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1.
J Virol ; 97(5): e0193022, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37093008

RESUMO

Inbred mouse lines vary in their ability to mount protective antiretroviral immune responses, and even closely related strains can exhibit opposing phenotypes upon retroviral infection. Here, we found that 129S mice inherit a previously unknown mechanism for the production of anti-murine leukemia virus (MLV) antibodies and control of infection. The resistant phenotype in 129S1 mice is controlled by two dominant loci that are independent from known MLV resistance genes. We also show that production of anti-MLV antibodies in 129S7 mice, but not 129S1 mice, is independent of interferon gamma signaling. Thus, our data indicate that 129S mice inherit an unknown mechanism for control of MLV infection and demonstrate that there is genetic variability in 129S substrains that affects their ability to mount antiviral immune responses. IMPORTANCE Understanding the genetic basis for production of protective antiviral immune responses is crucial for the development of novel vaccines and adjuvants. Additionally, characterizing the genetic and phenotypic variability in inbred mice has implications for the selection of strains for targeted mutagenesis, choice of controls, and for broader understanding of the requirements for protective immunity.


Assuntos
Camundongos Endogâmicos , Infecções por Retroviridae , Animais , Camundongos , Imunidade , Interferon gama , Vírus da Leucemia Murina/genética , Camundongos Endogâmicos/genética , Camundongos Endogâmicos/imunologia , Infecções por Retroviridae/imunologia
2.
Immunol Lett ; 237: 3-10, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34174253

RESUMO

Many studies of the autoimmune disease Sjögren's syndrome have been performed using spontaneous mouse models. In the present study, we describe the characteristics of McH/lpr-RA1 mice and propose their use as a novel murine model of autoimmune sialadenitis. The McH/lpr-RA1 mouse is a recombinant congenic strain derived from generation F54 or more of MRL-Faslpr x (MRL- Faslpr x C3H- Faslpr) F1. We show for the first time that this mouse spontaneously develops autoimmune sialadenitis and vasculitis in submandibular gland tissues. Sialadenitis was accompanied by extensive inflammatory cell infiltration and tissue destruction. Immunohistochemical studies revealed that the salivary gland lesions strongly expressed four sialadenitis-related molecules: SSA and SSB (autoantigens of Sjögren's syndrome), gp91phox (an accelerator of reactive oxygen species production) and single strand DNA (a marker of apoptotic cells). In contrast, expression of aquaporin-5 (AQP5), which stimulates salivary secretion was weak or negligible. Statistical correlation analyses indicated that the apoptosis of salivary gland cells provoked by oxidative stress contributed to the severe sialadenitis and reduced expression of AQP5. Our study has demonstrated that McH/lpr-RA1 mice spontaneously develop the pathognomonic features of autoimmune sialadenitis and thus could be used as a new animal model of Sjögren's syndrome.


Assuntos
Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Camundongos Endogâmicos/imunologia , Camundongos Mutantes/imunologia , Sialadenite/imunologia , Síndrome de Sjogren , Vasculite/imunologia , Animais , Animais Congênicos , Apoptose , Aquaporina 5/biossíntese , Aquaporina 5/genética , Autoantígenos/biossíntese , Autoantígenos/genética , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , DNA de Cadeia Simples/análise , Feminino , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos/genética , Camundongos Mutantes/genética , NADPH Oxidase 2/biossíntese , NADPH Oxidase 2/genética , Ribonucleoproteínas/biossíntese , Ribonucleoproteínas/genética , Índice de Gravidade de Doença , Sialadenite/genética , Sialadenite/patologia , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Glândula Submandibular/metabolismo , Glândula Submandibular/patologia , Vasculite/genética , Vasculite/patologia , Antígeno SS-B
3.
Birth Defects Res ; 111(16): 1178-1191, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228335

