RESUMEN
Two histocompatible substrains of BALB/c mice (BALB/cByJ, BALB/cAnNCr) are resistant and susceptible, respectively, to Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-1DD)--a model for viral etiology of human multiple sclerosis. BALB/cByJ mice become susceptible following low-dose irradiation given prior to infection. Resistance is restored by adoptive transfer of CD8+ (but not CD4+) splenic T cells from infected, unirradiated BALB/cByJ donors. In contrast resistance is conferred to BALB/cAnNCr mice by adoptive transfer of either CD4+ or CD8+ T cells from resistant BALB/cByJ donors. T cells from BALB/cAnNCr mice cannot confer protection. To integrate these two observations, we hypothesized that the BALB/cAnNCr mice possess precursors of the regulatory CD8+ T cells, but fail to activate them because they lack a critical CD4+ T-cell subpopulation. We tested this model using serial transfers. The transfer of CD4+ T cells from the BALB/cByJ to the BALB/cAnNCr mice permitted development of BALB/cAnNCr CD8+ T cells that in turn, provided resistance when transferred into susceptible recipients. The BALB/cByJ CD4+ T cells, which activated the CD8+ cells, were sensitive to low-dose irradiation, unlike CD4+ T cells involved in the later inflammatory demyelination. Thus, susceptibility of BALB/cAnNCr mice is due to a defective/absent CD4+ T-cell subset acting immediately after infection.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por Cardiovirus/inmunología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/virología , Theilovirus , Animales , Linfocitos T CD4-Positivos/efectos de la radiación , Linfocitos T CD8-positivos/inmunología , Susceptibilidad a Enfermedades/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBARESUMEN
BACKGROUND: Ethanol consumption impairs cell-mediated immunity and enhances humoral immunity. Among cell-mediated immune reactions, little is known of the effect of ethanol on chronic graft rejection. Allograft responses against the male-specific minor histocompatibility antigen, Hya, are widely used to study chronic graft rejection. METHODS: Female C57BL/6 (B6) mice were fed ethanol-containing liquid diets, were pair-fed an isocaloric liquid control diet, or were fed solid diet and water ad libitum. One week after diet initiation, the mice were grafted with split thickness, orthotopic male tail skin grafts, and the integrity of the grafts was monitored as the diet continued. Delayed hypersensitivity (DTH) was also determined in these same mice. In addition, Hya-cytolytic T-cell-deficient syngeneic major histocompatibility complex mutant B6.C-H2bm13 (bm13) and B6.C-H2bm14 (bm14) mice were assessed for skin graft rejection, DTH, and cytotoxic T-lymphocyte (CTL) activity. RESULTS: Ethanol-consuming female B6 mice are impaired in their ability to reject syngeneic male skin grafts and to develop Hya-specific DTH responses. To address the underlying mechanism, we show that Hya graft rejection correlates with DTH and not with CTL activity. Female B6 mice clearly differ from female bm13 and bm14 mice in their ability to generate CTLs against Hya antigen. Despite their inability to make Hya-specific CTL responses, bm13 and bm14 female mice, nevertheless, make Hya-specific DTH responses and ultimately reject Hya-disparate skin grafts, indicating that Hya-specific graft rejection results from DTH. Ethanol, by impairing Hya-specific DTH, inhibits Hya-specific skin graft rejection. CONCLUSIONS: We demonstrate that ethanol consumption impairs Hya-specific graft rejection. In addition, experiments with mice unable to generate anti-Hya CTLs support previous observations suggesting that DTH responses are sufficient to cause rejection of Hya-incompatible grafts.
