A survey of susceptibility to infection with Trichinella spiralis of inbred mouse strains sharing common H-2 alleles but different genetic backgrounds

Twenty-eight different inbred strains of mice representing five different H-2 haplotypes were compared for degree of susceptibility to a primary infection with Trichinella spiralis. Marked differences in susceptibility, measured by the average number of muscle larvae per host, were seen among strains of mice sharing common H-2 alleles. The genes controlling these differences must therefore map at loci outside the major histocompatibility complex. Strains of mice sharing the H-2k haplotype were generally more susceptible than strains expressing other haplotypes and strains expressing H-2q alleles were most resistant. Strains of mice were ranked in order of decreasing susceptibility. Knowledge of these ranking may be of value to researchers wishing to select strains of mice appropriate for studies on T. spiralis.     

Genetic regulation of early survival and cyst number after peroral Toxoplasma gondii infection of A x B/B x A recombinant inbred and B10 congenic mice

Genetics of two traits, survival and brain cyst number after peroral Toxoplasma gondii infection, were studied by using recombinant inbred strains of mice derived from resistant A/J (A) and susceptible C57BL/6J (B) progenitors, F1 progeny of crosses between A/J and C57BL/6J mice, and congenic mice (B10 background). Analysis of strain distribution pattern of survival of A x B/B x A recombinant mice indicated that survival is regulated by a minimum of five genes. One of these genes appears to be linked to the H-2 complex and another is related to an as yet unmapped gene controlling resistance to Ectromelia virus. Associations of defined traits with resistance or susceptibility to Toxoplasma cyst formation were also analyzed. Cyst number is regulated by a locus on chromosome 17 within 0 to 4 centimorgans of the H-2 complex (p = 0.001). Mice with the H-2a haplotype are resistant and those with the H-2b haplotype are susceptible. This analysis also indicated that the Bcg locus on chromosome 1 may effect cyst number (map distance = 12 centimorgans, p = 0.05). Resistance to cyst formation is a dominant trait. To analyze relative roles of H-2 and Bcg loci on cyst numbers, C57BL10 (B10)-derived congenic strains of mice with known H-2 and Bcg type were studied. These studies indicated that the H-2 complex locus has the primary effect on cyst number.     

Brugia malayi: establishment in inbred and outbred strains of mice

Immunocompetent mouse model for human filarial parasite Brugia malayi is urgently required in view of the paucity of commercial reagents for other susceptible rodent viz. mastomys and gerbil. Genes within the major histocompatibility complex have been reported to influence the susceptibility of mouse to helminth parasites. Attempts have therefore been made in the present investigation to experimentally infect various inbred strains of mice viz. NZB/BINJ, BALB/c, AKR, C(3)H, and SJL/J with H-2 haplotype (H-2: d, d, k, k, s, respectively) and outbred strains of mice viz. Parks and Swiss. Findings indicate that susceptibility of mice to B. malayi is strain associated. This is the first report on the successful completion of full developmental cycle of subperiodic B. malayi in NZB/BINJ, an immunocompetent mouse strain. In some of the other strains, partial development or low degree of establishment of worms was observed.     

Genetic susceptibility to post-thymectomy autoimmune diseases in mice

The strain distribution pattern of five different post-thymectomy autoimmune diseases was determined in 21 inbred and two congenic, resistant strains of mice. The results indicated that susceptibility genes outside the H-2 complex may be involved in the development of localized autoimmune diseases in neonatally thymectomized mice. Studies of recombinant inbred strains also showed that susceptibility to gastritis was not associated with the H-2 haplotype but appeared to be influenced by a minor histocompatibility locus. Possible linkage to the H-2 complex was suggested only in the development of coagulating gland adenitis. Although one experiment showed that susceptibility to orchitis and coagulating gland adenitis was inherited as a recessive trait, further studies are required to determine the exact mode of inheritance in each disease system.     