RESUMO

Literature suggests that murine allogeneic pregnancy models are an alternative approach for evaluating the developmental toxicity of immune-stimulating agents. In this study, multiple syngeneic and allogeneic murine pregnancy models were used to assess the potential embryo-fetal effects of four different murine antibodies (IgG1 or IgG2 ) that activate the immune system by binding to T-cell receptors (PD-L1, LAG-3, and GITR). The pregnancy models were generated by within and between matings of five different inbred strains of mice (CBA/CaJ, DBA/2J, BALB/c, C57BL/6, and CBA/J). The antibodies were administered every 2-3 days by intraperitoneal injection (n = 12-29/group) during gestation days 6 to 14. There were no differences in embryo-fetal endpoints between the allogeneic and syngeneic pregnancies. Additionally, treatment with the antibodies had no effect on mean postimplantation loss in either the syngeneic or allogeneic pregnancies despite confirmation of pharmacologically-relevant systemic exposures. These results suggest that allogeneic murine pregnancy models need further validation and testing before they can be reliably used as an alternative approach for assessing the developmental effects of agents that stimulate the immune system.


Assuntos
Imunoglobulina G/imunologia , Linfocinas/imunologia , Camundongos Endogâmicos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Antígeno B7-H1/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Modelos Animais , Gravidez , Reprodutibilidade dos Testes , Proteína do Gene 3 de Ativação de Linfócitos
4.
Brain Behav Immun ; 74: 121-132, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30171890

RESUMO

The present study was designed to investigate the correlation between the spatial and temporal aspects of immune responses and genetic heterogeneity in the progression of peripheral neuropathic pain. To address this issue, we first screened four inbred mouse strains (C57BL/6J, C3H/He, DBA/2, and A/J mice) to identify high- and low-responder strains to mechanical hypersensitivity induced by partial sciatic nerve ligation (pSNL). Among these strains, the C57BL/6J strain showed the highest vulnerability to pSNL-induced mechanical hypersensitivity, whereas the C3H/HeSlc strain was most resistant. C3H/HeSlc mice exhibited a significant increase in CD206-immunoreactivity (anti-inflammatory macrophages) in the dorsal root ganglia (DRG) at 3 and 7 days, and lower Iba1-immunoreactivity (microglia) in the spinal cord from 3 to 14 days after pSNL than C57BL/6J mice. These phenomena might be associated with a decrease in the production of inflammatory factors (interleukin-1ß, interleukin-6, and CX3CL1) in the DRG and the poor responsiveness of spinal microglia (i.e. microglial production of IL1ß, CCL2, and TNFα) against CX3CL1 in C3H/HeSlc mice. Behavioral experiments using bone marrow (BM) chimeric mice derived by crossing C3H/HeSlc and C57BL/6J strains showed that the strength of mechanical hypersensitivity 3 days following pSNL was inversely correlated with the increase in the ratio of anti-inflammatory/pro-inflammatory DRG macrophages, which was based on the BM-derived hematopoietic cells from donor mice. By contrast, the intensity of Iba1-immunoreactivity (microglia) in the spinal cord was dependent on the phenotypes of recipient mice, but not affected by the phenotypes of BM-derived donor hematopoietic cells. These findings suggest that the strain-specific aspects of DRG macrophages and spinal microglia might be related to the early and late phases of pSNL-induced mechanical hypersensitivity, respectively. This study presents a greater understanding of the differences in neuropathic pain among genetically heterogeneous inbred mouse strains, and provides further insights into the spatial and temporal roles of the immune system in the pathogenesis of neuropathic pain.


