Susceptibility and resistance of inbred mice to Paracoccidioides brasiliensis

Nine different inbred strains of mice inoculated intraperitoneally with yeast cells of Paracoccidioides brasiliensis showed significantly varying patterns of susceptibility. The A/SN strain was found to be the most resistant, while BIOD2/nSn, BIO.A and BIOD2/oSn the most susceptible strains. These susceptibility differences were not dependent on the size of challenge inocula and sex of animals. All strains studied showed a mean survival time proportional to the size of inocula used. Although almost all infected male mice presented a shorter survival time when compared with females, significant mortality differences between sexes were found only in two of the strains studied, namely BALB/c and BIOD2/nSn. The H-2 region did not influence the susceptibility pattern since the A/SN and BIO.A strains share the same H-2 haplotype and were respectively highly resistant and susceptible to P. brasiliensis. Furthermore, the presence of C5 and unresponsiveness to lipopolysaccharide had no influence on the mortality data observed. Specific antibodies were detected only in a small number of animals and titres were consistently low, appearing later in the resistant (A/SN) than in a susceptible strain (BIO.A). Omentum, spleen and liver were the most affected organs in both strains, but the susceptible mice had more granulomatous lesions and earlier dissemination of the fungus.     

Nature of the cross-protective antigen in subcellular vaccines of Streptococcus pneumoniae.

The susceptibility of inbred strains of mice to pulmonary blastomycosis was studied to derive information relevant to host resistance and genetic background. Initial studies with eight strains with various H-2 backgrounds revealed the C3H/HeJ strain to be highly susceptible and DBA/1J mice to be resistant. These observations were confirmed with various challenge inocula. These differences were not dependent on the size of the challenge, the strain of Blastomyces dermatitidis, host age, or ability of the challenge to penetrate to the lower airways. Differences between the susceptible and resistant strains in lymphocyte proliferation in vitro and delayed-type hypersensitivity in vivo after nonlethal subcutaneous infection were not demonstrated; the susceptible strain made a significantly greater antibody response to blastomyces antigens as determined by an enzyme-linked immunosorbent assay. The resistance of the C3H/HeN strain of mice, which differs from the C3H/HeJ in sensitivity to lipopolysaccharide and lacks the macrophage cytotoxicity defect of the latter, suggests that the susceptibility of C3H/HeJ mice is not related to their C3H background or the H-2 locus. As the A/HeJ strain, which also has a macrophage cytotoxicity defect, was found in this study to be the second most susceptible strain, this also suggests macrophages as the subject for further study with respect to the mechanism of genetic resistance to this infection.     

Genetics of murine resistance to Trypanosoma cruzi.

Resistance to the protozoan parasite Trypanosoma cruzi is governed by multiple genetic factors, including at least one coded for by a locus in or near the major histocompatibility complex of the mouse. The influence of the H-2 locus on resistance was evident when H-2 congenic mice on a strain background of intermediate resistance were challenged or when the survival of H-2 typed F2 mice was followed. The H-2k haplotype of the susceptible C3H/An strain was associated with higher mortality when compared with the H-2b haplotype of the resistant C57BL/10 strain. Genetic studies showed that resistance was a dominant trait and increased with genetic heterozygosity. F1 mice derived from crosses between resistant and susceptible strains, or even between two susceptible strains, were much more resistant than either parent. Crosses between two resistant strains, C57BL/6J and DBA/2J, led to resistant progeny in the F1 and F2 generations; but when recombinant inbred strains derived from these parental strains were challenged, susceptible strains were identified, indicating that different genes were responsible for resistance in the two strains.     

Histocompatibility-linked genetic control of susceptibility to age-dependent polioencephalomyelitis in mice.

Susceptibility to induction of immune polioencephalomyelitis (IPE) was found to be controlled by a gene that is closely linked to the H-2 complex. Whereas mice of the AKR (H-2k) strain were susceptible to IPE induction, H-2-congenic mice, AKR.H-2b (H-2b from C57BL/6) and AKR.M (H-2m), were resistant. However, susceptibility to IPE may be under additional control by a gene(s) outside of the H-2 region, since both C57BL/6 (H-2b) mice and congenic B6.H-2k mice (H-2k from AKR) were resistant to IPE induction. F1 hybrid mice derived from AKR (susceptible) and DBA/2 (resistant) mice were susceptible to IPE induction, indicating that susceptibility is dominant in at least one gene, but susceptibility developed at a later age in the hybrid mice than in AKR mice. B6.PL-Ly-2a Ly-3a/Cy, C57BR, C57L, PL, and RF strain mice were resistant to ipe induction. Thus, of the 12 inbred strains tested so far, only two (C58 and AKR) are susceptible to IPE.     