Quantitative variations in the expression of the mouse serum antigen Ss and its sex-limited allotype Slp

A radial immunodiffusion assay for quantitation of the Ss and Slp serum antigens is described. Significant differences between the mean serum concentrations of Ss and Slp were found among various inbred strains. Some of these differences have been shown to be associated with the H-2 haplotype. The quantitative difference between Slp levels associated with the H-2 ^a and H-2 ^S haplotypes has been used as a marker for the S region in the analysis of certain H-2 recombinant strains [A.TH, B10.S(7R), B10.S(9R), and B10.BSVS]. Male mice of two strains with the H-2 ^b haplotype have been shown to have significantly lower levels of Ss compared to males of the other strains tested. Male mice of every strain examined were found to have significantly higher levels of Ss in their serum than females of the same strain. The molecular relationship and developmental patterns of the Ss and Slp antigens have also been investigated using the radial immunodiffusion assay.     

Phenytoin teratogenicity in the primary and secondary mouse embryonic palate is influenced by the H-2 histocompatibility locus

Inbred and congenic strains of mice have been studied for susceptibility to phenytoin-induced cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP). The role of genes linked to the H-2 complex on chromosome 17 has been confirmed. Congenic strains with the A background have identical levels of spontaneous CLP, whereas those strains having the A background with the H-2a haplotype have significantly higher rates of induced CLP than their congenic partners with the H-2b or H-2s haplotype. No such significant difference in the degree of CLP produced by phenytoin is demonstrable in strains with the B background. Rates of isolated CP produced by phenytoin are significantly higher in strains with H-2a than in their congenic partner strains with either H-2b or H-2s, whether the background is A or B.     

Recombinants in the H-2S/H-2D interval of mouse chromosome 17 define the map position of a gene for cleft palate susceptibility

The H-2 region of mouse chromosome 17 is known to include one or more genes that affect susceptibility to cortisone-induced cleft palate. We have now studied congenic strains that possess crossovers in the interval between H-2S and H-2D and have observed significant differences in susceptibility among recombinants that had been believed to possess the same H-2 haplotypes. Pregnant mice were injected on days 11 through 14 of gestation with 100 mg of cortisone per kg of body weight. The frequency of cleft palate in B10.A(2R) was significantly greater than in B10.A(1R), despite the fact that both have H-2a/H-2b crossovers in the interval between the S and D loci and have the same alleles at all loci that have been previously characterized. Both B10.BAR5 and B10.BAR12 were significantly more susceptible than B10.A(18R), although these strains also share the same alleles at all loci that have been previously characterized. All three of these strains have H-2b/H-2a recombinant chromosomes, with crossovers in the S/D interval. Genetic linkage between H-2 and the high-susceptibility gene of B10.BAR5 was confirmed by testing H-2 homozygotes derived by intercrossing backcross animals. These data therefore suggest that a gene coding for susceptibility, which we designate Cps-1, maps in the 350-kb interval between H-2S and H-2D, and the congenic strains that we have found to be different have different crossover points within this interval. Alleles at the Cps-1 locus have embryonic effects, but no demonstrable effects on the maternal environment.     

Influence of H-2-linked genes on glucocorticoid receptors in the fetal mouse palate

The binding of ³H-dexamethasone to cytosolic receptors in fetal jaws and in cytosols and nuclei of primary cell cultures of fetal palates was studied in various congenic strains of mice. The amount of specific binding was greater in palatal tissues from B10.A and BlO.A(2R) mice than in B10 or B10.A(5R) preparations. These differences were not observed in the liver. Since the strains with higher levels of glucocorticoid receptor are known to be more susceptible to cortisone-induced cleft palate than the strains with low receptor levels, it is suggested that quantitative variation in receptor levels may be involved in determining H-2-linked differences in cleft-palate susceptibility. Whether or not this is the case, it appears that an H-2-linked gene affects the quantity of a cytosolic glucocorticoid-binding protein which translocates to the nucleus.     

Genetic control of the murine immune response to cholera toxin

This study was undertaken to determine whether previously noted differences in the immune response of inbred strains of mice to cholera toxin (CT) might be under immune response gene control. A series of inbred, congenic, and intra-H-2I region recombinant mouse strains were tested for responsiveness to CT after i.p. immunization with 0.1 micrograms CT in alum. Samples of plasma were collected at intervals before and after priming and boosting. IgG and IgA anti-CT were measured by ELISA. In three different sets of congenic strains, the level of IgG anti-CT clearly depended on the H-2 haplotype of the strain rather than on any background or Igh genes. Strains with the H-2b and H-2q haplotypes were high responders, and strains with the H-2k, H-2s and H-2d haplotypes were low responders. Within the H-2 complex, the IgG anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains. In contrast to these results with IgG anti-CT, plasma IgA anti-CT levels were uniformly low and indeterminate. We conclude that the murine IgG anti-CT response is controlled by a locus within the I-A subregion of H-2--a remarkable finding, considering the known abilities of this toxin to bind to and to directly stimulate lymphocytes.     