Assuntos
Camundongos Endogâmicos/imunologia , Neuralgia/etiologia , Neuralgia/imunologia , Animais , Modelos Animais de Doenças , Feminino , Gânglios Espinais/patologia , Hiperalgesia/etiologia , Imunidade Ativa/fisiologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Microglia/patologia , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/patologia , Medula Espinal/patologia
6.
Methods Mol Biol ; 598: 195-205, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19967515

RESUMO

Evaluation of cell-mediated immunity (CMI) is a significant component in any assessment designed to predict the full range of potential immunotoxic risk underlying health risks. Among measures of CMI, the cytotoxic T Lymphocyte (CTL) response is recognized as perhaps the most relevant functional measure that reflects cell-mediated acquired immune defense against viral infections and cancer. The CTL response against T-dependent antigens requires the cooperation of at least three different major categories of immune cells. These include professional antigen presenting cells (e.g., dendritic cells), CD4(+) T helper lymphocytes, and CD8(+) T effector lymphocytes. It is also among the few functional responses dependent on and, hence, capable of evaluating effective antigen presentation via both class I and class II molecules of the major histocompatibility complex (MHC). For this reason the CTL assay is an excellent candidate for evaluation of potential immunotoxicity. This chapter provides an example of a mouse CTL assay against influenza virus that has been utilized for this purpose.


Assuntos
Imunidade Celular/imunologia , Testes Imunológicos/métodos , Linfócitos T Citotóxicos/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos/imunologia , Orthomyxoviridae/imunologia , Linfócitos T Citotóxicos/citologia
7.
Methods Mol Biol ; 598: 207-19, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19967516

RESUMO

It is well known that natural killer (NK) cells are involved in defense against viruses and some tumors. NK cells kill target cells by the directed release of cytolytic granules that contain perforin, granzymes, and granulysin. It is increasingly important to evaluate NK cell function in immunotoxicity testing. NK cell function can be evaluated by determining cytolytic activity against target tumor cells by the (51)Cr-release assay and also by determining the number of NK cells in peripheral blood in humans and in the spleen in animals using flow cytometry. Recently, the intracellular levels of perforin, granzymes, and granulysin determined by flow cytometry have also been used in the evaluation of NK cell function. This chapter will describe the methods for NK cell assays in immunotoxicity testing.


Assuntos
Testes Imunológicos/métodos , Células Matadoras Naturais/imunologia , Testes de Toxicidade/métodos , Animais , Técnicas de Cultura de Células , Linhagem Celular , Citometria de Fluxo/métodos , Granzimas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos/imunologia , Perforina/metabolismo
8.
Inflamm Res ; 58(4): 204-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19169648

RESUMO

OBJECTIVE: Mice selected for a strong (AIRmax) or weak (AIRmin) acute inflammatory response present different susceptibilities to bacterial infections, autoimmune diseases and carcinogenesis. Variations in these phenotypes have been also detected in AIRmax and AIRmin mice rendered homozygous for Slc11a1 resistant (R) and susceptible (S) alleles. Our aim was to investigate if the phenotypic differences observed in these mice was related to the complement system. MATERIAL: AIRmax and AIRmin mice and AIRmax and AIRmin groups homozygous for the resistance (R) or susceptibility (S) alleles of the solute carrier family 11a1 member (Slc11a1) gene, formerly designated Nramp-1. METHODS AND RESULTS: While no difference in complement activity was detected in sera from AIRmax and AIRmin strains, all sera from AIRmax Slc11a1 resistant mice (AIRmax(RR)) presented no complement-dependent hemolytic activity. Furthermore, C5 was not found in their sera by immunodiffusion and, polymerase chain reaction and DNA sequencing of its gene demonstrated that AIRmax(RR) mice are homozygous for the C5 deficient (D) mutation previously described in A/J. Therefore, the C5D allele was fixed in homozygosis in AIRmax(RR) line. CONCLUSIONS: The AIRmax(RR) line is a new experimental mouse model in which a strong inflammatory response can be triggered in vivo in the absence of C5.


