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1.
Nat Commun ; 11(1): 6372, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311516

RESUMO

The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.


Assuntos
Células Estromais , Timo/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Epiteliais/imunologia , Matriz Extracelular , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Ratos , Regeneração , Timócitos , Timo/patologia , Timo/transplante , Tecidos Suporte
2.
Ecotoxicol Environ Saf ; 206: 111413, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33022443

RESUMO

Ammonia (NH3) gas is an atmospheric pollutant, produced from different sources. In poultry houses NH3 is produced from the biological process of liter, manure, and protein composition. It has been well documented that NH3 adversely effects the health of chickens. However, the underlying mechanism of NH3 toxicity on chicken thymus is still unknown. Thymus is an important immune organ, which play a critical role in eliciting protective immune responses to ensure healing process and elimination of harmful stimuli. The results showed that NH3 exposure reduced antioxidant activities and induced oxidative stress in thymus tissues. Histological observation showed normal morphology of chicken thymus in control group. In contrast, increased number of nuclear debris, vacuoles, and cristae break were seen in NH3 affected chickens. Ultrastructural analysis indicated mitochondrial breakdown, disappearance, vacuoles, and chromatin condensation in NH3 treated groups. The mRNA and protein expression of apoptosis related genes were significantly enhanced in the chicken thymus of NH3 affected chickens compared to control group. Moreover, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay results suggested that NH3 exposure increased positive stained nuclei in the chicken thymus. Meanwhile, NH3 exposure reduced the number of CD8+ T-lymphocytes, decreased the adenosine triphosphate (ATPase) activities. The mRNA and protein expression of autophagy, energy metabolism, and mitochondrial dynamics proteins were altered by NH3 exposure. In summary, these results showed that NH3 induced oxidative stress, apoptosis and autophagic cell death (ACD), which could be the possible causes of immune damage and structural impairment in chicken thymus.


Assuntos
Poluentes Atmosféricos/toxicidade , Amônia/toxicidade , Apoptose/efeitos dos fármacos , Galinhas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/genética , Timo/imunologia , Timo/metabolismo , Timo/patologia
3.
J Comput Assist Tomogr ; 44(6): 865-869, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976257

RESUMO

OBJECTIVE: The aim of the study was to evaluate computed tomography (CT) imaging findings of hyperdense thymic atrophy after chemotherapy in pediatric patients with extrathoracic malignancies. METHODS: Seventy-eight pediatric patients with extrathoracic malignancies, who developed thymic atrophy after chemotherapy, were included in this study. All patients underwent CT imaging before and after chemotherapy. We retrospectively reviewed the CT images. Hyperdense thymic atrophy was defined as thymic atrophy with high CT attenuation (≥80 HU). RESULTS: Hyperdense thymic atrophy after chemotherapy was observed in 7 (9%) of 78 patients. Age (4.3 ± 2.4 vs 8.4 ± 5.4 years, P < 0.01), thymic CT attenuation before chemotherapy (70.4 ± 18.8 vs 55.2 ± 11.9 HU, P < 0.01), reduction rate in thymic area (0.76 ± 0.06 vs 0.60 ± 0.22, P < 0.01), and thymic CT attenuation change (30.3 ± 15.2 vs -16.8 ± 24.0 HU, P < 0.01) were significantly different between patients with and without hyperdense thymic atrophy after chemotherapy. Thymic CT attenuation after chemotherapy (61.2 ± 23.8 vs 33.8 ± 30.1 HU, P < 0.01) and thymic CT attenuation change (-1.3 ± 21.2 vs -19.3 ± 27.9 HU, P < 0.01) were significantly different between patients 5 years or younger (n = 29) and 6 years or older (n = 49). CONCLUSIONS: Hyperdense thymic atrophy after chemotherapy was observed in 9% of pediatric patients with extrathoracic malignancies. It was associated with younger age, greater thymic CT attenuation before chemotherapy, larger reduction rate in thymic area, and greater thymic CT attenuation change.


Assuntos
Doenças Linfáticas/induzido quimicamente , Doenças Linfáticas/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Timo/diagnóstico por imagem , Timo/patologia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Atrofia/induzido quimicamente , Atrofia/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Doenças Linfáticas/patologia , Masculino , Estudos Retrospectivos
4.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32817213