Asunto(s)
Consumo de Bebidas Alcohólicas , Supervivencia de Injerto , Antígeno H-Y/análisis , Trasplante de Piel , Animales , Epítopos , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Antígeno H-Y/inmunología , Hipersensibilidad Tardía/inmunología , Hipersensibilidad Tardía/fisiopatología , Complejo Mayor de Histocompatibilidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación/inmunología , Trasplante de Piel/inmunología , Linfocitos T Citotóxicos/fisiología , Factores de TiempoRESUMEN
Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which induces an immune-mediated demyelinating disease in susceptible strains of mice and serves as a relevant animal model for multiple sclerosis. Treatment with low dose irradiation prior to infection with the BeAn strain of TMEV renders the genetically resistant BALB/cByJ (C/cByJ) mice susceptible to disease. Previous studies have shown that disease resistance in the C/cByJ is mediated by a 'regulatory' CD8(+) T cell population, which does not appear to function via a cytolytic mechanism. We show here that TMEV-specific CD4(+) T cell blasts transferred into susceptible, irradiated C/cByJ accelerate clinical disease and enhance TMEV-specific DTH and proliferation in these animals. Significantly, CD8(+) cells from infected, resistant C/cByJ mice specifically downregulate the in vivo disease potentiation and diminish virus specific DTH, and proliferative and pro-inflammatory cytokine responses (IFNgamma and IL-2) in recipients of TMEV-specific CD4(+) T cell blasts. These results indicate that TMEV infection of resistant C/cByJ mice induces a radiosensitive population of regulatory CD8(+) T cells which actively downregulate inherent Th1 responses which have disease initiating potential.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/fisiología , Infecciones por Cardiovirus/etiología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/virología , Theilovirus/inmunología , Animales , Linfocitos T CD4-Positivos/patología , División Celular/fisiología , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Regulación hacia Abajo , Hipersensibilidad Tardía/fisiopatología , Hipersensibilidad Tardía/virología , Ratones , Ratones Endogámicos BALB C , Células TH1/metabolismoRESUMEN
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is an excellent model for human multiple sclerosis. Within the BALB/c strain, BALB/cAnNCr mice are susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice become susceptible when irradiated. Adoptive transfer of CD8+ splenic T cells from resistant BALB/cByJ donors protect irradiated BALB/cByJ, as well as BALB/cAnNCr recipients, from development of TMEV-IDD. Anti-TMEV CTL activities in BALB/cAnNCr, BALB/cByJ and irradiated BALB/cByJ mice are comparable. A population of splenic CD4+ T cells in BALB/cByJ donors has also been identified which can protect both susceptible BALB/cAnNCr and irradiated BALB/cByJ recipients from TMEV-IDD via adoptive transfer.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Enfermedades Desmielinizantes/inmunología , Theilovirus/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Trasplante de Células , Enfermedades Desmielinizantes/virología , Susceptibilidad a Enfermedades , Fibrosarcoma , Rayos gamma , Cinética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neuroinmunomodulación/inmunología , Bazo/citología , Bazo/inmunología , Bazo/efectos de la radiación , Timectomía , Células Tumorales CultivadasRESUMEN
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and experimental allergic encephalomyelitis are the principal immunologically mediated, genetically controlled models of multiple sclerosis. Previous studies using different mapping techniques identified susceptibility loci for both diseases on chromosomes 3, 6, and 17. To more precisely map these TMEV and experimental allergic encephalomyelitis loci relative to each other, linkage analysis using microsatellite markers and a (BALB/cByJ x DBA/2J) x BALB/cByJ backcross population segregating for TMEV-induced disease was conducted. Comparisonwise and chromosomewise critical values based on permutation theory were estimated for each chromosome. Evidence for linkage to markers on chromosome 17 was not seen. Chromosomewise linkage (p = 0.13) was detected with D6 Mit36 and D6 Mit149 (marker-specific chromosomewise p values = 0.02) at 40.4 cM on chromosome 6. Chromosomewise linkage (p < 0.01) (marker-specific chromosomewise p value = 0.0) and comparisonwise linkage (p < < 0.0001) to D3 Mit156 at 33.9 cM on chromosome 3 were observed along with chromosomewise linkage (p < 0.05) and comparisonwise linkage (p < < 0.0001) to D3 Mit29, D3 Mit311, D3 Mit28, and D3 Mit11 from 33.9 to 37.2 cM, respectively. Significant linkage to D3 Mit156 places Tmevd2 1.1 cM proximal of D3 Mit101 (35 cM), the maximally linked marker to the eae3 susceptibility gene. Maximum likelihood estimates conducted by multilocus linkage analysis localized Tmevd2 within a 95% confidence interval bordered by D3 Mit29 and D3 Mit10, at 33.9 and 37.2 cM, respectively. Taken together these results suggest that Tmevd2 and eae3 may represent either a single, common susceptibility gene or members of a gene complex involved in central nervous system immunopathology.