Assuntos
Complemento C5 , Inflamação/genética , Camundongos Endogâmicos , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/imunologia , Ativação do Complemento , Complemento C5/genética , Complemento C5/imunologia , Via Alternativa do Complemento/imunologia , Feminino , Predisposição Genética para Doença , Hemólise , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos/genética , Camundongos Endogâmicos/imunologia
9.
J Parasitol ; 94(2): 551-3, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18564762

RESUMO

A retrospective study of our 14-yr records on experimental Taenia crassiceps (ORF(fast) line) cysticercosis (n = 1,198) shows that in 16 of 17 different mice strains, female mice are more frequently infected and carry larger individual parasite loads than males. However, sexual differences in parasite loads significantly varies between strains in relation to their different genetic backgrounds (BALB > C57Bl = OTHERS > C3H). The coefficient of variation in all female mice is significantly smaller than that of all males, an indication of males' more potent, but erratically effective, restraint of cysticercus growth. Similar positive growth bias for female mice is shown by other lines of cysticerci, i.e., HYG(slow) and WFU(slow). These results contravene the usual expectation of female hosts being more resistant than males to parasite infections, and they point to the multiple factors that combined determine sex related differences of mice to experimental cysticercosis infection.


Assuntos
Cisticercose/parasitologia , Cysticercus/crescimento & desenvolvimento , Camundongos Endogâmicos/imunologia , Camundongos Endogâmicos/parasitologia , Caracteres Sexuais , Animais , Feminino , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos/genética , Estudos Retrospectivos , Distribuição por Sexo
10.
An Acad Bras Cienc ; 80(1): 85-99, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18345378

RESUMO

Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d) developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, we observed that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii.


Assuntos
Haplótipos/genética , Complexo Principal de Histocompatibilidade/genética , Camundongos Endogâmicos/imunologia , Toxoplasma/genética , Toxoplasmose Animal/imunologia , Toxoplasmose Cerebral/imunologia , Animais , Modelos Animais de Doenças , Genótipo , Interferon gama/deficiência , Interferon gama/imunologia , Interleucina-12/deficiência , Interleucina-12/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos/genética , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/imunologia , Fatores de Tempo , Receptores Toll-Like/imunologia , Toxoplasma/patogenicidade , Toxoplasmose Animal/parasitologia , Toxoplasmose Animal/patologia , Toxoplasmose Cerebral/parasitologia , Toxoplasmose Cerebral/patologia , Virulência/genética
11.
An. acad. bras. ciênc ; 80(1): 85-99, Mar. 2008. graf, tab
Artigo em Inglês | LILACS | ID: lil-477417

RESUMO

Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d) developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, weobserved that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii.


Cepas de Toxoplasma gondii que apresentam o genótipo I/III são associadas a toxoplasmose ocular adquirida em humanos. No presente trabalho, nós utilizamos um modelo da doença em camundongos para caracterizar mecanismos imunológicos envolvidos na resistência do hospedeiro à infecção por aquelas cepas. Escolhemos as cepas D8, G2 e P-Br, que causam infecção crônica em camundongos, semelhante à toxoplasmose humana. Camundongos deficientes em MyD88, IFN-G e IL-12 foram susceptíveis a infecções com todas as três linhagens do parasita. Esses dados indicam a importância de mecanismos inatos no controle da infecção. Por outro lado, o haplótipo do MHC não influenciou na resistência/susceptibilidade, na medida em que linhagens de camundongos com um mesmo "background'' genético, mas diferentes haplótipos de MHC (H2b e H2d) apresentam o índice de mortalidade e número de cistos semelhantes após a infecção com aquelas cepas do parasita. Em contraste, o "background'' genético de C57BL/6, mas não o haplótipo de MHC, foi crítico para o desenvolvimento de inflamação intestinal causada pelas cepas estudadas. Finalmente, com relação aos mecanismos efetores, observamos que linfócitos B e T CD8+ controlam a sobrevivência após infecção. Por outro lado, a ativação da enzima óxido nítrico sintase induzida foi um fator importante para controle do número de cistos cerebrais em camundongos infectados com cepas do Tipo I/III. Esses achados são relevantes para o melhor entendimento dos mecanismos imunológicos envolvidos na proteção e patogênese durante infecção com T. gondii.


