RESUMO
Avian poxvirus infections typically manifest as 2 forms: cutaneous ("dry") pox, characterized by proliferative nodules on the skin, and diphtheritic ("wet") pox, characterized by plaques of caseous exudate in the oropharynx and upper respiratory and gastrointestinal tracts. Systemic spread of virus to visceral organs beyond the skin and mucous membranes is rarely reported. Out of 151 cases diagnosed with avian poxvirus over a 20-year period at a zoological institution, 22 were characterized as having systemic involvement based on histopathology and molecular findings. Gross lesions in systemic cases included soft white nodules scattered throughout the liver, spleen, and kidneys. Two histopathologic patterns emerged: (1) widespread histiocytic inflammation in visceral organs with intrahistiocytic viral inclusions and (2) severe, localized dry or wet pox lesions with poxvirus-like inclusions within dermal and subepithelial histiocytes. In situ hybridization targeting the core P4b protein gene confirmed the presence of poxvirus DNA within histiocytes in both patterns. Polymerase chain reaction was performed targeting the reticuloendothelial virus long terminal repeat (REV LTR) flanking region and the core P4b protein gene. Sequences of the REV LTR flanking region from all systemic pox cases were identical to a previously described condorpox virus isolated from an Andean condor with systemic pox. Sequences of the core P4b protein gene from all systemic pox cases grouped into cluster 2 of the B1 subclade of canarypox viruses. Systemic involvement of avian poxvirus likely occurs as a result of infection with certain strain variations in combination with various possible host and environmental factors.
Assuntos
Avipoxvirus , Doenças das Aves , Infecções por Poxviridae , Animais , Vírus da Varíola dos Canários , Avipoxvirus/genética , Doenças das Aves/patologia , Aves , Infecções por Poxviridae/veterinária , Infecções por Poxviridae/patologia , FilogeniaRESUMO
Isospora infections are common in both wild and captive passerine species. Many bird species have been shown to have co-evolved with a particular species of Isospora. Disease can range from subclinical to severe and fatal, making infection and transmission of this parasite a concern for birds under managed care, particularly in institutions housing endangered species for breeding and reintroduction purposes. Whether birds in mixed-species enclosures represent a risk factor for severe isosporiasis due to infection with non-host-adapted strains is of concern for institutions managing these populations. To begin answering this question, we sought to characterize the host-specificity of Isospora spp. in a large number of passerine birds via retrospective sequencing of mitochondrial gene cytochrome c oxidase subunit I (COI). Despite outliers, Isospora sequences largely grouped by host species and/or host family. Additional research is warranted into the degree of interspecies transmission and host-switching of Isospora parasites, and risk factors for the development of severe disease in passerine birds.
RESUMO
This study combined a social network analysis and whole-genome sequencing (WGS) to test for general patterns of contagious spread of a mycobacterial infection for which pathways of disease acquisition are not well understood. Our population included 275 cases diagnosed with avian mycobacteriosis that were nested in a source population of 16,430 birds at San Diego Zoo Wildlife Alliance facilities from 1992 through mid-2014. Mycobacteria species were determined using conventional methods and whole genome sequencing (WGS). Mycobacterium avium avium (MAA) and Mycobacterium genavense were the most common species of mycobacteria identified and were present in different proportions across bird taxa. A social network for the birds was constructed from the source population to identify directly and indirectly connected cases during time periods relevant to disease transmission. Associations between network connectivity and genetic similarity of mycobacteria (as determined by clusters of genotypes separated by few single nucleotide polymorphisms, or SNPs) were then evaluated in observed and randomly generated network permutations. Findings showed that some genotypes clustered along pathways of bird connectivity, while others were dispersed throughout the network. The proportion of directly connected birds having a similar mycobacterial genotype was 0.36 and significant (p<0.05). This proportion was higher (0.58) and significant for MAA but not for M. genavense. Evaluations of SNP distributions also showed genotypes of MAA were more related in connected birds than expected by chance; however, no significant patterns of genetic relatedness were identified for M. genavense, although data were sparse. Integrating the WGS analysis of mycobacteria with a social network analysis of their host birds revealed significant genetic clustering along pathways of connectivity, namely for MAA. These findings are consistent with a contagious process occurring in some, but not all, case clusters.