RESUMO

While feline leukemia virus (FeLV) has been shown to infect felid species other than the endemic domestic cat host, differences in FeLV susceptibility among species has not been evaluated. Previous reports have noted a negative correlation between endogenous FeLV (enFeLV) copy number and exogenous FeLV (exFeLV) infection outcomes in domestic cats. Since felids outside the genus Felis do not harbor enFeLV genomes, we hypothesized absence of enFeLV results in more severe disease consequences in felid species lacking these genomic elements. We infected primary fibroblasts isolated from domestic cats (Felis catus) and pumas (Puma concolor) with FeLV and quantitated proviral and viral antigen loads. Domestic cat enFeLV env and long terminal repeat (LTR) copy numbers were determined for each individual and compared to FeLV viral outcomes. FeLV proviral and antigen levels were also measured in 6 naturally infected domestic cats and 11 naturally infected Florida panthers (P. concolor coryi). We demonstrated that puma fibroblasts are more permissive to FeLV than domestic cat cells, and domestic cat FeLV restriction was highly related to enFeLV-LTR copy number. Terminal tissues from FeLV-infected Florida panthers and domestic cats had similar exFeLV proviral copy numbers, but Florida panther tissues have higher FeLV antigen loads. Our work indicates that enFeLV-LTR elements negatively correlate with exogenous FeLV replication. Further, Puma concolor samples lacking enFeLV are more permissive to FeLV infection than domestic cat samples, suggesting that endogenization can play a beneficial role in mitigating exogenous retroviral infections. Conversely, presence of endogenous retroelements may relate to new host susceptibility during viral spillover events.IMPORTANCE Feline leukemia virus (FeLV) can infect a variety of felid species. Only the primary domestic cat host and related small cat species harbor a related endogenous virus in their genomes. Previous studies noted a negative association between the endogenous virus copy number and exogenous virus infection in domestic cats. This report shows that puma cells, which lack endogenous FeLV, produce more virus more rapidly than domestic cat fibroblasts following cell culture challenge. We document a strong association between domestic cat cell susceptibility and FeLV long terminal repeat (LTR) copy number, similar to observations in natural FeLV infections. Viral replication does not, however, correlate with FeLV env copy number, suggesting that this effect is specific to FeLV-LTR elements. This discovery indicates a protective capacity of the endogenous virus against the exogenous form, either via direct interference or indirectly via gene regulation, and may suggest evolutionary outcomes of retroviral endogenization.


Assuntos
Variações do Número de Cópias de DNA , Produtos do Gene env/genética , Vírus da Leucemia Felina/genética , Vírus da Leucemia Felina/patogenicidade , Leucemia Felina/virologia , Puma/virologia , Animais , Medula Óssea/patologia , Medula Óssea/virologia , Gatos , Feminino , Fibroblastos/patologia , Fibroblastos/virologia , Produtos do Gene env/metabolismo , Especificidade de Hospedeiro , Vírus da Leucemia Felina/metabolismo , Leucemia Felina/patologia , Linfonodos/patologia , Linfonodos/virologia , Masculino , Cultura Primária de Células , Baço/patologia , Baço/virologia , Sequências Repetidas Terminais , Timo/patologia , Timo/virologia , Carga Viral , Replicação Viral/genética
5.
PLoS One ; 15(6): e0235090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569270

RESUMO

Tumor is a prevalent great threat to public health worldwide and multidrug resistance (MDR) of tumor is a leading cause of chemotherapy failure. Nanomedicine has shown prospects in overcoming the problem. Doxorubicin (DOX), a broad-spectrum anticancer drug, showed limited efficacy due to MDR. Herein, a doxorubicin containing pectin nanocell (DOX-PEC-NC) of core-shell structure, a pectin nanoparticle encapsulated with liposome-like membrane was developed. The DOX-PEC-NC, spheroid in shape and sized around 150 nm, exerted better sustained release behavior than doxorubicin loading pectin nanoparticle (DOX-PEC-NP) or liposome (DOX-LIP). In vitro anticancer study showed marked accumulation of doxorubicin in different tumor cells as well as reversal of MDR in HepG2/ADR cells and MCF-7/ADR cells caused by treatment of DOX-PEC-NC. In H22 tumor-bearing mice, DOX-PEC-NC showed higher anticancer efficacy and lower toxicity than doxorubicin. DOX-PEC-NC can improve anticancer activity and reduce side effect of doxorubicin due to increased intracellular accumulation and reversal of MDR in tumor cells, which may be a promising nanoscale drug delivery vehicle for chemotherapeutic agents.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Pectinas/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Nanopartículas/ultraestrutura , Baço/patologia , Timo/patologia
6.
Sci Rep ; 10(1): 10024, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572036

RESUMO

T-cell receptor gene beta (TCRß) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRß sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRß rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRß gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRß gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/- mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRß rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Deleção de Genes , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas Repressoras/genética , Animais , Linfócitos B , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Contagem de Linfócitos , Camundongos Knockout , Linfócitos T , Timo/patologia
7.
Ecotoxicol Environ Saf ; 200: 110715, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32450432