Virus specificity of cytotoxic T lymphocytes generated during acute lymphocytic choriomeningitis virus infection: role of the H-2 region in determining cross-reactivity for different lymphocytic choriomeningitis virus strains

We have compared the relatedness of five different strains of lymphocytic choriomeningitis virus (LCMV) as assessed by LCMV-specific cytotoxic T lymphocytes (CTL). Several different mouse strains were injected with each of the five LCMV strains, and the cross-reactivity of virus-specific CTL generated during the acute infection was tested by killing on a panel of target cells infected with the various LCMV strains. We found that the cross-reactivity pattern of LCMV-specific CTL generated in mice of H-2d haplotype (BALB/c WEHI and DBA/2) was strikingly different from that in mice of H-2b haplotype (C57BL/6 and C3H.Sw/Sn), suggesting that the fine specificity of LCMV-specific CTL is a function of the H-2 region. The characteristic cross-reactivity patterns were also observed in (C57BL/6 X DBA/2)F1 mice, demonstrating that the repertoire of the H-2b- and H-2d-restricted LCMV-specific CTL is not changed as a result of complementation by gene products of the other major histocompatibility haplotype. Studies with congenic BALB.B10 and (BALB.B10 X BALB/c)F1 mice firmly established that the characteristic cross-reactivity patterns of LCMV-specific CTL map to the H-2 region and are not influenced by background genes outside the major histocompatibility locus. These results suggest that LCMV determinants seen in the context of H-2d-restricting elements are different from those seen in the context of H-2b-restricting elements. Moreover, our studies show that CTL can be used as probes for dissecting differences among various LCMV strains, but the degree of relatedness between the different LCMV strains is not absolute when measured by CTL recognition. Since the H-2 region regulates the fine specificity of CTL generated during LCMV infection in its natural host, the degree of cross-protective immunity developed during a viral infection apparently depends on the major histocompatibility haplotype. The importance of these findings lies in understanding susceptibility or resistance of various host populations to viral infections and in designing vaccination programs to provide immunity.     

Localization of mouse Pgk-2 gene at the D end of the H-2 complex (1)

A survey of the Pgk-2 alleles carried by H-2 congenic lines of mice has established that the Pgk-2 locus is near the D end of the H-2 complex on chromosome 17. A comparison among inbred strains of the alleles for Pgk-2, H-2, and two other genes in this vicinity, Tla and Ce-2, has revealed a remarkable correlation suggestive of strong linkage disequilibrium in the wild mice from which the inbred strains were derived.     

Genetic control of susceptibility to mite-associated ulcerative dermatitis

Variable susceptibility to mite-associated ulcerative dermatitis (MAUD) attributable to Myobia musculi infestation was studied in breeding stocks of sixteen inbred strains of mice. Statistical evaluation of 41 occurrences of lesion among 1,517 mice of the various strains indicated that significant differences in the frequency of MAUD were associated with differences in genetic background and in the H-2 type. These findings suggest that the occurrence of an ulcerative skin lesion in inbred mice exposed to M. musculi is controlled by at least two genes. Lesion susceptibility appears to be profoundly affected by a non-H-2 linked gene or gene combination shared by all C57Bl background strains. In addition, a major influence is exerted by one or more genes within the H-2 complex.     

