the AD-infected than in normal minks from the same population. This supports and extends the data in the literature indicating that the frequencies of certain human Gm allotypes are significantly higher among patients with multiple sclerosis, some oncological and other diseases compared with normal humans. Individual testing of 110 adult Standard minks before and after artificial inoculation with the AD virus demonstrated that change in allotype frequencies results from the activation of the expression of H3 and/or H4 in many individuals. The obtained results make it possible to consider the regulation of the expression of the two CH genes of immunoglobulins as allotype-specific.
A brief review summarized the results we obtained with the identification, analysis of population distribution, genetics, expression, and evolution of 12 IgG allotypes in the American mink and several closely related mustelids. The American mink is a unique species with respect to expressed allotypic polymorphism of Ig lambda chains. In contrast to the rabbit, human, mouse and rat, the phenotypic expression of IgC gamma allotypes shows unusual variations which mask their true genetic relationships (linkage of C gamma genes; C gamma = constant region of IgG chains). The allotypic IgG polymorphism in the American mink during mustelid phylogenesis underwent saltatory change. A parallelism between the data on changes in IgG allotype frequencies in man and mink in disease is emphasized. In mink, these changes are provided by allotype-specific activation of the expression of the 2 CH genes (CH = constant region of the Ig heavy chains). The results make apparent the need of including more taxa in investigations of Ig genetics. In addition, the Aleutian disease of the mink is presented as a model of human disease.
110 ranch-raised minks were injected with the Aleutian disease virus. Allotypes of constant regions of gamma-heavy chains of the mink immunoglobulins secreted have been analysed during 3 months. Activation of the expression of two markers (H3 and/or H4) up to minor or to nominal level (above 200 micrograms/ml) was observed. No such enhancement of expression of two other allotypes (H6 and H8) was found. The results suggest that the expression of two mink immunoglobulin CH genes induced by viral infection has allotype-specific regulation.
We describe here the inheritance of H6, one of the six known allotypes of the gamma-chain constant region of mink immunoglobulin (IgG). H6 is not present in minor concentrations in the serum, and its phenotypic expression is stable. However, in offspring of some of (H6-)X(H6-) crosses. H6 appeared unexpectedly and, by contrast, it disappeared in some H6+/H6+ homozygote offspring. Based on pedigree analysis, a transregulation of H6 expression in the serum by an autosomal recessive gene not linked to the structural allotype gene is postulated.
IgG polymorphism (allotypes H3, H4, H6 and H8 of constant region of the gamma-chain) was investigated in healthy and affected with Aleutian disease (AD) minks from two Siberian and one Danish populations. In all three populations, the expression of H3 and H4 allotypes was strongly associated with AD. Among the AD minks the frequency of H6, H8 phenotype was found to be decreased, whereas the frequency of H3, H4, H6, H8 phenotype was significantly increased. At the same time, the populational distribution of the rest phenotypes was similar among healthy and AD minks. The H3, H4, H6, H8 minks showed the highest pathomorphological characteristics of AD. Based on the data concerning mink H3 and H4, and human Gm allotypes, their role as possible genetic markers for hereditary susceptibility to distinct disease is discussed.
Two new allotypes of the light (L) chains IgG, L4 and L5, were identified in the mink with dispecific antiserum produced by immunization with allogenic IgG. By means of hybrid IgG molecules and proteolytic fragments, L4 and L5 were localized on the C region of the L chain. L4 and L5 occurred frequently in the three mink populations studied and L4 and L5 are inherited independently of the known mink C gamma allotypes. L4 and L5 are encoded by closely linked genes. The antigenic specificities of L4 and L5 were not identified in the closely related Mustelidae and in the other mammalian representatives. Consequently, L4 and L5 are species specific to mink. Determination of the phenotype combinations of the five allotypes on the L chains (including the new L4 and L5) demonstrated the existence of seven combinations only with a predominance of L1,2,3; L4,5, and L1,2,3,4,5 phenotypes. Based on the results obtained, it is concluded that the mink C lambda locus has a complex organization. A model for the mink C lambda locus with at least three or possibly five linked genes is suggested.
Optimum conditions were established to obtain mink-mouse interspecific hybridomas secreting mink IgG in fusions of mouse myelomas with mink immune spleen cells. Minks were immunized with allogeneic IgG, and the spleen cells were fused with three mouse myeloma lines P3-X63-Ag8.653, NSO and Sp2/0-Ag14. Of these, P3-X63-Ag8.653 and NSO were found to be the best fusion partners giving the highest yield of hybrid clones and number of IgG secreting clones. Cloning of mink-mouse hybridomas was efficient when BALB/c nu/nu peritoneal and spleen cells were used as feeders. The ten clonal lines produced secreted intact mink IgG molecules as shown by SDS-PAGE and subsequent immunoblotting. The secretion level of IgG ranged from 5 to 200 ng/ml in the clonal lines.
