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1.
Commun Biol ; 6(1): 244, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36879097

RESUMO

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P263-V313-L331 and L263-M313-S331, imparting sensitization and resistance respectively. Unexpectedly, we found several wild-derived inbred strains that carry the resistant HRH1 allotype (L263-M313-S331) but exhibit histamine sensitization. This suggests the existence of a locus modifying pertussis-dependent histamine sensitization. Congenic mapping identified the location of this modifier locus on mouse chromosome 6 within a functional linkage disequilibrium domain encoding multiple loci controlling sensitization to histamine. We utilized interval-specific single-nucleotide polymorphism (SNP) based association testing across laboratory and wild-derived inbred mouse strains and functional prioritization analyses to identify candidate genes for this modifier locus. Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2 are candidate genes within this modifier locus, which we named Bphse, enhancer of Bordetella pertussis induced histamine sensitization. Taken together, these results identify, using the evolutionarily significant diversity of wild-derived inbred mice, additional genetic mechanisms controlling histamine sensitization.


Assuntos
Bordetella pertussis , Histamina , Animais , Camundongos , Bordetella pertussis/genética , Toxina Pertussis , Transdução de Sinais , Proteínas do Sistema Complemento , Loci Gênicos , Glicoproteínas de Membrana , Peptídeos e Proteínas de Sinalização Intracelular , Ribonucleoproteínas
2.
G3 (Bethesda) ; 9(12): 4223-4233, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31645420

RESUMO

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often ad hoc and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Histh). Histh is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Histh risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in the Histh locus by predicting functional association with multiple Histh-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes included Cxcl12, Ret, Cacna1c, and Cntn3, all of which had strong functional associations and were proximal to SNPs segregating with Histh. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in challenging cases involving large QTL and extreme trait complexity.


Assuntos
Mapeamento Cromossômico , Histamina/genética , Hipersensibilidade/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Animais , Camundongos
3.
Acta Neuropathol ; 138(1): 103-121, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30877432

RESUMO

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10S55L mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.


Assuntos
Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Mutação com Ganho de Função/genética , Mitocôndrias/genética , Animais , Estudos de Associação Genética , Camundongos Transgênicos , Mitocôndrias/patologia , Membranas Mitocondriais/metabolismo , Mutação/genética , Doença de Parkinson/genética
4.
Immunity ; 47(2): 310-322.e7, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813660

RESUMO

Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.


Assuntos
Anticorpos Neutralizantes , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunidade Humoral , Vírus do Tumor Mamário do Camundongo/imunologia , Vírus Rauscher/imunologia , Infecções por Retroviridae/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Apresentação de Antígeno/genética , Biologia Computacional , Feminino , Predisposição Genética para Doença , Antígenos HLA-D/genética , Células HeLa , Hepatite B/imunologia , Hepatite B/transmissão , Hepatite C/imunologia , Hepatite C/transmissão , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Imunidade Humoral/genética , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Mutação/genética , Polimorfismo Genético , Infecções por Retroviridae/transmissão
5.
Proc Natl Acad Sci U S A ; 114(13): 3491-3496, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28242695

RESUMO

Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17-producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.


Assuntos
Vírus da Influenza A/fisiologia , Influenza Humana/genética , Cromossomo Y/genética , Animais , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Influenza Humana/imunologia , Influenza Humana/virologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Fatores Sexuais , Linfócitos T/imunologia , Virulência
6.
FASEB J ; 31(6): 2709-2719, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28292961

RESUMO

Month-season of birth (M-SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M-SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M-SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M-SOB with the lowest birth rate were less susceptible to EAE than mice born during the M-SOB with the highest birth rate. We also show that the M-SOB effect on EAE susceptibility is associated with differential production of multiple cytokines/chemokines by neuroantigen-specific T cells that are known to play a role in EAE pathogenesis. Taken together, these results support the existence of an M-SOB effect that may reflect seasonally dependent developmental differences in adaptive immune responses to self-antigens independent of external stimuli, including exposure to sunlight and vitamin D. Moreover, our documentation of an M-SOB effect on EAE susceptibility in mice allows for modeling and detailed analysis of mechanisms that underlie the M-SOB effect in not only MS but in numerous other diseases in which M-SOB impacts susceptibility.-Reynolds, J. D., Case, L. K., Krementsov, D. N., Raza, A., Bartiss, R., Teuscher, C. Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.