MurineTaenia crassiceps cysticercosis: H-2 complex and sex influence on susceptibility

Several inbred strains of mice were infected by intraperitoneal injection of tenTaenia crassiceps cysticerci per mouse. Genes linked with the major histocompatibility complex (H-2) were found to influence parasite growth greatly, as demonstrated by the different parasite loads of H-2 congenic mice with BALB background: BALB/c (H-2d) mice were the most susceptible, whereas BALB/k (H-2k) and BALB/b (H-2b) animals were comparatively resistant. Non-H-2 genes had no significant effect on susceptibility in H-2d strains, as reflected by the similar parasite loads in BALB/c, DBA/2, and (BALB/cxDBA/2)F1 mice. Using the H-2b (BALB/b, C57BL/6J) and H-2k (C3H/HeJ, BALB/k, and C3HeB/FeJ) strains, we found that non-H-2 background genes caused a small but significant influence on parasite load. A recombinant mouse strain alleles (K^k, I^k, S^d, D^d) was also susceptible, indicating that S and/or D regions of the H-2d complex are probably involved in the control of resistance to murine cysticercosis. Females of all mouse strains were more susceptible than males. The same effects were observed for H-2 genes and sex, with two strains ofT. crassiceps differing in their rate of growth.     

Resistance to Paracoccidioides brasiliensis in mice is controlled by a single dominant autosomal gene.

In a previous report it was shown that there are resistant, susceptible, and intermediate strains of mice to intraperitoneal Paracoccidioides brasiliensis infection. In the present work, we investigated the type of inheritance and the number of genes that determine resistance to paracoccidioidomycosis. Parental and hybrid mice were inoculated intraperitoneally with 5 X 10(6) P. brasiliensis yeast cells, and mortality was scored daily. Analysis of susceptible and resistant parental strains and of F1, F2, and backcross mice showed that the resistance to P. brasiliensis seems to be controlled genetically by a single dominant gene, which we designated the Pbr locus. The mean survival times of susceptible F2 and backcross hybrids were very similar to that of the susceptible parent. Examination of the pathological changes observed in parental and F1 mice, 6 months after infection, showed that F1 offspring presented a similar number and distribution of lesions to those of the resistant strains. The Pbr gene is not linked to H-2, Hc, and albino genes. Furthermore, resistance to paracoccidioidomycosis is controlled by an autosomal gene.     

Genetic Susceptibility to the Induction of Murine Experimental Autoimmune Orchitis (EAO) without Adjuvant. I. Comparison of Pathology,Delayed Type Hypersensitivity,and Antibody

In the present study, it was demonstrated that there were marked strain differences in susceptibility to the induction of our new murine model of experimental autoimmune orchitis (EAO; definite orchitis with hypospermatogenesis) induced by two or three sc injections with viable syngeneic testicular germ cells (TC) without any adjuvants. Among 12 inbred strains of mice examined, the A/J (H-2^a), C3H/He (H-2^k), and C3H/HeN (H-2^k) strains were highly susceptible, whereas the C57BL/6N (H-2^b), C57BL/10Sn (H-2^b), BALB/cAnN (H-2^d), AKR/N (H-2^k), CBA/JN (H-2^k), C3H/HeJ (H2^k), and MRL/lpr (H-2^k) strains were low susceptible, and the DBA/2N (H-2^d) as well as C3H/BiKi (H-2^k) strains were resistant. In particular, mice of the H-2^k haplotype demonstrated varying degrees of susceptibility, from highly to totally resistant, to the induction of EAO. Disease susceptibility to this type of EAO does not seem to be associated with a particular H-2 haplotype.All mice of the highly susceptible strains that received two injections of TC (TC×2) developed a significant increase in both levels of delayed footpad reaction (DFR) to TC and anti-TC antibodies measured by ELISA. In the low susceptible and the resistant strains receiving TC×2 or TC×3, there was no correlation between the immune responses and the susceptibility to disease in these strains, with the exception of the BALB/cAnN mice receiving TC×3. The low susceptible and the resistant mice that received TC×2 were classified into four groups based on the DFR and antibody response: the C57BL/6N, BALB/cAnN, CBA/JN, and C3H/HeJ strains were both positive, and the C57BL/10Sn and AKR/N strains were both negative or very low; the DBA/2N and MRL/lpr strains showed negative DFR and positive antibody response, and the C3H/BiKi strain showed quite the opposite. Almost all mice of the 12 inbred strains that received TC×3 showed positive antibody response, although its level varied. There seems to be no linkage between the cell-mediated and humoral immune responses and the H-2 locus in our new EAO model.     