Assuntos
Animais , Camundongos , Haplótipos/genética , Complexo Principal de Histocompatibilidade/genética , Camundongos Endogâmicos/imunologia , Toxoplasma/genética , Toxoplasmose Animal/imunologia , Toxoplasmose Cerebral/imunologia , Modelos Animais de Doenças , Genótipo , Interferon gama/deficiência , Interferon gama/imunologia , /deficiência , /imunologia , Complexo Principal de Histocompatibilidade/imunologia , Camundongos Endogâmicos/genética , /deficiência , /imunologia , Fatores de Tempo , Receptores Toll-Like/imunologia , Toxoplasma/patogenicidade , Toxoplasmose Animal/parasitologia , Toxoplasmose Animal/patologia , Toxoplasmose Cerebral/parasitologia , Toxoplasmose Cerebral/patologia , Virulência/genética
12.
Lab Invest ; 87(1): 14-28, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17170739

RESUMO

The NZM2410 and NZM TAN (TAN) are two of 27 inbred strains derived from an intercross between the NZW and NZB strains. NZM2410 mice develop a highly penetrant lupus nephritis mediated by three susceptibility loci, Sle1, Sle2 and Sle3. These three loci have been combined on a C57BL/6 background in a triple congenic strain that reconstitutes the NZM2410 autoimmune phenotype. Remarkably, inspite of the presence of Sle1, Sle2 and Sle3, TAN mice display a mild autoimmune phenotype reminiscent of NZW. Contrary to the lupus-prone strains, the majority of TAN CD4(+) T cells are in a naïve-inactivated stage. TAN mice show B-cell developmental abnormalities similar to lupus-prone mice, such an accumulation of transitional T1 cells and peritoneal B-1a cells. TAN mice show, however, a unique expansion of the splenic marginal zone, in which B cells express high levels of CD5 and CD9, fail to migrate to the follicles in response to LPS, and show sub-optimal binding of T-independent type 2 antigens. Therefore, TAN mice present a functional silencing of marginal zone B cells, which have been previously implicated with autoimmune process. The TAN strain thus provides a novel model for the analysis of the genetic determinants of B-cell autoreactivity.


Assuntos
Subpopulações de Linfócitos B/imunologia , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Linfonodos/imunologia , Camundongos Endogâmicos/genética , Repetições de Microssatélites/genética , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Linfócitos B/imunologia , Modelos Animais de Doenças , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Córtex Renal/patologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/genética , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Endogâmicos/imunologia , Baço/citologia , Baço/imunologia
13.
Int Immunol ; 18(11): 1509-19, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16943258

RESUMO

CD4+CD25+Foxp3+ regulatory T lymphocytes are crucial for maintenance of immunological tolerance to self and innocuous non-self, are known to modulate immunity to tumors and infectious agents and can induce transplantation tolerance. Surprisingly, only a single genetic polymorphism is known to modulate regulatory T cell (Treg) development in the thymus, leading to a lethal autoimmune disorder. Here, we show that considerably different levels of Tregs are found in the thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical Tregs develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte-intrinsic manner and that levels of thymic Foxp3+ Tregs correlate to those found in the periphery. Using several congenic mouse strains, we mapped one of the at least two genetic loci capable of quantitatively modulating thymic Treg development to a

Assuntos
Antígenos de Superfície/metabolismo , Diferenciação Celular/genética , Fatores de Transcrição Forkhead/metabolismo , Genes MHC da Classe II/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia , Timo/citologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Feminino , Genes MHC da Classe II/fisiologia , Camundongos , Camundongos Endogâmicos/imunologia , Linfócitos T Reguladores/citologia , Telômero/fisiologia , Timo/imunologia
14.
Mamm Genome ; 17(6): 575-83, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16783639