Leishmania donovani infection in heterozygous and recombinant H-2 haplotype mice

On a B10 (Lshs) genetic background the development of acquired T-cell-mediated immunity to Leishmania donovani infection in mice is under H-2-linked genetic control. Three phenotypic patterns of recovery were previously observed: "early cure" (H-2s, H-2r), "cure" (H-2b) and "noncure" (H-2d, H-2q, H-2f), with cure behaving as a recessive trait in H-2b/H-2d mice. In this study the long-term response to L. donovani is followed over 130 days of infection in eight recombinant haplotype strains and in six further heterozygous haplotype combinations. Noncure in B10.HTG mice, which carry d alleles for loci at the K end and b alleles for loci at the D end of H-2, confirms that H-2-linked genetic control of the acquired response to L. donovani infection is located in the K end. The complex pattern of dominance relationships observed in the additional heterozygous haplotypes studied, the variable phenotypic response of H-2k mice and of recombinant haplotype strains carrying IEk in common, and the differential early curing activity observed in heterozygotes involving the s but not the r early cure haplotype and in recombinant haplotype mice carrying s alleles to the left of IE suggest, however, that more than one subregion (IE and presumably IA) are involved. Results are interpreted in the light of immunoregulatory T-cell populations previously demonstrated in noncure, cure, and early cure strains.     

Genetic susceptibility to chlamydial salpingitis and subsequent infertility in mice.

Groups of mice from genetically defined inbred strains were infected genitally with a pathogenic human strain of Chlamydia trachomatis and their subsequent fertility was compared. The CBA, C3H (H-2o) and C3H/He-mg (H-2k) mice were less fertile than control mice, at least up to 6 months after infection. In contrast, fertility was not impaired in BALB/c mice or in congenic BALB/K mice, which had the H-2k haplotype. Reduced fertility was paralleled by the extent of histological oviductal inflammation in mice of each strain. No salpingitis was seen 21 days after infection in the BALB strains, but lesions were apparent in CBA and C3H strains up to about 70 days after inoculation and these sometimes developed into hydrosalpinges. These results indicate that susceptibility to chlamydial salpingitis and subsequent infertility is under genetic control. This control was not simply associated with the major H-2 gene complex, as mouse strains of the same haplotype (H-2k) differed in susceptibility. The fertility of BALB/c (H-2d) and BALB/K (H-2k) strains was no different from that of controls, and congenic C3H mice of differing H-2 haplotypes (H-2k and H-2o) showed reduced fertility. Although all the infected F1 (BALB/K x C3H/He-mg) mice produced litters at the same rate as untreated controls, the litters were considerably smaller. This was due to the occurrence of unilateral pregnancies in the mice inoculated under the ovarian bursae and possibly also to early fetal death in mice inoculated directly in the uterus. These findings emphasize the importance of early diagnosis and treatment of infection of the lower genital tract of women.     

Wild-derived inbred mice have a novel basis of susceptibility to polyomavirus-induced tumors

Polyomavirus induces a broad array of tumors when introduced into newborn mice of certain standard inbred strains, notably those bearing the H-2(k) haplotype. Susceptibility in these mice is conferred by an endogenous mouse mammary tumor virus superantigen (Mtv-7 sag) that acts to delete T cells required for polyomavirus-induced tumor immunosurveillance. In the present study we show that mice of two wild-derived inbred strains, PERA/Ei (PE) and CZECH II/Ei (CZ), are highly susceptible to polyomavirus but carry no detectable Mtv sag-related sequences and show no evidence of Vbeta deletion. C57BR/cdJ (BR) mice, which are H-2(k) but lack the endogenous Mtv-7, are highly resistant based on an effective anti-polyomavirus tumor immune response. When crossed with BR, both PE and CZ mice transmit their susceptibility in a dominant fashion, indicating a mechanism(s) that overrides the immune response of BR. Susceptibility in PE and CZ mice is not based on interference with antigen processing or presentation since cytotoxic T cells from BR can efficiently kill F(1)-derived tumor cells in vitro. The expected precursors of polyomavirus-specific cytotoxic T cells are present in both the wild inbred animals and their F(1) progeny. These findings indicate a novel basis of susceptibility that operates independently of endogenous superantigen and prevents the development of tumor immunity.     