Assuntos
Animais de Zoológico/genética , Aves/microbiologia , Infecções por Mycobacterium/veterinária , Mycobacterium avium/genética , Mycobacterium/genética , Tuberculose Aviária/genética , Sequenciamento Completo do Genoma/veterinária , Animais , Animais de Zoológico/microbiologia , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/transmissão , Análise de Rede Social , Tuberculose Aviária/microbiologia , Tuberculose Aviária/transmissãoRESUMO
Viral metagenomic analysis of the liver of a black headed python (Aspidites melanocephalus) euthanized for a proliferative spinal lesion of unknown etiology yielded the first characterized genome of a reptile-infecting circovirus (black-headed python circovirus or BhPyCV). BhPyCV-specific in situ hybridization (ISH) showed that viral nucleic acids were strongly expressed in the intestinal lining and mucosa and multifocally in the liver. To investigate the presence of this virus in other snakes and its possible pathogenicity, 17 snakes in the python family with spinal disease were screened with ISH yielding a second BhP positive in intestinal tissue, and a Boelen's python (Morelia boeleni) positive in the liver. BhPyCV specific PCR was used to screen available frozen tissues from 13 of these pythons, four additional deceased pythons with and without spinal disease, and fecal samples from 37 live snakes of multiple species with unknown disease status. PCR detected multiple positive tissues in both of the ISH positive BhP and in the feces of another two live BhP and two live annulated tree boas (Corallus annulatus). Preliminary analysis indicates this circovirus can infect BhPs where it was found in 4/5 BhPs tested (2/2 with spinal disease, 2/3 live with unknown status), Boelen's python (1/2 with spinal disease), and annulated tree boa (2/6 live with unknown status) but was not detected in other python species with the same spinal lesions. This circovirus' causal or contributory role in spinal disease remains speculative and not well supported by these initial data.
Assuntos
Boidae/virologia , Infecções por Circoviridae/veterinária , Circovirus , Trato Gastrointestinal/virologia , Fígado/virologia , Animais , Circovirus/genética , Genoma Viral/genética , Hibridização In Situ/veterinária , Masculino , Filogenia , Reação em Cadeia da Polimerase/veterinária , Serpentes/virologiaRESUMO
METHODS: Mycobacteria isolated from more than 100 birds diagnosed with avian mycobacteriosis at the San Diego Zoo and its Safari Park were cultured postmortem and had their whole genomes sequenced. Computational workflows were developed and applied to identify the mycobacterial species in each DNA sample, to find single-nucleotide polymorphisms (SNPs) between samples of the same species, to further differentiate SNPs between as many as three different genotypes within a single sample, and to identify which samples are closely clustered genomically. RESULTS: Nine species of mycobacteria were found in 123 samples from 105 birds. The most common species were Mycobacterium avium and Mycobacterium genavense, which were in 49 and 48 birds, respectively. Most birds contained only a single mycobacterial species, but two birds contained a mixture of two species. The M. avium samples represent diverse strains of M. avium avium and M. avium hominissuis, with many pairs of samples differing by hundreds or thousands of SNPs across their common genome. By contrast, the M. genavense samples are much closer genomically; samples from 46 of 48 birds differ from each other by less than 110 SNPs. Some birds contained two, three, or even four genotypes of the same bacterial species. Such infections were found in 4 of 49 birds (8%) with M. avium and in 11 of 48 birds (23%) with M. genavense. Most were mixed infections, in which the bird was infected by multiple mycobacterial strains, but three infections with two genotypes differing by ≤ 10 SNPs were likely the result of within-host evolution. The samples from 31 birds with M. avium can be grouped into nine clusters within which any sample is ≤ 12 SNPs from at least one other sample in the cluster. Similarly, the samples from 40 birds with M. genavense can be grouped into ten such clusters. Information about these genomic clusters is being used in an ongoing, companion study of mycobacterial transmission to help inform management of bird collections.
Assuntos
Doenças das Aves/microbiologia , Genoma Bacteriano , Genômica , Infecções por Mycobacterium/veterinária , Mycobacterium/classificação , Mycobacterium/genética , Animais , California , Biologia Computacional/métodos , Bases de Dados de Ácidos Nucleicos , Genômica/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Mycobacterium avium/genética , Filogenia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases.