Genetics of resistance to African trypanosomes: role of the H-2 locus in determining resistance to infection with Trypanosoma rhodesiense.

Susceptibility and resistance to Trypanosoma rhodesiense infections in inbred and H-2 congenic strains of mice were studied. Mean survival times and patterns of parasitemia were examined. C3HeB/FeJ mice were highly susceptible; CBA/J, A/J, and BALB/cByJ mice displayed an intermediate level of susceptibility; whereas C57BL/10 mice were highly resistant. H-2 congenic strains with the BL/10 background resembled the BL/10 parental type, thereby suggesting that the major histocompatibility complex does not play a major role in regulating resistance and susceptibility to infection with T. rhodesiense.     

Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype.

Six common inbred strains of mice and their F1 hybrids were examined for resistance to infection with the H37Rv strain of Mycobacterium tuberculosis. According to survival times after inoculation of 10(5) CFU intravenously (i.v.), the mice could be classified as being either highly susceptible (CBA, DBA/2, C3H, 129/SvJ) or highly resistant (BALB/c and C57BL/6). F1 hybrids of susceptible and resistant strains were resistant. Although an examination of a limited number of H-2 congenic strains showed that the H-2k haplotype could confer susceptibility on a resistant strain, it was evident that non-major histocompatibility complex (MHC) genes were much more important. Resistant strains all possessed the susceptibility allele of the anti-microbial resistance gene, Nramp1. Results obtained with selected strains infected with 10(2) CFU of M. tuberculosis by aerosol agreed with the results obtained with mice infected i.v. The size of the bacterial inoculum was important in distinguishing between resistant and susceptible strains, in that a 10(7) inoculum overcame the resistance advantage of one strain over another.     

The relative importance of Ah versus H-2 genotype on Trichinella resistance following exposure to 3-methylcholanthrene

The relative influence of Ah vs H-2 genotype on the outcome of Trichinella spiralis (Tsp) infections of mice was examined following methylcholanthrene (MC) treatment. Female mice of four inbred strains were treated with MC and infected 24 h later with Tsp muscle larvae. The strains, with their respective major histocompatibility complex (MHC) haplotype, aryl hydrocarbon hydroxylase responsiveness (Ah phenotype) and level of susceptibility to Tsp infection, were: C3HeB/FeJ (C3), H-2k, Ahb, Tsp susceptible; C57BL/10.BR (B10.BR), H-2k, Ahb, Tsp susceptible; C57BL/10.Q (B10.Q), H-2q, Ahb, Tsp resistant; and AKR/J (AK), H-2k, Ahd, Tsp resistant. The proliferative response of splenic lymphocytes to crude Tsp L1 stage antigen was significantly depressed in all MC-treated groups, with the exception of the B10.BR strain. MC administered at 40 mg/kg impaired the ability of C3 and B10.Q mice to eliminate adult worms. At 80 mg/kg, C3 strain mice were also impaired, as well as AK strain mice. The fecundity of female worms recovered from B10 or AK strain mice was not significantly altered by MC treatment, although female worms from treated C3 mice exhibited increased fecundity on day 9 post infection. Muscle larvae burdens of MC-treated B10 and C3 mice were elevated, while those of AK strain mice were unaffected. These data suggest that with acute exposures to MC, the immunogenetic resistance or susceptibility of a given mouse strain may have a more pronounced effect on immune depression and the severity of Tsp infection than does the Ah phenotype.     