RESUMO

Gene expression QTL (eQTL) mapping can suggest candidate regulatory relationships between genes. Recent advances in mammalian phenotype annotation such as mammalian phenotype ontology (MPO) enable systematic analysis of the phenotypic spectrum subserved by many genes. In this study we combined eQTL mapping and phenotypic spectrum analysis to predict gene regulatory relationships. Five pairs of genes with similar phenotypic effects and potential regulatory relationships suggested by eQTL mapping were identified. Lines of evidence supporting some of the predicted regulatory relationships were obtained from biological literature. A particularly notable example is that promoter sequence analysis and real-time PCR assays support the predicted regulation of protein kinase C epsilon (Prkce) by cAMP responsive element binding protein 1 (Creb1). Our results show that the combination of gene eQTL mapping and phenotypic spectrum analysis may provide a valuable approach to uncovering gene regulatory relations underlying mammalian phenotypes.


Assuntos
Mapeamento Cromossômico , Regulação da Expressão Gênica , Camundongos Endogâmicos/genética , Fenótipo , Locos de Características Quantitativas , Animais , Mapeamento Cromossômico/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos/imunologia , Camundongos Endogâmicos/parasitologia , Células NIH 3T3 , Células PC12 , Ratos
15.
Am J Respir Cell Mol Biol ; 35(4): 415-23, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16690987

RESUMO

When the fungus Stachybotrys chartarum is inhaled, its mycotoxins may cause lung injury and inflammation. The severity of human responses to S. chartarum in both occupational and home settings varies widely. To explore these differences, we intratracheally instilled C3H/HeJ, BALB/c, and C57BL/6J mice with S. chartarum spores suspended in saline. One day later, the mice were humanely killed, bronchoalveolar lavage (BAL) was performed, and biochemical and cellular indicators of lung injury and inflammation were measured. BALB/c mice showed the highest myeloperoxidase activity, albumin and hemoglobin levels, and neutrophil numbers in their BAL among the three strains. BALB/c was the only strain to show significant increases in keratinocyte-derived cytokine (KC), monocyte chemotactic protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, MIP-1gamma, MIP-2, RANTES, IL-1alpha, IL-1beta, IL-3, IL-6, IL-18, leukemia inhibitory factor, macrophage colony-stimulating factor, and TNF-alpha. A model of allergen-induced airway inflammation was examined to assess whether underlying allergic inflammation might contribute to increased susceptibility to S. chartarum-induced pulmonary inflammation and injury. Surprisingly, in BALB/c mice, ovalbumin-induced airway inflammation produced a protective effect against some S. chartarum-induced pulmonary responses. This is the first report of mammalian strain differences affecting responses to S. chartarum. These responses differ from those reported for LPS and other fungi. Analogous underlying genetic differences may contribute to the wide range of sensitivity to Stachybotrys among humans.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Pneumopatias Fúngicas/imunologia , Camundongos Endogâmicos/genética , Pneumonia/microbiologia , Stachybotrys/patogenicidade , Receptor 4 Toll-Like/fisiologia , Animais , Quimiocinas/análise , Citocinas/análise , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hemoglobinas/análise , Insulina/análise , Insulina de Ação Prolongada , Insulina Regular Humana , Camundongos , Camundongos Endogâmicos/imunologia , Camundongos Endogâmicos/microbiologia , Pneumonia/imunologia , Hipersensibilidade Respiratória/imunologia , Albumina Sérica/análise , Albumina Sérica Humana , Especificidade da Espécie
16.
Proc Natl Acad Sci U S A ; 103(7): 2292-7, 2006 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-16455798

RESUMO

Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta, although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células da Medula Óssea/imunologia , Interferon beta/biossíntese , Lipopolissacarídeos/imunologia , Camundongos Endogâmicos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Células da Medula Óssea/metabolismo , Suscetibilidade a Doenças , Regulação para Baixo , Retroalimentação Fisiológica , Feminino , Leishmaniose Cutânea/imunologia , Lipopolissacarídeos/farmacologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide , Receptor de Interferon alfa e beta , Receptores de Interferon/genética , Receptores de Interferon/metabolismo
17.
Bull Exp Biol Med ; 137(6): 622-4, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15455101