RESUMO
As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET), cerebrospinal fluid (CSF) examination assaying Aß1-42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history-hence the need for cost-effective screening measures for early dementia.
RESUMO
Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.
Assuntos
Pré-Eclâmpsia/fisiopatologia , Proteínas RGS/fisiologia , Adaptação Fisiológica , Angiotensina II/metabolismo , Animais , Feminino , Camundongos , Estresse Oxidativo , Gravidez , Proteínas RGS/genéticaRESUMO
A captive 'survival assurance' population of 56 endangered boreal toads Anaxyrus boreas boreas, housed within a cosmopolitan collection of amphibians originating from Southeast Asia and other locations, experienced high mortality (91%) in April to July 2010. Histological examination demonstrated lesions consistent with ranaviral disease, including multicentric necrosis of skin, kidney, liver, spleen, and hematopoietic tissue, vasculitis, and myriad basophilic intracytoplasmic inclusion bodies. Initial confirmation of ranavirus infection was made by Taqman real-time PCR analysis of a portion of the major capsid protein (MCP) gene and detection of iridovirus-like particles by transmission electron microscopy. Preliminary DNA sequence analysis of the MCP, DNA polymerase, and neurofilament protein (NFP) genes demonstrated highest identity with Bohle iridovirus (BIV). A virus, tentatively designated zoo ranavirus (ZRV), was subsequently isolated, and viral protein profiles, restriction fragment length polymorphism analysis, and next generation DNA sequencing were performed. Comparison of a concatenated set of 4 ZRV genes, for which BIV sequence data are available, with sequence data from representative ranaviruses confirmed that ZRV was most similar to BIV. This is the first report of a BIV-like agent outside of Australia. However, it is not clear whether ZRV is a novel North American variant of BIV or whether it was acquired by exposure to amphibians co-inhabiting the same facility and originating from different geographic locations. Lastly, several surviving toads remained PCR-positive 10 wk after the conclusion of the outbreak. This finding has implications for the management of amphibians destined for use in reintroduction programs, as their release may inadvertently lead to viral dissemination.
Assuntos
Bufonidae/virologia , Iridovirus/isolamento & purificação , Viroses/veterinária , Animais , DNA Viral/genética , DNA Viral/isolamento & purificação , Surtos de Doenças/veterinária , Hospitais Veterinários , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Virais , Viroses/virologiaRESUMO
Abstract Mycoplasmas are an important cause of upper respiratory tract disease (URTD) in desert tortoises (Gopherus agassizii) and have been a main focus in attempts to mitigate disease-based population declines. Infection risk can vary with an animal's population of origin, making screening tests popular tools for determining infection status in individuals and populations. To provide additional methods for investigating URTD we developed quantitative PCR (qPCR) assays specific for agents causing clinical signs of URTD: Mycoplasma agassizii, Mycoplasma testudineum, and Testudinid herpesvirus 2 (TeHV2) and tested necropsied desert tortoises housed at the Desert Tortoise Conservation Center in Las Vegas, Nevada, USA, as well as wild desert tortoises (n=3), during 2010. Findings were compared with M. agassizii enzyme-linked immunosorbent assay (ELISA) data. Based on qPCR, the prevalence of M. agassizii was 75% (33/44) and the prevalence of TeHV2 was 48% (20/42) in the evaluated population. Both agents were also present in the wild tortoises. Mycoplasma testudineum was not detected. The M. agassizii ELISA and qPCR results did not always agree. More tortoises were positive for M. agassizii by nasal mucosa testing than by nasal flush. Our findings suggest that mycoplasmas are not the only agents of concern and that a single M. agassizii ELISA or nasal flush qPCR alone failed to identify all potentially infected animals in a population. Caution should be exercised in using these tests for disposition decisions.