Resistance to Paracoccidioides brasiliensis infection is linked to a preferential Th1 immune response, whereas susceptibility is associated with absence of IFN-gamma production.

The secretion of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-5, and IL-10 by antigen-stimulated lymph node cells, eosinophil maturation, and the antibody isotypes produced were examined during intraperitoneal infection of susceptible (B10.A) and resistant (A/Sn) mice with Paracoccidioides brasiliensis. Lymph node cells from resistant mice produced early and sustained levels of IFN-gamma and IL-2, whereas susceptible animals secreted low to undetectable amounts of these type 1 cytokines. Both mouse strains presented late and transient production of IL-4, whereas IL-10 was produced constantly throughout the course of disease. Resistant animals produced increasing levels of IL-5 in the chronic phase of the infection (from the eighth week on), whereas susceptible mice showed two peaks of IL-5 production, at the first and twelfth weeks after infection. Only the susceptible strain presented medullary and splenic eosinophilia concomitant with the raised IL-5 production. In resistant mice, the levels of IgG2a antibodies were significantly higher than those observed in susceptible mice, which preferentially secreted IgG2b and IgA isotypes. Taken together, these results demonstrate that a sustained production of IFN-gamma and IL-2 and a predominant secretion of IgG2a antibodies are associated with resistance to P. brasiliensis. In contrast, the production of low levels of IFN-gamma, early secretion of high levels of IL-5 and IL-10, eosinophilia, and a preferential secretion of IgG2b and IgA isotypes characterize the progressive disease in susceptible animals.     

Different virulence levels of the species of Sporothrix in a murine model

A comparative study on the experimental pathogenicity of five species of Sporothrix of clinical interest, Sporothrix albicans , Sporothrix brasiliensis , Sporothrix globosa , Sporothrix mexicana , and Sporothrix schenckii sensu stricto, was performed using an immunocompetent murine model. Two strains of each species and two levels of inoculum for each strain (2 × 10⁷ and 2 × 10⁴ conidia/animal) were tested by intravenous inoculation of mice (ten per group). Mortality was caused by the low inoculum of one strain of S. brasiliensis only, and the high inocula of S. brasiliensis and S. schenckii strains. Other inocula and other species tested did not kill any of the experimental animals. Tissue burden studies showed fungal spread to kidneys, lungs, spleen, brain, and testicles. S. brasiliensis was recovered extensively from all of the studied organs, and S. schenckii and S. globosa were recovered in lower amounts. Histopathological studies revealed differences in the lesions, which ranged from local inflammation with a low number of fungal cells at the injection site in mice infected with S. globosa , to massive infiltration of fungal cells in organs of those infected with S. brasiliensis . Our findings showed that S. brasiliensis and S. schenckii were the most virulent species, and suggest that lesional mechanisms could be species-specific.     

Genetic control of resistance to Mycoplasma pulmonis infection in mice.

The differences in susceptibility of various inbred strains of mice to a highly pathogenic strain of Mycoplasma pulmonis CT (T2) has been known for some time. We assessed the genetic control of resistance to T2 infection. Tracheolung lavage samples and lungs of mice were assessed for T2 organisms after intratracheal injection of T2. We found that H-2b (C57BL/6 (B6) and H-2k B10.BR mice were resistant, whereas H-2b A.By, H-2k C3H/Bi, H-2k C3H/HeJ (C3H), and H-2b BALB.B mice were susceptible. We also typed individual B6C3F2 mice for H-2 and for resistance to T2 and observed that resistance to T2 infections is controlled by a single dominant gene not linked to H-2. Histologic examination revealed severe lung lesions typical of M. pulmonis infections in susceptible C3H mice, in contrast to minimal lung lesions in resistant B6 mice. No significant titers of local or systemic antimycoplasma antibodies were detected in either resistant or susceptible mice at 5 days postinfection. Macrophages taken from uninfected B6 or C3H mice failed to inhibit growth of T2 in vitro. However, macrophages from B6 mice did inhibit growth of T2 much better than C3H macrophages when harvested on day 5 of infection. Thus, there is an association between activation of macrophage bactericidal function and genetic resistance to growth of T2 organisms.     