RESUMO

Copper (Cu) is a necessary trace mineral due to its biological activity. Excessive Cu can induce inflammatory response in humans and animals, but the underlying mechanism is still unknown. Here, 240 broilers were used to study the effects of excessive Cu on oxidative stress and NF-κB-mediated inflammatory responses in immune organs. Chickens were fed with diet containing different concentrations of Cu (11, 110, 220, and 330 mg of Cu/kg dry matter). The experiment lasted for 49 days. Spleen, thymus, and bursa of Fabricius (BF) on day 49 were collected for histopathological observation and assessment of oxidative stress status. Additionally, the mRNA and protein levels of NF-κB and inflammatory cytokines were also analyzed. The results indicated that excess Cu could increase the number and area of splenic corpuscle as well as the ratio of cortex and medulla in thymus and BF. Furthermore, excessive Cu intake could decrease activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); but increase contents of malondialdehyde (MDA), TNF-α, IL-1, IL-1ß; up-regulate mRNA levels of TNF-α, IFN-γ, IL-1, IL-1ß, IL-2, iNOS, COX-2, NF-κB and protein levels of TNF-α, IFN-γ, NF-κB, p-NF-κB in immune organs. In conclusion, excessive Cu could cause pathologic changes and induce oxidative stress with triggered NF-κB pathway, and might further regulate the inflammatory response in immune organs of chicken.


Assuntos
Galinhas/imunologia , Cobre/toxicidade , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Bolsa de Fabricius/enzimologia , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/metabolismo , Bolsa de Fabricius/patologia , Catalase/metabolismo , Galinhas/genética , Galinhas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Inflamação/genética , Inflamação/metabolismo , Malondialdeído/metabolismo , NF-kappa B/genética , Baço/enzimologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Superóxido Dismutase/metabolismo , Timo/enzimologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
9.
Rev. argent. radiol ; 84(2): 55-60, abr. 2020. graf
Artigo em Espanhol | LILACS | ID: biblio-1125856

RESUMO

Resumen La pesquisa incidental de lesiones tímicas ha aumentado. Una adecuada aproximación a esas lesiones en la tomografía computada por emisión de positrones (PET-CT) es fundamental, pues se usa como parte de la mayoría de los procedimientos de planificación oncológica. Se han seleccionado casos representativos respecto de los aspectos más importantes de las imágenes de timo en PET-CT y cómo esa técnica puede contribuir a un diagnóstico preciso o a la planificación del tratamiento. Específicamente, presentamos una descripción general de las lesiones tímicas comunes y los imitadores de enfermedad, con énfasis en los hallazgos en PET-CT, incorporando también ejemplos de resonancia magnética (RM).


Abstract Incidental thymic lesion findings have increased. An adequate characterization of these lesions in positron emission computed tomography (PET-CT) is essential, since it is used as part of most oncological planning procedures. Representative cases have been selected regarding the most important aspects of thymus imaging in PET-CT and how this technique can contribute to an accurate diagnosis or treatment planning. Specifically, we present a general description of common thymic lesions and disease mimics, with an emphasis on PET-CT findings, also incorporating examples of magnetic resonance imaging.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Timo/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Timo/fisiologia , Timo/patologia , Hiperplasia do Timo/diagnóstico por imagem , Neoplasias do Timo/diagnóstico por imagem , Espectroscopia de Ressonância Magnética , Linfoma/diagnóstico por imagem
10.
Scand J Immunol ; 92(1): e12886, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32243615

RESUMO

This study aimed to investigate the effect of long non-coding RNA XLOC_003810 on the activation of CD4+ T cells and expression of PD-1/PD-L1 in patients with myasthenia gravis-related thymoma (MG-T). Thymus specimens and thymic mononuclear cells were obtained from MG and MG-T patients or cardiac surgery patients undergoing thoracotomy who were selected as negative controls (NC). XLOC_003810 expression was examined using quantitative real-time PCR (qRT-PCR). Frequency of CD4+ T cells and proportion of CD4+ PD-1+ T cells and CD14+ PD-L1+ monocytes were quantified by flow cytometry. The release of inflammatory cytokines was measured by qRT-PCR and enzyme-linked immunosorbent assay. Compared with the NC group, expression of XLOC_003810, frequency of CD4+ T cells and the production of inflammatory cytokines were increased in patients with MG and MG-T. XLOC_003810 overexpression significantly increased the frequency of CD4+ T cells, facilitated the production of inflammatory cytokines and decreased the proportion of CD4+ PD-1+ T cells and CD14+ PD-L1+ monocytes in the thymic mononuclear cells. In contrast, XLOC_003810 knockdown exerted the opposite effect. Together, XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 pathway in patients with MG-T.