Assuntos
Infecções por Herpesviridae/veterinária , Herpesviridae/isolamento & purificação , Infecções por Mycoplasma/veterinária , Mycoplasma/isolamento & purificação , Tartarugas , Animais , Herpesviridae/classificação , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/virologia , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/microbiologia , Nevada/epidemiologia , Reação em Cadeia da Polimerase/veterinária , Vigilância da População , Prevalência , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/veterinária , Infecções Respiratórias/virologiaRESUMO
RATIONALE: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation. OBJECTIVE: To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways. METHODS AND RESULTS: We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin-angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension. CONCLUSIONS: Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gαq-coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.
Assuntos
Pressão Sanguínea/fisiologia , Vasos Sanguíneos/fisiologia , Homeostase/fisiologia , Músculo Liso Vascular/fisiologia , Proteínas RGS/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Hipertensão/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase C/fisiologia , Proteínas RGS/deficiência , Proteínas RGS/genética , Transdução de Sinais/fisiologia , Vasoconstrição/fisiologia , Quinases Associadas a rho/fisiologiaRESUMO
Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.
Assuntos
Golfinho Nariz-de-Garrafa , Papillomaviridae/genética , Infecções por Papillomavirus/veterinária , Vírus Reordenados/genética , Seleção Genética , Animais , Doenças dos Genitais Masculinos/veterinária , Doenças dos Genitais Masculinos/virologia , Genoma Viral , Masculino , Técnicas de Amplificação de Ácido Nucleico , Infecções por Papillomavirus/virologia , FilogeniaRESUMO
Chronic innocuous aeroallergen exposure attenuates CD4(+) T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11b(lo) and CD11b(hi) AMDC and the delivery of OVA to airway draining lymph nodes by CD8α(-) migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4(+) T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4(+) T cells.
Assuntos
Alérgenos/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Tolerância Imunológica , Ovalbumina/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Mucosa Respiratória/imunologia , Administração por Inalação , Alérgenos/imunologia , Alérgenos/toxicidade , Sequência de Aminoácidos , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Dados de Sequência Molecular , Ovalbumina/imunologia , Ovalbumina/toxicidade , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismoRESUMO
The severity of allergic diseases may be modified by vitamin D. However, the immune pathways modulated by the active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], are yet to be fully elucidated. In this study, naturally occurring CD4(+) CD25(+) cells from the skin-draining lymph nodes (SDLN) of mice treated with topical 1,25(OH)(2)D(3) had an increased ability to suppress T helper type 2 (Th2) -skewed immune responses. CD4(+) CD25(+) cells transferred from mice treated with topical 1,25(OH)(2)D(3) into ovalbumin (OVA) -sensitized mice challenged intranasally with OVA 18 hr later, significantly suppressed the capacity of airway-draining lymph node (ADLN) cells to proliferate and secrete cytokines in response to further OVA stimulation ex vivo. The CD4(+) CD25(+) cells from 1,25(OH)(2)D(3)-treated mice also reduced airway hyperresponsiveness and the proportions of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF). To test the effect of 1,25(OH)(2)D(3) on cells able to respond to a specific antigen, CD4(+) CD25(+) cells were purified from the SDLN of OVA-T-cell receptor (TCR) transgenic mice treated 4 days earlier with topical 1,25(OH)(2)D(3). CD4(+) CD25(+) cells from OVA-TCR mice treated with 1,25(OH)(2)D(3) were able to alter BALF cell content and suppress ADLN responses to a similar degree to those cells from non-transgenic mice, suggesting that the effect of 1,25(OH)(2)D(3) was not related to TCR signalling. In summary, topical 1,25(OH)(2)D(3) increased the regulatory capacity of CD4(+) CD25(+) cells from the SDLN to suppress Th2-mediated allergic airway disease. This work highlights how local 1,25(OH)(2)D(3) production by lung epithelial cells may modulate the suppressive activity of local regulatory T cells.