Cryptosporidium infection in major histocompatibility complex congeneic strains of mice: variation in susceptibility and the role of T-cell cytokine responses

Studies with murine infection models have shown that immunity to the protozoan parasite Cryptosporidium involves T-cells and interferon-gamma (IFN-γ) activity. The present study was performed to compare the course of infection of Cryptosporidium muris in major histocompatibility complex (MHC) congeneic strains of mice and examine the relationship between susceptibility to infection and production of T-cell cytokines. In experiments with BALB mice, the BALB/c strain (H-2 ^d) produced significantly fewer oocysts and recovered from infection sooner than the BALB/B (H-2 ^b) or BALB/K (H-2 ^k) strains. BALB/B X BALB/c F1 hybrid mice were found to express the more susceptible phenotype of the BALB/B parent strain, indicating that the gene(s) in the H-2 locus conferring increased susceptibility to C. muris infection was dominant. At different times during infection of the resistant BALB/c strain and the susceptible BALB/B strain, splenocytes were cultured with soluble parasite antigen and measurements were made of production of a number of T-cell cytokines. Similar patterns of increasing levels of IFN-γ and interleukin 2 (IL-2) were observed in both the resistant and susceptible strains during the patent stage of infection, indicating that production of these type 1 T-helper-cell (TH1) cytokines (i.e. involved in cell-mediated responses) correlated with the development of immunity. This also suggested that the increased susceptibility of BALB/B mice was not associated with a defective TH1 cytokine response. In the study of TH2 cytokines (involved in induction of an antibody response), low levels of IL-10 were detected during infection of BALB/c and BALB/B mice. In contrast, although IL-4 was released by splenocytes of both strains, significantly larger amounts were obtained from cells of the susceptible BALB/B mice in the early stages of infection. Thus, the H-2-dependent variation in susceptibility to infection between these BALB strains correlated with a difference in the pattern of IL-4 secretion. Received: 11 July 1996 / Accepted: 15 September 1996     

Susceptibility of inbred strains of mice to Trypanosoma congolense: correlation with changes in spleen lymphocyte populations.

A comparison was made of the susceptibility of eight inbred strains of mice to infection with Trypanosoma congolense. Marked differences in susceptibility as judged by survival were found between the different strains. The capacity of certain strains to survive longer than others appeared to be related to their ability to limit the numbers of trypanosomes in the circulation. There was no difference in the infectivity of T. congolense for mice of high and low susceptibility. Furthermore, the findings of similar prepatent periods suggested that the initial replication rate was similar in the different strains. These findings suggested that the level of parasitaemia in different strains of may reflect differences in the nature of quality of the immune response to the trypanosome. In all of the strains of mice a marked increase in splenic B and null lymphocytes was found. This, allied to the finding of an increase in the background plaque-forming cells to sheep erythrocytes, indicated, as suggested by other workers, that trypanosome infection results in a non-specific polyclonal activation of lymphocytes, and that this affects primarily B lymphocytes. In strains of mice which survived longest, i.e. C57B1/6J and AKR/A, the increase in splenic B and null cells was less marked. Whether this is associated with a decreased susceptibility of these strains to polyclonal activation induced by trypanosome infection, or whether it is merely the result of lower levels of parasitaemia, remains to be determined. By comparing T. congolense infection in three strains of mice congenic at the H-2 locus, representing H-2a, H-2b and H-2k haplotypes, it was found that the susceptibility was not associated with the H-2 haplotype. The finding that (A/J X C57B1/6J)F1 hybrids were of similar susceptibility as the C57B1/6J parents indicated that the relative resistance of this strain is inherited as a dominant trait, although in the early stages of infection the F1 hybrids consistently showed somewhat higher levels of parasitaemia than the C57B1/6J mice. Athymic nude mice and surgically splenectomized mice were found to be more susceptible to T. congolense infection than intact mice of the same strain. However, the effect of splenectomy was much less pronounced in C57B1/6J mice than in the relatively more susceptible BALB/c/A mice.     