Asunto(s)
Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/inmunología , Encefalomielitis Autoinmune Experimental/genética , Regulación de la Expresión Génica/inmunología , Theilovirus/genética , Animales , Mapeo Cromosómico , Susceptibilidad a Enfermedades , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Ligamiento Genético , Marcadores Genéticos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Poliomielitis/genética , Poliomielitis/inmunologíaRESUMEN
A spontaneous variant of the mouse class I major histocompatibility complex D(b) gene, designated D(bm28), is characterized. This mutation consists of a cluster of nucleotide substitutions in exon 3 that resembles the product of a classical gene conversion event in that the substituted nucleotides appear to be templated. However, D(bm28) is distinctive, because no single donor gene containing the nucleotide sequence of the mutation exists in the genome of the parent strain. The mutation is consistent with the expected result of an interaction of two donor genes at the target locus during a single recombination event. While no known genetic mechanism gives rise to this class of mutation, we have established that 10 percent of spontaneous class I mutations in the mouse major histocompatibility complex have this complex phenotype. This process occurs at the D locus and the K locus. The significance of this kind of genetic interaction may extend beyond the major histocompatibility complex and have importance in shaping other multigene families.
Asunto(s)
Variación Genética , Antígenos H-2/genética , Antígenos de Histocompatibilidad Clase I/genética , Recombinación Genética , Animales , Clonación Molecular , Reparación del ADN , ADN Complementario/genética , Biblioteca Genómica , Antígeno de Histocompatibilidad H-2D , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia de ADNRESUMEN
Mutation rates of H2 and non-H2 histocompatibility genes in the mouse are examined over a 25-year period. Detected by skin graft rejections, the mutations were screened in inbred and hybrid mice from a continuously maintained and monitored colony and from a regularly supplied set of mice provided from the National Cancer Institute for monitoring of genetic integrity. Twenty-five H2 mutations were recovered, involving the K, D, L, and Ab loci, as well as over 80 mutations of non-H2 histocompatibility genes. Aside from a single allele at a single locus (H2-Kb), the spontaneous mutation rate of H2 class I genes appears to be equivalent to that found estimated for non-H2 histocompatibility genes, and comparable to rates reported for a variety of mouse genes. This is in contrast with previous suggestions that H2 genes mutate at orders of magnitude greater than do "average" mammalian genes. The discrepancy is attributed to the H2-Kb gene which accounts for over half of all reported H2 mutations and which mutates spontaneously at a rate of 1-2 x 10(-4) per gene per generation. Furthermore, over half of the spontaneous H2-Kb mutations result in a single mutant phenotype (the "bg" group) which involve similar changes at amino acid residues 116 and 121. Thus, the high spontaneous mutation rate for H2-Kb appears to be the exception among major histocompatibility genes, rather than the rule.
Asunto(s)
Antígenos H-2/genética , Animales , Femenino , Antígeno de Histocompatibilidad H-2D , Masculino , Ratones , Ratones Endogámicos/genética , Ratones Endogámicos/inmunología , Ratones Mutantes/genética , Ratones Mutantes/inmunología , MutaciónRESUMEN
On intracerebral infection with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV), certain mouse strains develop a chronic demyelinating disease similar both clinically and pathologically to human multiple sclerosis. Other strains remain resistant. We previously established that differential susceptibility to this demyelinating disease exists among BALB/c substrains, with BALB/cAnNCr mice being susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice are rendered susceptible to TMEV-induced demyelination on exposure to low dose gamma-irradiation before TMEV infection. BALB/cAnNCr and irradiated, infected BALB/cByJ animals are protected against TMEV-induced demyelination by the transfer of a splenic population from TMEV-infected BALB/cByJ donors. Resistance to demyelination appears to be mediated by a CD8+ radiosensitive population, which is induced on infection with TMEV and which must act early to establish resistance to TMEV-induced demyelination.