Corticosteroid-induced cleft palate in mice and H-2 haplotype: Maternal and embryonic effects

This report confirms and expands on the original preliminary observations made by Bonner and Slavkin that corticosteroid-induced cleft palate in mice is associated with H-2 haplotype. Using three congenic strains, B10, B10.A, and B10.D2, our studies demonstrate that B10.A (H-2 ^b) is most susceptible and B10.D2 (H-2 ^d) is least susceptible, B10 (H-2 ^b) being intermediate. Variation in fetal loss among strains accounts for less than 1 percent of the variation in cleft-palate frequency among strains; variation in H-2 haplotype, however, accounts for more than 60 percent of the variation in cleft-palate frequency. With regard to all possible reciprocal F₁ hybrids, our results indicate that while there is a significant maternal effect, maternal haplotype can account for only 11 percent of the variation in cleft-palate frequency among crosses. Embryonic haplotype accounts for 17 percent of the variation, which is indicative of an important embryonic effect. Finally, our studies suggest that susceptibility to corticosteroid-induced cleft palate is associated with the K end of the H-2 complex.     

Polymorphism of Unique Noncoding DNA Sequences in Wild and Laboratory Mice

Two DNA probes, D17Tu1 and D17Tu2, were isolated from a genomic DNA library containing only two mouse chromosomes, one of which is chromosome 17, carrying the major histocompatibility complex (H-2), as well as the t complex genes. The D17Tu1 probe was mapped to the centromeric region of chromosome 17 and the D17Tu2 probe to the S region of the H-2 complex. Neither of the two probes appeared to detect any genes, but both contained unique, nonrepetitive sequences. Typing of DNA obtained from a large panel of mice revealed the presence of four D17Tu1 patterns in inbred mouse strains, one very common, one less common, and two present in one strain each. The two common patterns could not be detected in appreciable frequencies in the European wild mice tested (one of the two patterns was, however, found in Australian wild mice). Conversely, the patterns found frequently in European wild mice are absent in the laboratory mice. We therefore conclude that wild mice from the sampled regions of Europe could not have provided the ancestral stocks from which inbred strains were derived. Only one D17Tu1 pattern was found in all the populations of Mus musculus tested, while eight patterns were found in Mus domesticus, with virtually all the populations being polymorphic. We suggest that this difference reflects different modes in which the two species colonized Europe. The distribution of the D17Tu2 patterns in inbred strains correlates with the distribution of H-2 haplotypes.     

Regulation of immune responses via genetically restricted cellular interactions. II. I-region-restricted cooperation between idiotypic and anti-idiotypic B lymphocytes

Immunization of BALB/c mice with MOPC-104E myeloma protein induced idiotype-specific enhancing cells which acted on anti-dextran antibody-producing cells. The enhancing cells have surface phenotypes of B cells. Using BALB/c H-2 congenic strains, it was found that the cooperation between anti-idiotypic-enhancing B lymphocytes and dextran-primed B lymphocytes was controlled by major histocompatibility gene complex. Here we have described the loci which restrict the successful cooperation between B lymphocytes, wherein it was revealed that the interaction was restricted to the I-A and I-E subregions in H-2k haplotype and the I-A subregion in H-2b haplotype. Utilizing several monoclonal antibodies specific for Ia antigens, it was revealed that the enhancing B lymphocyte activity was completely inhibited by the pretreatment of antibody-producing B cells with anti-Ia.7 in H-2d haplotype as well as H-2k, and with anti-I-A antibody in H-2b haplotype. The results suggest that the anti-idiotypic B-lymphocyte response to the self idiotype is under control of H-linked immune response (Ir) gene.     

Stable genotypic composition of blood cells in allophenic mice derived from congenic C57BL/6 strains

Random shifts in blood cell genotypic composition are commonly observed in allophenic mice. This phenomenon was studied in 16 mosaic mice produced from very closely related strains, and no such changes were observed in the mosaic composition of erythrocytes, platelets, and lymphocytes over a period of 14 weeks. Furthermore, the mosaic distribution of a large group (66) of these mosaic mice was markedly biased in favor of those animals containing major contributions of both strains. This contrasts with what is normally found in collections of allophenic mice, in which the mosaic distribution curves are usually much flatter. While most allophenic mice have been produced from inbred strains with many genetic differences our results were obtained with congenic strains. This suggests that both properties, the unstable mosaic composition of blood cells and the flat mosaic distribution curves, are caused by specific genetic differences between cells of the two strains and are not inherent properties of allophenic mice. We propose that genetic differences cause these phenomena by inhibiting the mixing of cells of the two strains. Such might occur for example if, throughout development, cells of the same H-2 haplotype had greater affinity for each other than for ones of disparate H-2 haplotypes.