RESUMO

We revealed differences in quantitative composition and functional activity of lymphoid cells in intact mice of different strains. Cellularity and counts of lymphoid elements in hemopoietic and lymphoid organs, proliferative activity of T and B lymphocytes, and counts of CD4+ and CD8+ lymphocytes in the spleen were minimum in CC57W and Balb/c mice and maximum in CBA/CaLac and DBA/2 mice. The highest absolute content of lymphoid elements in the spleen was detected in Balb/c mice, while CC57W mice had the highest content of these elements in the thymus.


Assuntos
Linfócitos/citologia , Linfócitos/metabolismo , Camundongos Endogâmicos/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Camundongos , Baço/citologia , Baço/imunologia , Timo/citologia , Timo/imunologia
18.
Crit Rev Immunol ; 24(1): 39-65, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14995913

RESUMO

The germinal center reaction is the foundation of T-cell-dependent humoral responses. Antigen-specific B cells recruited into germinal centers undergo a complex cellular program that allows for extensive expansion, isotype switching, somatic hypermutation, and differentiation into antibody-forming cells and memory cells. Importantly, the germinal center environment filters the repertoire of differentiating B cells such that high affinity variants are preferentially selected while low affinity or self-reactive clones are eliminated by apoptosis. The present article reviews the many processes that govern germinal center B-cell differentiation, as well as the cellular and molecular elements necessary to initiate and sustain a germinal center response. The major histologic features of the germinal center are also discussed, as well as the current dominant models of the germinal center reaction in humans and mice. Finally, a new model of murine B-cell differentiation is described on the basis of a multiparameter flow cytometric kinetic analysis of germinal center B cells.


Assuntos
Formação de Anticorpos/imunologia , Centro Germinativo/imunologia , Animais , Formação de Anticorpos/fisiologia , Antígenos/imunologia , Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/fisiologia , Linfócitos B/imunologia , Linfócitos B/fisiologia , Diferenciação Celular/imunologia , Diferenciação Celular/fisiologia , Citometria de Fluxo , Regulação da Expressão Gênica/imunologia , Centro Germinativo/citologia , Centro Germinativo/fisiologia , Haptenos/imunologia , Humanos , Camundongos , Camundongos Endogâmicos/imunologia , Modelos Imunológicos , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia
19.
Oral Microbiol Immunol ; 18(6): 364-70, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14622342

RESUMO

This study examined the nature of the infiltrating cells in Porphyromonas gingivalis-induced lesions and immunoglobulins in the serum samples of BALB/c (H-2d), C57BL6 (H-2b), DBA/2J (H-2d) and CBA/CaH (H-2k) mice. Mice were immunized intraperitoneally with P. gingivalis outer membrane antigens or sham-immunized with phosphate-buffered saline followed by subcutaneous challenge with live organisms 1 week after the final immunization. The resulting skin abscesses were excised 7 days later, cryostat sections cut and an immunoperoxidase method used to detect the presence of CD4+ and CD8+ T-cell subsets, CD14+ macrophages and CD19+ B cells. Peroxidase positive neutrophils and IgG1- and IgG2a-producing plasma cells were also identified. Anti P. gingivalis IgG1 and IgG2a subclass antibodies were determined in serum obtained by cardiac puncture. Very few CD8+ T cells and CD19+ B cells were found in any of the lesions. The percentages of CD4+ cells, CD14+ cells and neutrophils were similar in lesions of immunized BALB/c and C57BL6 mice, with a trend towards a higher percentage of CD14+ cells in sham-immunized mice. The percentage of CD14+ cells was higher than that of CD4+ cells in immunized compared with sham-immunized DBA/2J mice. The percentages of CD4+ and CD14+ cells predominated in immunized CBA/CaH mice and CD4+ cells in sham-immunized CBA/CaH mice. The percentage of neutrophils in immunized CBA/CaH mice was significantly lower than that of CD14+ cells and CD4+ cells in sham-immunized mice. IgG1+ plasma cells were more dominant than IgG2a+ cells in immunized BALB/c, C57BL6 and DBA/2J mice, whereas IgG2a+ plasma cells were more obvious in sham-immunized mice. IgG2a+ plasma cells were predominant in immunized and sham-immunized CBA/CaH mice. In the serum, specific anti-P. gingivalis IgG2a antibody levels (Th1 response) were higher than IgG1 levels (Th2 response) in sham-immunized CBA/CaH and DBA/2J mice. In immunized BALB/c mice, IgG2a levels were lower than IgG1 levels, while IgG2a levels were higher in immunized C57BL6 mice. In conclusion, this study has shown differences in the proportion of infiltrating leukocytes and in the subclasses of immunoglobulin produced locally and systemically in response to P. gingivalis in different strains of mice, suggesting a degree of genetic control over the response to P. gingivalis.