Asunto(s)
Linfocitos T CD8-positivos/trasplante , Inmunoterapia Adoptiva , Poliomielitis/inmunología , Poliomielitis/prevención & control , Theilovirus/inmunología , Animales , Linfocitos T CD8-positivos/efectos de la radiación , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/prevención & control , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta en la Radiación , Tolerancia Inmunológica/efectos de la radiación , Inmunidad Innata/efectos de la radiación , Ratones , Ratones Endogámicos BALB C , Poliomielitis/patología , Bazo/trasplanteRESUMEN
Theiler's murine encephalomyelitis virus (TMEV) infection and experimental allergic encephalomyelitis (EAE) are considered among the best models of human multiple sclerosis (MS). In both models, clinical disease is characterized by paralysis, while pathological changes consist of inflammatory demyelination. In both models there is a genetic influence on susceptibility/resistance to the development of disease. This has been thoroughly studied in TMEV infection, and it has been found to depend on both major histocompatibility complex (MHC) and non-MHC genes. At least four genes have been so far identified. Because of this genetic influence, some strains of mice are more susceptible to both clinical and pathological changes than others, and susceptibility appears to best correlate with the ability of a certain murine strain to develop a delayed-type hypersensitivity (DTH) response to viral antigens. We have also observed that even among mice which are equally susceptible clinically, striking differences may be seen under pathological examination. These consist of different gradients of severity of inflammation, particularly in regards to the macrophage component. There is an inverse relationship between the number of macrophages, and their length of stay in the CNS, and the ability of mice to remyelinate their lesions. The most severe lesions are in SJL/J mice, and remyelination in this strain is extremely poor. The least severe lesions in terms of macrophage invasion are in strains such as NZW and RIIIS/J, and these are able to remyelinate lesions very successfully. Murine chronic relapsing EAE (CR-EAE) shows pathological changes in many ways similar to those in TMEV-infected SJL/J mice, although less severe in terms of degrees of macrophage infiltration and tissue destruction. Mice with CR-EAE have a correspondingly limited ability to remyelinate their lesions. In both models the pathology appears to be mediated through a DTH response. However, while in EAE the DTH response is clearly against neuroantigens, the response in TMEV infection is against the virus itself. The end result in both models would be that of myelin destruction through a lymphotoxin-cytokine-mediated mechanism. The importance of the DTH response in both models is well illustrated by the effects of tolerance induction in EAE and TMEV infection to neuroantigens and virus, respectively. These are important models of human MS, since the current hypothesis is that a viral infection early in life, on the appropriate genetic background, may trigger a secondary misdirected immune response which could be directed either against myelin antigens and/or possible persistent virus(es).
Asunto(s)
Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/patología , Poliomielitis/patología , Theilovirus , Animales , Enfermedades Desmielinizantes/patología , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Hipersensibilidad Tardía , Ratones , Esclerosis Múltiple/inmunología , Poliomielitis/inmunologíaRESUMEN
Development of murine AIDS in mice following infection with LP-BM5 murine leukaemia virus (MuLV) is highly strain dependent, with strain differences determined by genes within and outside H-2. Among H-2 genes, the Dd gene is the most closely associated with resistance to LP-BM5 MuLV infection. However, the Dd-mediated resistance is highly influenced by outside H-2 genes, i.e. A lineage strains are more resistant than mice strains of B6/B10 lineage. In this study, the mice having BALB background were analysed and, similarly to A lineage mice, only Dd gene products were found to be required to provide resistance to LP-BM5 MuLV infection. Furthermore, BALB/c Kh mice bearing both Dd and Ld genes clearly showed obviously higher resistance than BALB/c-H-2dm2 mice solely having the Dd gene. In addition, in the long-term observation of the effect of the Dd gene on B6/B10 background mice, D8 mice having the Dd gene as a transgene and expressing a high level Dd gene product showed higher resistance than naturally recombinant B10.A(18R) mice. These results suggest that the MAIDS resistance associated with the D end loci is dependent on the level of expression of an MHC class I gene.