Assuntos
Suscetibilidade a Doenças , Encefalite , Doença de Hashimoto , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito/toxicidade , Animais , Coeficiente de Natalidade , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Doença de Hashimoto/induzido quimicamente , Camundongos , Camundongos Endogâmicos , Esclerose Múltipla/etiologia , Fragmentos de Peptídeos/toxicidade , Estudos Retrospectivos , Fatores de Risco , Estações do Ano
7.
Elife ; 42015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25974216

RESUMO

IL-6 plays an important role in determining the fate of effector CD4 cells and the cytokines that these cells produce. Here we identify a novel molecular mechanism by which IL-6 regulates CD4 cell effector function. We show that IL-6-dependent signal facilitates the formation of mitochondrial respiratory chain supercomplexes to sustain high mitochondrial membrane potential late during activation of CD4 cells. Mitochondrial hyperpolarization caused by IL-6 is uncoupled from the production of ATP by oxidative phosphorylation. However, it is a mechanism to raise the levels of mitochondrial Ca(2+) late during activation of CD4 cells. Increased levels of mitochondrial Ca(2+) in the presence of IL-6 are used to prolong Il4 and Il21 expression in effector CD4 cells. Thus, the effect of IL-6 on mitochondrial membrane potential and mitochondrial Ca(2+) is an alternative pathway by which IL-6 regulates effector function of CD4 cells and it could contribute to the pathogenesis of inflammatory diseases.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Cálcio/metabolismo , Interleucina-6/metabolismo , Potenciais da Membrana/fisiologia , Mitocôndrias/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Sinalização do Cálcio/fisiologia , Interleucina-6/deficiência , Interleucina-6/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Membranas Mitocondriais/fisiologia , Transdução de Sinais/fisiologia , Proteínas de Transporte Vesicular
8.
Biol Sex Differ ; 6: 6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25866616

RESUMO

Sexually dimorphic traits arise through the combined effects of sex hormones and sex chromosomes on sex-biased gene expression, and experimental mouse models have been instrumental in determining their relative contribution in modulating sex differences. A role for the Y chromosome (ChrY) in mediating sex differences outside of development and reproduction has historically been overlooked due to its unusual genetic composition and the predominant testes-specific expression of ChrY-encoded genes. However, ample evidence now exists supporting ChrY as a mediator of other physiological traits in males, and genetic variation in ChrY has been linked to several diseases, including heart disease, cancer, and autoimmune diseases in experimental animal models, as well as humans. The genetic and molecular mechanisms by which ChrY modulates phenotypic variation in males remain unknown but may be a function of copy number variation between homologous X-Y multicopy genes driving differential gene expression. Here, we review the literature identifying an association between ChrY polymorphism and phenotypic variation and present the current evidence depicting the mammalian ChrY as a member of the regulatory genome in males and as a factor influencing paternal parent-of-origin effects in female offspring.

9.
FASEB J ; 29(8): 3446-57, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25917331

RESUMO

Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammatory disease influenced by genetics and the environment. MS incidence in female subjects has approximately tripled in the last century, suggesting a sex-specific environmental influence. Recent animal and human studies have implicated dietary sodium as a risk factor in MS, whereby high sodium augmented the generation of T helper (Th) 17 cells and exacerbated experimental autoimmune encephalomyelitis (EAE), the principal model of MS. However, whether dietary sodium interacts with sex or genetics remains unknown. Here, we show that high dietary sodium exacerbates EAE in a strain- and sex-specific fashion. In C57BL6/J mice, exposure to a high-salt diet exacerbated disease in both sexes, while in SJL/JCrHsd mice, it did so only in females. In further support of a genetic component, we found that sodium failed to modify EAE course in C57BL6/J mice carrying a 129/Sv-derived interval on chromosome 17. Furthermore, we found that the high-sodium diet did not augment Th17 or Th1 responses, but it did result in increased blood-brain barrier permeability and brain pathology. Our results demonstrate that the effects of dietary sodium on autoimmune neuroinflammation are sex specific, genetically controlled, and CNS mediated.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Sódio na Dieta/efeitos adversos , Animais , Barreira Hematoencefálica/metabolismo , Cromossomos Humanos Par 17/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Fatores de Risco , Caracteres Sexuais , Sódio na Dieta/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
10.
Genome Biol ; 16: 28, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25886764