Anti-Gag cytolytic T lymphocytes specific for an alternative translational reading frame-derived epitope and resistance versus susceptibility to retrovirus-induced murine AIDS in F(1) mice

Murine AIDS (MAIDS) develops in susceptible mouse strains after infection with the LP-BM5 murine leukemia virus complex that contains causative defective, and ecotropic helper, retroviruses. We previously demonstrated that the MAIDS-resistant H-2(d) strains BALB/cByJ and C57BL/KsJ generate MHC class I (K(d)) restricted virus-specific CD8(+) cytolytic T lymphocytes (CTLs) that lyse cells expressing either defective or ecotropic gag proteins. In contrast, the congenic BALB.B and closely related C57BL/6J MAIDS-susceptible H-2(b) strains were unable to serve as a source of gag-specific CTLs (Schwarz and Green, 1994), suggesting that anti-gag CTLs might provide a basis for resistance to MAIDS. Although its susceptibility to MAIDS was unknown, the (BALB/c x C57BL/6J) F(1) (CBY6F(1)) strain could also produce H-2(d)-, but not H-2(b)-, restricted, anti-gag CTLs (Schwarz and Green, 1994). Because of this correlation between anti-gag CTLs and resistance to MAIDS, it was important to provide more direct evidence in support of CTL-mediated protection and to determine both the fine specificity of CByB6F(1) anti-gag CTLs, in comparison with the resistant C57BL/Ks and BALB/c strains, and the susceptibility of this F(1) strain to LP-BM5-induced MAIDS. We report here that no symptoms of MAIDS were observed in CBY6F(1) (H-2(dxb)) mice. For F(2) mice, in contrast to the high susceptibility of H-2(b/b) mice, 77% of H-2(d/d) and 81% of H-2(b/d) F(2) mice did not exhibit MAIDS after LP-BM5 infection. These results are in contrast to other published studies that concluded that susceptibility, rather than resistance, is dominant in F(1) (resistant x susceptible or susceptible x resistant) mice. We also show that CBY6F(1) anti-gag CTLs exhibit a fine specificity shared by the MAIDS-resistant BALB/c and C57BL/Ks strains, that is, the immunodominant gag epitope, SYNTGRFPPL, encoded by an alternative open reading frame. Together with our direct demonstration here that in vivo monoclonal antibody (mAb) depletion of CD8(+) T cells converts genetically resistant mice to MAIDS susceptibility, these data on the ability to mount anti-ORF2/SYNTGRFPPL, gag-specific CTL responses strongly suggest that CTLs are a primary factor in determining MAIDS resistance. Accordingly, given the K(d)-restricted nature of the CTLs, the main genetic determinant of resistance appeared to be the codominant expression of the resistant H-2(d) haplotype. Interestingly, however, 19% of H-2(d/b) and 23% of the H-2(d/d) F(2) mice had at least one clinical aspect of MAIDS, suggesting that a non-MHC genetic determinant(s) can negatively influence T-cell protection and thus disease outcome Copyright 2000 Academic Press.     

Susceptibility of inbred mouse strains to infection with Serpula (Treponema) hyodysenteriae.

Several inbred strains of mice were inoculated with Serpula (Treponema) hyodysenteriae B204 to determine susceptibility to infection. Challenge doses of 10(7) or 10(8) spirochetes induced cecal lesions in C3H/HeJ mice and other C3H strains of mice. However, more than a 100-fold difference existed between the dose required to induce lesions in 50% of the infected C3H/HeJ mice (8.3 x 10(7)) and that required to induce them in 50% of the infected C3H/HeN mice (5 x 10(5)). C3H/HeJ mice lack a splenocyte mitogenic response to Escherichia coli lipopolysaccharide but exhibited a mitogenic response comparable to those of other C3H strains of mice when stimulated with S. hyodysenteriae endotoxin (butanol-water extract). Different inbred strains exhibited different susceptibilities to infection, with the strain C3H/HeN being the most susceptible on the basis of colonization and development of macroscopic cecal lesions. The ity gene had no apparent effect on susceptibility of mice challenged with S. hyodysenteriae. The involvement of the H-2 haplotype with susceptibility is unclear, but the mice bearing H-2k were more susceptible than mice with the H-2b, H-2d, or H-2q haplotype. These data support the hypothesis that the host's responsiveness to lipopolysaccharide influences the susceptibility to infection with S. hyodysenteriae. However, differences in susceptibility between inbred mice exist independent of the lps locus, suggesting that there are other inherent differences between mouse strains that affect susceptibility to infection by S. hyodysenteriae.     