Asunto(s)
Genes MHC Clase I , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Animales , Inmunidad Innata , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Síndrome de Inmunodeficiencia Adquirida del Murino/genéticaRESUMEN
Theiler's murine encephalomyelitis virus (TMEV) produces a chronic disease in its natural host, the mouse, characterised by primary inflammatory demyelination of the spinal cord. This viral infection is considered a very good model for human MS because the pathogenesis of myelin injury is mediated through the host immune response. Susceptibility and/or resistance to the demyelinating disease depend on multiple genes both in and outside the major histocompatibility complex (MHC). The pathological lesions in animals with different degrees of susceptibility vary in both their severity and in their ability to become remyelinated. In general, animals with intermediate levels of susceptibility show the best potential for remyelination. Most crosses of susceptible animals with resistant strains carrying the H-2b haplotype are resistant with only a couple of exceptions. One such exception is the (SJL/J x C57L/J)F1 hybrid, which is susceptible to the disease. To study whether the resistant genotype of C57L/J mice could modify the phenotypic expression of pathological lesions characteristic of the highly susceptible SJL/J mouse, we performed a light microscopical and ultrastructural study of the spinal cord of both parental strains and their F1 progeny. We focused particularly on the relationship between severity of inflammation, and especially macrophage infiltration, and the subsequent remyelinating potential of lesions. The results show a dramatic difference between the ability to remyelinate lesions by infected SJL/J mice vs similarly infected (SJL/L x C57L/J)F1 hybrids, and suggest an important influence by resistant genes in modulating the phenotypic expression of disease, including the ability to stimulate oligodendroglia-mediated remyelination.
Asunto(s)
Encefalopatías/genética , Encefalopatías/virología , Ratones Endogámicos C57BL/genética , Ratones Endogámicos/genética , Vaina de Mielina/fisiología , Oligodendroglía/fisiología , Poliomielitis/complicaciones , Theilovirus/crecimiento & desarrollo , Animales , Encefalopatías/patología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/virología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/virología , Predisposición Genética a la Enfermedad , Hibridación Genética , Inmunidad Innata/genética , Ratones , Vaina de Mielina/virología , Oligodendroglía/ultraestructura , Oligodendroglía/virología , Poliomielitis/genética , Poliomielitis/patología , Médula Espinal/patología , Médula Espinal/ultraestructura , Médula Espinal/virologíaRESUMEN
SWR/J mice are susceptible to immune-mediated central (CNS) demyelination following infection by Theiler's murine encephalomyelitis virus (TMEV). SWR/J susceptibility is genetically dominant, when outcrossed to resistant H-2b strains. Non-H-2 differences between C57BL/6 and C57L/J (both H-2b) alter effects of 'susceptibility' genes, especially H-2q, from SWR/J. Genetic analysis of differential susceptibility to demyelination between SWR/J and C57L/J indicates that one copy of H-2q is sufficient for disease, and that SWR/J mice carry a non-H-2 gene which can lead to disease in the absence of H-2q. Differential susceptibility between SWR/J and C57BL/6 is determined by a single non-H-2 locus, which may or may not be the same as that differing between SWR/J and C57L/J.
Asunto(s)
Enfermedades Desmielinizantes/genética , Poliomielitis/genética , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Susceptibilidad a Enfermedades , Femenino , Antígenos H-2/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factores SexualesRESUMEN
We report differences among BALB/c substrains in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, an immune-mediated inflammatory demyelinating disease and experimental model for human multiple sclerosis. BALB/cJ and BALB/cAnNCr mice are susceptible, while BALB/cByJ and BALB/cCum are resistant. Hybrids between BALB/cBy and BALB/cAnNCr were intermediate, although closer to the resistant parent. Backcrosses gave results compatible with differential susceptibility being related to a single segregating locus. Exposure of resistant BALB/cByJ mice to low dose irradiation, 2 days prior to infection, rendered them susceptible to TMEV-induced demyelination. The susceptibility pattern of TMEV-induced demyelinating disease among BALB/c substrains is distinct from those of several autoimmune disorders.