Assuntos
Calcitriol/imunologia , Linfonodos/imunologia , Hipersensibilidade Respiratória/imunologia , Pele/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Calcitriol/biossíntese , Calcitriol/farmacologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/metabolismo , Pele/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Células Th2/metabolismo , Células Th2/patologiaRESUMO
Airways hyperresponsiveness (AHR) is one of the major clinical features of allergic airways disease including allergic asthma, however the immunological mechanisms leading to the induction and regulation of this disorder are not fully understood. In this review we will summarise the evidence of a number of studies, principally in murine models of AHR, suggesting a central role for respiratory tract dendritic cells (RTDC) in the induction of AHR through the generation of lung-homing, allergen-specific effector T cells. We will also summarise the evidence supporting a role for regulatory T cells in the attenuation of AHR and will propose that, as a counterpoint to their capacity to induce AHR, RTDC may also play a role in the attenuation of AHR through the generation of regulatory T cells (T(reg)). A better understanding of the relationship between the physiological and immunological responses to allergen-induced AHR attenuation, and particularly the role of RTDC and T(reg) in this process, will be essential for the development of new treatments and therapies.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Células Dendríticas/imunologia , Sistema Respiratório/imunologia , Linfócitos T Reguladores/imunologia , Aerossóis , Animais , Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Exposição por Inalação , Sistema Respiratório/fisiopatologiaRESUMO
It is widely accepted that atopic asthma depends on an allergic response in the airway, yet the immune mechanisms that underlie the development of airway hyperresponsiveness (AHR) are poorly understood. Mouse models of asthma have been developed to study the pathobiology of this disease, but there is considerable strain variation in the induction of allergic disease and AHR. The aim of this study was to compare the development of AHR in BALB/c, 129/Sv, and C57BL/6 mice after sensitization and challenge with ovalbumin (OVA). AHR to methacholine was measured using a modification of the forced oscillation technique in anesthetized, tracheostomized mice to distinguish between airway and parenchymal responses. Whereas all strains showed signs of allergic sensitization, BALB/c was the only strain to develop AHR, which was associated with the highest number of activated (CD69(+)) CD4(+) T cells in the airway wall and the highest levels of circulating OVA-specific IgG(1). AHR did not correlate with total or antigen-specific IgE. We assessed the relative contribution of CD4(+) T cells and specific IgG(1) to the development of AHR in BALB/c mice using adoptive transfer of OVA-specific CD4(+) T cells from DO11.10 mice. AHR developed in these mice in a progressive fashion following multiple OVA challenges. There was no evidence that antigen-specific antibody had a synergistic effect in this model, and we concluded that the number of antigen-specific T cells activated and recruited to the airway wall was crucial for development of AHR.
Assuntos
Resistência das Vias Respiratórias/imunologia , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Linfócitos T CD4-Positivos/imunologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstritores/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Lectinas Tipo C , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Ovalbumina/farmacologia , Organismos Livres de Patógenos EspecíficosRESUMO
Understanding the mechanisms involved in respiratory tolerance to inhaled allergens could potentially result in improved therapies for asthma and allergic diseases. Airway hyperresponsiveness (AHR) is a major feature of allergic asthma, thus the aim of the current study was to investigate mechanisms underlying suppression of allergen-induced AHR during chronic allergen exposure. Adult BALB/c mice were systemically sensitized with ovalbumin (OVA) in adjuvant and then challenged with a single 3 or 6 wk of OVA aerosols. Airway and parenchymal responses to inhaled methacholine (MCh), inflammatory cell counts, cytokines, OVA-specific IgE and IgG(1), parenchymal histology, and numbers of airway CD4(+)69(+) activated and CD4(+)25(+)FoxP3(+) regulatory T (Treg) cells were assessed 24 h after the final aerosol. Single OVA challenge resulted in AHR, eosinophilia, increased serum OVA-specific IgE, and T helper 2 (Th2) cytokines in bronchoalveolar lavage (BAL) but no difference in numbers of Treg compared with control mice. Three weeks of OVA challenges resulted in suppression of AHR and greater numbers of airway Treg cells and increased transforming growth factor-beta(1) (TGFbeta(1)) compared with control mice despite the presence of increased eosinophilia, OVA-specific IgE and IgG(1), and airway remodeling. Six weeks of OVA challenges restored AHR, whereas airway Treg numbers, TGFbeta(1), BAL eosinophilia, and Th2 cytokines returned to control levels. Partial in vivo depletion or adoptive transfer of Treg cells restored or inhibited AHR, respectively, but did not affect TGFbeta(1) or Th2 cytokine production. In conclusion, AHR suppression is mediated by airway Treg cells and potentially via a paracrine induction of TGFbeta(1) in the airways.