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. II. Survey of host immune responses and central nervous system virus titers in inbred mouse strains

Previous studies using mouse strains with limited genetic differences and H-2 haplotypes demonstrated that susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease strongly correlated with chronically high levels of TMEV-specific delayed-type hypersensitivity (DTH), but not with TMEV-specific T cell proliferation (Tprlf), serum antibody responses, or with CNS virus titers. To determine if this correlation would be supported by analysis of these parameters in a more thorough genetic survey, ten inbred mouse strains, representing a wide variety of genetic backgrounds and H-2 haplotypes, were inoculated intracerebrally (i.c.) with the BeAn strain of TMEV. Significant TMEV-specific DTH was observed in all highly susceptible strains, but was not detectable in intermediate and resistant strains. TMEV-specific serum antibody titers also appeared to correlate with susceptibility to demyelinating disease, however even resistant strains had high antibody responses. Significant differences in CNS TMEV titers existed between strains, but did not correlate with disease susceptibility. DTH and Tprlf responses were observed in 3/4 resistant strains following peripheral immunization with UV-inactivated TMEV indicating that most resistant strains are genetically capable of mounting virus-specific cell-mediated immune (CMI) responses. The data extends our knowledge of host immune responses and virus titers in many different inbred mouse strains persistently infected with TMEV, supports the hypothesis that the demyelination in highly susceptible mice involves a TMEV-specific DTH response, and suggests that the genetic ability to mount specific DTH responses is necessary, but not sufficient for development of the demyelinating disease.     

Contribution of H-2 and non-H-2 genes in the control of mercury-induced autoimmunity

Mercury-induced autoimmunity is characterized by a T cell-dependent B cell activation (mainly of IgG1 and IgE isotypes), production of anti-nucleolar autoantibodies (ANolA) and the formation of renal IgG deposits. The autoimmunity is to a large extent controlled by genetic factors. We studied 15 different inbred mouse strains of seven H-2 (mouse MHC) genotypes to determine the importance of H-2 and non-H-2 background genes in mercury-induced autoimmunity. The tested strains exhibited a diverse autoimmune response to mercury. In each H-2 genotype, there was at least one strain which responded to mercury by the production of high levels of IgG1 and IgE Ig as well as by the development of high titers of renal IgG1 deposits. Only mouse strains with H-2(s) and H-2(q) genotypes, irrespective of their background genes, produced ANolA after mercury treatment. Only SJL (H-2(s)) and A.SW (H-2(s)) mice were highly susceptible to all characteristics of mercury-induced autoimmunity. NZB (H-2(d)) mice were also highly susceptible, but they did not develop ANolA. Only the DBA/2 (H-2(d)) strain was found to be resistant to all tested mercury-induced autoimmune manifestations, suggesting that non-responsiveness to mercury in DBA/2 mice was largely influenced by non H-2 genes. These findings imply that H-2 genes mainly determine the susceptibility to mercury-induced ANolA production, whereas non-H-2 genes control the susceptibility to and the severity of the B cell activation and renal IgG deposition.     

Experimental murine paracoccidioidomycosis: relationship among the dissemination of the infection, humoral and cellular immune responses.

The dissemination of Paracoccidioides brasiliensis cells to the heart, omentum/pancreas, spleen, liver and lungs, assessed by colony forming unit (CFU) counts, the levels of specific antibodies to this fungal agent (by ELISA), and the specific DTH reaction were studied in susceptible (B10.A) and resistant (A/Sn) mice. The animals were infected intraperitoneally with P. brasiliensis yeast cells and were evaluated 2, 4, 12 and 16 weeks later. The most remarkable differences between the two mouse strains were observed 16 weeks after infection, when B10.A mice displayed high numbers of CFU in all examined organs, except the heart, high antibody titres, and depressed DTH response. At this point, A/Sn mice presented low or absent CFU in all organs, low antibody titres and expressive DTH response. The CFU counts were shown to be a reliable parameter to discriminate susceptible from resistant animals. The fungal load in the most affected organs correlated with the antibody titres and was inversely correlated with the intensity of the DTH reaction. The patterns of immune response in this model mimic human paracoccidioidomycosis, in which high specific antibody levels and depressed DTH reactions are found in multifocal and severe forms of the disease.