RESUMO

BACKGROUND: The prevalence of some autoimmune diseases is greater in females compared with males, although disease severity is often greater in males. The reason for this sexual dimorphism is unknown, but it may reflect negative selection of Y chromosome-bearing sperm during spermatogenesis or male fetuses early in the course of conception/pregnancy. Previously, we showed that the sexual dimorphism in experimental autoimmune encephalomyelitis (EAE) is associated with copy number variation (CNV) in Y chromosome multicopy genes. Here, we test the hypothesis that CNV in Y chromosome multicopy genes influences the paternal parent-of-origin effect on EAE susceptibility in female mice. RESULTS: We show that C57BL/6 J consomic strains of mice possessing an identical X chromosome and CNV in Y chromosome multicopy genes exhibit sperm head abnormalities and female-biased sex ratio. This is consistent with X-Y intragenomic conflict arising from an imbalance in CNV between homologous X:Y chromosome multicopy genes. These males also display paternal transmission of EAE to female offspring and differential loading of microRNAs within the sperm nucleus. Furthermore, in humans, families of probands with multiple sclerosis similarly exhibit a female-biased sex ratio, whereas families of probands affected with non-sexually dimorphic autoimmune diseases exhibit unbiased sex ratios. CONCLUSIONS: These findings provide evidence for a mechanism at the level of the male gamete that contributes to the sexual dimorphism in EAE and paternal parent-of-origin effects in female mice, raising the possibility that a similar mechanism may contribute to the sexual dimorphism in multiple sclerosis.


Assuntos
Doenças Autoimunes/genética , Variações do Número de Cópias de DNA/genética , Encefalomielite Autoimune Experimental/genética , Dosagem de Genes , Ligação Genética , Caracteres Sexuais , Cromossomo Y/genética , Animais , Animais Recém-Nascidos , Linfócitos T CD4-Positivos/metabolismo , Citocinas/biossíntese , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Padrões de Herança/genética , Modelos Lineares , Ativação Linfocitária/imunologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Fenótipo , Razão de Masculinidade , Espermatogênese/genética , Espermatozoides/metabolismo , Cromossomo X/genética
11.
PLoS One ; 10(2): e0117993, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25671658

RESUMO

Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity.


Assuntos
Autoimunidade/genética , Autoimunidade/fisiologia , Sistema Nervoso Central/imunologia , Caracteres Sexuais , Animais , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Simulação por Computador , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Variação Genética , Genômica , Hormônios Esteroides Gonadais/metabolismo , Masculino , Camundongos , Transdução de Sinais
12.
FASEB J ; 28(12): 5042-54, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25212221

RESUMO

The estrogens are female sex hormones that are involved in a variety of physiological processes, including reproductive development and function, wound healing, and bone growth. They are mainly known for their roles in reproductive tissues--specifically, 17ß-estradiol (E2), the primary estrogen, which is secreted by the ovaries and induces cellular proliferation and growth of the uterus and mammary glands. In addition to the role of estrogens in promoting tissue growth and development during normal physiological states, they have a well-established role in determining susceptibility to disease, particularly cancer, in reproductive tissues. The responsiveness of various tissues to estrogen is genetically controlled, with marked quantitative variation observed across multiple species, including humans. This variation presents both researchers and clinicians with a veritable physiological puzzle, the pieces of which--many of them unknown--are complex and difficult to fit together. Although genetics is known to play a major role in determining sensitivity to estrogens, there are other factors, including parent of origin and the maternal environment, that are intimately linked to heritable phenotypes but do not represent genotype, per se. The objectives of this review article were to summarize the current knowledge of the role of genotype, and uterine and neonatal environments, in phenotypic variation in the response to estrogens; to discuss recent findings and the potential mechanisms involved; and to highlight exciting research opportunities for the future.