Asunto(s)
Enfermedades Desmielinizantes/genética , Theilovirus , Animales , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/inmunología , Susceptibilidad a Enfermedades , Prueba de Histocompatibilidad , Ratones , Ratones Endogámicos BALB C , Especificidad de la EspecieRESUMEN
The transcripts encoding two strongly alloantigenic class I mutant molecules, Kdm4 and Kdm5, were characterized and found to encode products that differ from the parental Kd glycoprotein by single amino acid substitutions. The Kdm4 molecule has an amino acid change at position 114, an integral component of a beta-sheet associated with pockets D and E of the peptide binding site. The basis for strong alloantigenicity of the variant molecule can be attributed to differences in peptide binding that were visualized by HPLC analysis of eluted peptides. In contrast, the Kdm5 molecule differs from the parent at position 158, a component of the alpha-helix that is not associated with any of the pockets of the peptide binding site. No differences in peptide binding by Kdm5 in comparison with the parent Kd molecule were seen by HPLC, suggesting that the variant and parent molecules bind the same set of peptides. The ability of (dm4 x dm5) F1 hybrid mice to recognize and lyse BALB/c stimulator cells indicates that the alloantigenic properties determined by the 158 substitution result from the interactions of the alpha-helix regions (changed in dm5) with the pockets of the binding site (changed in dm4). We conclude that self peptides shared by the F1 hybrid and the BALB/c stimulator cells are recognized in the context of structural features of the helices of the Ag-presenting molecule as alloantigenic determinants.
Asunto(s)
Antígenos H-2/inmunología , Secuencia de Aminoácidos , Animales , Autoantígenos/inmunología , Secuencia de Bases , Sitios de Unión , Femenino , Antígenos H-2/química , Antígenos H-2/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Mutación , Péptidos/inmunología , Empalme del ARNRESUMEN
Using H-2 recombinant and mutant mice, the Rfv-1 gene influencing spontaneous recovery from Friend retrovirus (FV)-induced leukaemia was mapped in the D locus. Two Db alleles were required for full recovery, and a single Dd transgene did not convey increased susceptibility to FV in the presence of homozygous Db/b genotype. The results suggest that an increase in the expression of Db may lead to more effective stimulation of FV-specific CTL.
Asunto(s)
Virus de la Leucemia Murina de Friend , Leucemia Experimental/genética , Alelos , Animales , Mapeo Cromosómico , Genotipo , Antígenos H-2/genética , Haplotipos , Leucemia Experimental/inmunología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Intracerebral inoculation of susceptible mice with Theiler's murine encephalomyelitis virus induces a demyelinating disease that is similar to human multiple sclerosis. This murine model for human multiple sclerosis is apparently immune-mediated and the genes involved in the immune response influence the outcome of disease susceptibility as observed with human multiple sclerosis. These genes include the MHC and TCR genes. However, the functional relationships among these genes on the disease susceptibility has not yet been studied. In this study, we demonstrate that the effect of the H-2s genotype from susceptible SJL/J mice overrides the resistant effect of the BALB/c TCR beta-chain gene in CXJ recombinant-inbred and BALB.S congenic mice. These results strongly suggest the presence of a hierarchy of genes involved in the immune response in Theiler's murine encephalomyelitis virus-induced demyelinating disease.