Assuntos
Imunoglobulina G/imunologia , Leucócitos/imunologia , Camundongos Endogâmicos/microbiologia , Porphyromonas gingivalis/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Antígenos CD19/análise , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunoglobulina G/genética , Leucócitos/microbiologia , Receptores de Lipopolissacarídeos/análise , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos/imunologia , Neutrófilos/imunologia , Fenótipo , Plasmócitos/imunologia
20.
Clin Exp Allergy ; 33(3): 386-93, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12614454

RESUMO

BACKGROUND: Airway hyper-responsiveness (AHR), chronic airway inflammation and predominance of the T helper type-2 (Th2; IL-4, IL-5, IL-13) over the Th1 (IL-2, IFN-gamma) immune response are hallmarks of asthma. Alveolar macrophages (AM) are the most numerous cells in the airway lumen, where they represent the first immune cell population encountered by inhaled antigens. AM act as antigen-presenting cells (APC) and they release various soluble mediators and enzymes. AM thus play a prominent role in the modulation of the local immunity in airways. In allergic airways, AM have been implicated in the pathogenesis of inflammation by promoting the Th2 versus the Th1 cytokine patterns. OBJECTIVES: Infections with attenuated bacteria or challenges with bacterial products may involve AM. Such stimuli have been shown to potentially restore the Th1/Th2 balance in asthmatic airways, but they also induce the release of inflammatory mediators. We investigated the response of AM when stimulated by two preparations of non-proliferating Bacillus Calmette-Guérin (BCG). METHODS: We evaluated the cytokine production by AM from BP2 and C57BL/6 mice when cultured with heat-killed (HK) and extended freeze-dried (EFD) BCG. We then investigated in vivo the release of soluble factors in the airway lumen of mice after instillation of these BCG preparations. Finally, we studied the profile of cytokine transcripts in the lung of mice pre-treated with BCG and then challenged with ovalbumin (OVA). RESULTS: HK BCG induced the production of both TNF-alpha and IL-12, and did not prevent high levels of Th2 cytokine transcripts. In contrast, EFD BCG induced a response dominated by the production of IL-12, with no later over-expression of Th2 cytokine transcripts. CONCLUSION: Our results show that EFD BCG induce the release of the Th1-promoting cytokine IL-12 by AM, without the deleterious effects of HK BCG. These data suggest that EFD BCG may be considered as a potential novel treatment to restore the Th1/Th2 imbalance in asthma.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Asma/prevenção & controle , Vacina BCG/administração & dosagem , Interleucina-12/biossíntese , Macrófagos Alveolares/fisiologia , Administração Intranasal , Animais , Asma/imunologia , Asma/fisiopatologia , Contagem de Células/métodos , Células Cultivadas , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Liofilização , Temperatura Alta , Imunização , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos/imunologia , Ovalbumina/imunologia , Reação em Cadeia da Polimerase/métodos , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Fator de Necrose Tumoral alfa/biossíntese
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