Assuntos
Estrogênios/fisiologia , Animais , Feminino , Humanos , Glândulas Mamárias Humanas/fisiologia , Útero/fisiologia , Vagina/fisiologia
13.
Endocrinology ; 155(8): 3025-35, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24708240

RESUMO

The uterotropic response of the uterus to 17ß-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high (C57BL6/J; B6) or low (C3H/HeJ; C3H) responders to E2 led to the identification of quantitative trait loci (QTL) associated with phenotypic variation in uterine growth and leukocyte infiltration. Like the uterus, phenotypic variation in the responsiveness of the mammary gland to E2 during both normal and pathologic conditions has been reported. In the current experiment, we utilized an E2-specific model of mammary ductal growth combined with a microarray approach to determine the degree to which genotype influences the responsiveness of the mammary gland to E2, including the associated transcriptional programs, in B6 and C3H mice. Our results reveal that E2-induced mammary ductal growth and ductal morphology are genetically controlled. In addition, we observed a paradoxical effect of mammary ductal growth in response to E2 compared with what has been reported for the uterus; B6 is a high responder for the uterus and was a low responder for mammary ductal growth, whereas the reverse was observed for C3H. In contrast, B6 was a high responder for mammary ductal side branching. The B6 phenotype was associated with increased mammary epithelial cell proliferation and apoptosis, and a distinct E2-induced transcriptional program. These findings lay the groundwork for future experiments designed to investigate the genes and mechanisms underlying phenotypic variation in tissue-specific sensitivity to systemic and environmental estrogens during various physiological and disease states.


Assuntos
Estradiol/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/crescimento & desenvolvimento , Maturidade Sexual/genética , Animais , Apoptose , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células Epiteliais/fisiologia , Feminino , Genótipo , Camundongos , Camundongos Endogâmicos C3H , Útero/fisiologia
14.
FASEB J ; 28(4): 1898-909, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24371118

RESUMO

Histamine and its receptors are important in both multiple sclerosis and experimental allergic encephalomyelitis (EAE). C57BL/6J (B6) mice deficient for the histamine H2 receptor (H2RKO) are less susceptible to EAE and exhibit blunted Th1 responses. However, whether decreased antigen-specific T-cell effector responses in H2RKO mice were due to a lack of H2R signaling in CD4(+) T cells or antigen-presenting cells has remained unclear. We generated transgenic mice expressing H2R specifically in T cells on the H2RKO background, and, using wild-type B6 and H2RKO mice as controls, induced EAE either in the presence or absence of the ancillary adjuvant pertussis toxin (PTX), which models the effects of infectious inflammatory stimuli on autoimmune disease. We monitored the mice for clinical signs of EAE and neuropathology, as well as effector T-cell responses using flow cytometry. EAE severity and neuropathology in H2RKO mice expressing H2R exclusively in T cells become equal to those in wild-type B6 mice only when PTX is used to elicit disease. EAE complementation was associated with frequencies of CD4(+)IFN-γ(+) and CD4(+)IL-17(+) cells that are equal to or greater than those in wild-type B6, respectively. Thus, the regulation of encephalitogenic T-cell responses and EAE susceptibility by H2R signaling in CD4(+) T cells is dependent on gene × environment interactions.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Receptores Histamínicos H2/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Expressão Gênica/imunologia , Predisposição Genética para Doença , Células HEK293 , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Toxina Pertussis/administração & dosagem , Toxina Pertussis/imunologia , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Transdução de Sinais/genética , Linfócitos T/metabolismo
15.
J Immunol ; 191(2): 614-22, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23772030

RESUMO

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein-coupled receptors: H1, H2, H3, and H4 (histamine receptors; H(1-4)R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood-brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase-deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35-55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein-coupled-HRs (H(1-4)RKO mice). In this article, we report that in contrast to HDCKO mice, H(1-4)RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H(1-4)RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1-4RKO mice suggest that HA may signal independently of H1-4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Histamina/metabolismo , Histidina Descarboxilase/genética , Receptores Histamínicos/genética , Receptores Histamínicos/metabolismo , Animais , Células Apresentadoras de Antígenos , Barreira Hematoencefálica/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/metabolismo , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores Histamínicos/deficiência , Transdução de Sinais
16.
Toxicol Sci ; 135(1): 91-102, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23798566

RESUMO

Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk.