Asunto(s)
Enfermedades Desmielinizantes/inmunología , Infecciones por Enterovirus/complicaciones , Antígenos H-2/genética , Complejo Mayor de Histocompatibilidad , Virus Maus Elberfeld , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Animales , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Genotipo , Ratones , Ratones Endogámicos BALB CRESUMEN
The histocompatibility loss mutation H-2dm6 was derived from a mouse treated with the chemical mutagen ethylnitrosourea, and previous mapping studies implicated Dd as the affected locus. Southern blot analyses of DNA from H-2dm6 cells did not detect major deletions in the Ddm6 gene, suggesting that H-2dm6 was different from the previously characterized D region mutants H-2dm1 and H-2dm2. RNA blot analysis identified Ddm6 transcripts of appropriate size and a Ddm6 protein was immunoprecipitated from biosynthetically labeled H-2dm6 cells. Interestingly, the Ddm6 protein showed no beta 2m association and was only precipitated by a mAb to the alpha 3 domain. Furthermore, oligosaccharide maturation and low levels of surface expression of Ddm6 molecules were detected. However, the surface Ddm6 was nonfunctional as a target Ag in in vitro cytotoxicity assays, consistent with its original in vivo detection as a loss mutation. Sequence analyses of Ddm6 cDNA identified a single nucleotide base difference from wild-type, resulting in the substitution of a Trp to Arg at position 133. The significance of this substitution is discussed in the context of other class I expression variants.
Asunto(s)
Antígenos H-2/metabolismo , Microglobulina beta-2/metabolismo , Animales , Secuencia de Bases , Northern Blotting , Membrana Celular/metabolismo , Citotoxicidad Inmunológica , Antígenos H-2/química , Antígenos H-2/genética , Antígeno de Histocompatibilidad H-2D , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Mutación , Sondas de Oligonucleótidos/química , Reacción en Cadena de la Polimerasa , Pruebas de Precipitina , Unión Proteica , Conformación ProteicaRESUMEN
Multiple sclerosis (MS) is a demyelinating disease in humans which affects females more frequently than males. Theiler's murine encephalomyelitis virus (TMEV) induces demyelination similar to human MS in susceptible strains of mice after intracerebral inoculation. In this paper we report that sex influences susceptibility to TMEV-induced demyelination in certain genotypes derived from C57L/J and SJL/J or SWR/J mice. This is the first report of an animal model for MS that shows an association between sex and susceptibility, and this information may facilitate the investigation of human MS.
Asunto(s)
Modelos Animales de Enfermedad , Virus Maus Elberfeld/patogenicidad , Esclerosis Múltiple/etiología , Animales , Enfermedades Desmielinizantes/etiología , Susceptibilidad a Enfermedades , Genotipo , Antígenos H-2/genética , Ratones , Ratones Endogámicos , Esclerosis Múltiple/genética , Factores SexualesRESUMEN
The "bg" series of MHC mutations is the most prevalent type of mutations of Kb in C57BL/6 mice screened by reciprocal tail skin grafting. The basis for identification of this series of mutations is the incompatibility of grafts between the parental B6 and the mutant. This series takes the longest to reciprocally reject the skin grafts. The series can be subdivided into "bg 1" and "bg 2" groups based on Kb-restricted recognition of virus-infected mutant target cells. The biochemical basis for these mutations are amino acid substitutions at residues 116 and 121 of the Kb transplantation antigen. These substitutions do not alter monoclonal antibody binding sites. The structural basis of MAb binding and the genetic basis of the mutation are discussed.
Asunto(s)
Antígenos H-2/genética , Antígenos de Histocompatibilidad/genética , Ratones Mutantes/genética , Mutación , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Sitios de Unión , Antígenos de Histocompatibilidad/inmunología , Ratones , Datos de Secuencia MolecularRESUMEN
Theiler's virus-induced demyelinating disease results from a chronic infection in the white matter of the central nervous system and provides an excellent model for human multiple sclerosis. Like multiple sclerosis, there are genetic risk factors in disease development, including genes associated with the major histocompatibility complex and with those encoding the beta chain of the T-cell receptor. Comparisons of the susceptible DBA/2 and resistant C57BL/6 strains have indicated an important role for the H-2D locus and for a non-H-2 gene (not involving the beta chain of the T-cell receptor) in differential susceptibility. In the present report, analysis of recombinant-inbred strains (BXD) between the DBA/2 and C57BL/6 strains indicated that this non-H-2 locus is located at the centromeric end of chromosome 3 near (4 +/- 4 centimorgans) the carbonic anhydrase-2 (Car-2) enzyme locus.