Quantitative expression of C gamma-allotype H4 of mink immunoglobulins was studied by enzyme-linked immunosorbent assay. The results presented suggest that production of H4 is under specific regulation. the concentration of H4 varies three orders of magnitude (10-10,000 micrograms/ml) from one mink to another. Fifteen percent of the sera of normal minks have the low H4 concentration, undetectable by the standard procedure of double immunodiffusion routinely used to test mink IgG allotypes. However, expression of these 'minor' allotypes may be significantly enhanced by hyperimmunization. Instability of this kind seems to be the main cause of earlier described deviations from Mendelian inheritance of C gamma-allotypes H2, H3 and H4.
A new allotype of the mink light chains, designated L3, was identified. This allotype is inherited as a Mendelian character at a frequency of 0.46 in the mink population. Data were obtained indicating that L3 is independent of the C gamma-heavy chain allotypes of mink immunoglobulins. The gene L3 is closely linked to a gene encoding L1, another light chain allotype. Alloantigens L1 and L3 are presumably markers of the light chains of two different subtypes. In contrast to L1, which occurs in many mammalian species, L3 is species-specific, i.e., it is a case of light chain polymorphism representative of the whole mink species.
Mink Aleutian disease (AD) is characterized by intensive proliferation of B-lymphocytes and hypergammaglobulinemia. Populational distribution of five genetic immunoglobulin markers (light chain allotype L1 and C gamma-allotypes H2, H3, H6 and H8) in minks of different coat color (Sapphire, Standard and Topaz) was studied. The groups of infected minks differed significantly from healthy ones in the distribution of the H3 allotype: the frequencies of some phenotypes--H3, H6, H8 and L1, H3, H6, H8 (Sapphire, Standard). H2, H3, H6, H8 and L1, H2, H3, H6, H8 (Sapphire) were increased significantly. At the same time, the frequencies of H6, H8; L1, H6, H8 and H2, H6, H8; L1, H2, H6, H8 were decreased in the AD population. The preferential stimulation of proliferation of the H3 + B-lymphocyte clones is suggested.
The non-expression of parental allotype among mink F1 offsprings of monohybrid analyzing crosses was established for C gamma-allotypes. A phenotype ratio 0:1, instead of the expected Mendelian 1:1, was observed in some families. The non-expression of allotype may occur in the progeny of mink with normal allotypic specificity. Deviations of allotypic expression had both qualitative and quantitative nature and did not depend on the direction of crossings. Sometimes, the appearance of allotype in a mink could not be expected on the basis of its pedigree. Instability of expression and inheritance of H2, H3 and H4 in many families may have masked the allelic or linkage relationships of these genetic markers.
By means of intraspecific immunization of domestic mink (Mustela vison Schr.), 8, in all probability, complex IgG allotypes were detected in their sera. Based on the results of analysis of the preparations of the IgG heavy (H) and light (L) chains, as well as proteolytic IgG fragments, we assigned the allotypes detected to three groups: (1) marker of the L chain, L1; (2) allotypes of the C region of gamma-chains (H2, H3, H4, H6, and H8) and conformational allotype H7; (3) conformational allotype 5 with unknown location on the chains.
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Population distribution and inheritance pattern were analyzed in mink IgG allotypes: L1 (L chains), H2, H3, H4, H6, H7, and H8 (the constant region of the H chains, i.e. C gamma-allotypes) and conformational allotype 5 with unknown chain localization. Contrary to expectation, neither allelism, nor close linkage were demonstrated for these allotypes. The major feature of the inheritance of H2, H3, and H4 C gamma-allotypes, as well as allotype 5, was significant excess of negative (without these allotypes) progeny in the F1 generation from monohybrid cross. The explanation offered for this departure of the C gamma-allotypes from normal Mendelian genetics suggests widespread latencies of their expression in mink.
The antigenic specificities of six (1--6) IgG allotypes of the domestic mink were tested in the sera of closely related species of Mustelidae family and distant mammalian species. It was found that allotypes 1 and 5 are ancient. Their antigenic specificities were established not only in Mustelidae, but also in other taxonomic orders of mammals. Allotypes 3 and 2 are phylogenetically younger; they were detected only in Mustelidae. Allotypes 4 and 6 appear to be unique to the domestic mink. The instantaneous evolutionary emergence of complex allotypes 4 and 6 is difficult to explain by a rapid accumulation of gene point mutations during phylogenesis. Activation in the domestic mink of those immunoglobulin genes, which are silent or poorly expressed in closely related Mustelidae, is suggested as a more plausible explanation.
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