Assuntos
Compostos Benzidrílicos/toxicidade , Encefalomielite Autoimune Experimental/induzido quimicamente , Disruptores Endócrinos/toxicidade , Feto/efeitos dos fármacos , Esclerose Múltipla/induzido quimicamente , Fenóis/toxicidade , Animais , Feminino , Interferon gama/biossíntese , Interleucina-17/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Risco
17.
Genome Res ; 23(9): 1474-85, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23800453

RESUMO

Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4(+) T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY-mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4(+) T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly up-regulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Additionally, we show that ChrY polymorphism can determine the sexual dimorphism in EAE and myocarditis. In humans, an analysis of the CD4(+) T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, as in Drosophila, these data establish the mammalian ChrY as a member of the regulatory genome due to its ability to epigenetically regulate genome-wide gene expression in immune cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/genética , Predisposição Genética para Doença , Macrófagos/metabolismo , Miocardite/genética , Transcriptoma , Cromossomo Y/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular , Animais , Variações do Número de Cópias de DNA , Feminino , Dosagem de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Caracteres Sexuais
18.
FASEB J ; 27(5): 1874-86, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23371066

RESUMO

The uterotropic response of the uterus to 17ß-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high [C57BL/6J (B6)] or low [C3H/HeJ (C3H)] responders to E2 led to the identification of quantitative trait (QT) loci associated with phenotypic variation in uterine growth and leukocyte infiltration. The mechanisms underlying differential responsiveness to E2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E2-regulated transcriptional signatures with genetically controlled high and low responses to E2 and their segregation in (C57BL/6J×C3H/HeJ) F1 hybrids. Among the 6664 E2-regulated transcripts, analysis of cellular functions of those that were strain specific indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 (Birc1a) in C3H vs. B6 following treatment with E2. In addition, several differentially expressed transcripts reside within our previously identified QT loci, including the ERα-tethering factor Runx1, demonstrated to enhance E2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states.


Assuntos
Caspase 3/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Proteína Inibidora de Apoptose Neuronal/genética , Transcrição Gênica/genética , Útero/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Células Epiteliais/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Peroxidase/genética , Análise Serial de Proteínas , Locos de Características Quantitativas/fisiologia , Transcrição Gênica/efeitos dos fármacos , Transcriptoma , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento
19.
Cell Immunol ; 278(1-2): 27-34, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23121973

RESUMO

The histamine H(1) receptor (Hrh1/H(1)R) was identified as an autoimmune disease gene in experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Previously, we showed that selective re-expression of H(1)R by endothelial cells or T cells in H(1)RKO mice significantly reduced or complemented EAE severity and cytokine responses, respectively. H(1)R regulates innate immune cells, which in turn influences peripheral and central nervous system CD4(+) T cell effector responses. Therefore, we selectively re-expressed H(1)R in CD11b(+) cells of H(1)RKO mice to test the hypothesis that H(1)R signaling in these cells contributes to EAE susceptibility. We demonstrate that transgenic re-expression of H(1)R by H(1)RKO-CD11b(+) cells neither complements EAE susceptibility nor T cell cytokine responses highlighting the cell-specific effects of Hrh1 in the pathogenesis of EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.


Assuntos
Antígenos CD1/imunologia , Encefalomielite Autoimune Experimental/imunologia , Receptores Histamínicos H1/imunologia , Animais , Antígenos CD1/genética , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Expressão Gênica , Predisposição Genética para Doença , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Especificidade de Órgãos , Receptores Histamínicos H1/deficiência , Receptores Histamínicos H1/genética , Índice de Gravidade de Doença , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
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