Assuntos
Antígeno B7-H1/biossíntese , Linfócitos T CD4-Positivos/imunologia , Miastenia Gravis/genética , RNA Longo não Codificante/genética , Timoma/genética , Neoplasias do Timo/genética , Contagem de Linfócito CD4 , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Receptores Colinérgicos/imunologia , Timoma/imunologia , Timo/imunologia , Timo/patologia , Neoplasias do Timo/imunologia
11.
Yakugaku Zasshi ; 140(4): 509-512, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238633

RESUMO

The thymus is a vital organ for functional immune systems, and is the site of T cell development, which plays a central role in cellular immune defenses. Unlike other major organs, the thymus is highly dynamic in size and structure. It shrinks immediately upon bacterial infection, aging, pregnancy, mental stress, nutritional deficiency, and more. The reduction in size and function of the thymus during such biological events is called thymic involution or thymic atrophy; thymic involution is a particularly important issue because dysfunctional T cell immunity increases the risks of tumorigenesis and infectious diseases. However, the molecular mechanisms underlying thymic involution remain obscure. Our recent study indicated that blood vessels are remodeled during thymic involution that occurs upon aging, estradiol-treatment, or nutritional deficiency. We also found that prostanoid synthesis is induced during thymic involution. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), aspirin or etodolac, at least partially inhibited thymic involution-induced remodeling of the blood vessels, suggesting that prostanoids are involved in blood vessel remodeling. Our results revealed the potential role of blood vessel remodeling during thymic involution, which can lead to biological stress-induced immunosenescence.


Assuntos
Vasos Sanguíneos/imunologia , Vasos Sanguíneos/fisiopatologia , Estresse Fisiológico/imunologia , Estresse Psicológico/imunologia , Timo/imunologia , Remodelação Vascular , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Humanos , Camundongos , Prostaglandinas/metabolismo , Prostaglandinas/fisiologia , Estresse Fisiológico/fisiologia , Linfócitos T/imunologia , Timo/patologia , Remodelação Vascular/efeitos dos fármacos
12.
Vet Microbiol ; 243: 108639, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32273018

RESUMO

In the last decade, the outbreaks caused by virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains from both PRRSV-1 and PRRSV-2 have considerably increased. PRRSV is able to modulate the host's immune response through the induction of apoptosis of cells in lymphoid organs like thymus, increasing the susceptibility to secondary infectious agents. The present study aimed to compare the impact of two PRRSV-1 strains, a field low virulent strain (3249 strain) and a virulent strain (Lena strain), in the thymus of infected pigs, focusing on clinical signs, histological analysis, viraemia, thymus viral load and the study of the different routes of apoptosis phenomena by immunohistochemistry. Sera and thymus samples were collected from infected animals with 3249 strain, Lena strain and mock-infected animals at 1, 3, 6, 8 and 13 days post-infection (dpi). Lena-infected animals showed severe clinical disease, high sera and thymus viral loads with evident thymic atrophy since 6 dpi, matching with PRRSV-N protein, TUNEL and cCasp3 expression in the thymic cortex. In both infected groups, there was an increase in the number of cells expressing molecules related to the extrinsic pathway of apoptosis (cCasp8 and Fas) in cortex and medulla, showing an important role in the apoptosis induction produced in thymus of PRRSV-infected piglets. The extensive apoptosis in the thymus through this pathway would lead to a decrease in the number of mature T lymphocytes and the sustained release of viral particles, which may explain the greater severity of the clinical signs observed in Lena-infected pigs.


Assuntos
Apoptose , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Transdução de Sinais , Timo/patologia , Timo/virologia , Animais , Atrofia , Caspase 3/metabolismo , Imuno-Histoquímica , Suínos , Carga Viral , Viremia , Virulência
13.
Med Sci Monit ; 26: e920594, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32157074

RESUMO

BACKGROUND Protein 4.1R (EPB41) is the main cytoskeleton component of the erythrocyte membrane and may be involved in cell migration and adhesion. Previous research discovered overexpression of 4.1R in the thymus of patients with myasthenia gravis (MG). The protein 4.1R on dendritic cells may play a pivotal role in MG pathogenesis. This research investigated the effects of small interfering RNA 4.1R-siRNA on cell migration, cell cycle, and surface antigen expression of DC2.4 mouse dendritic cells, thus providing a new direction for the study of MG pathogenesis. MATERIAL AND METHODS Three 4.1R-specific siRNAs were designed, and the expression of 4.1R was detected by real-time PCR at the mRNA level and Western blot analysis at the protein level to select out the most efficient siRNAs. Changes in cell morphology were observed and cell migration ability was analyzed by Transwell assay. Cell cycle and surface antigen were both analyzed by flow cytometry. RESULTS The cell bodies of DC2.4 diminished, the synapses were increased, and protuberance became more obvious after being transfected with 4.1R-siRNA. After knockdown of 4.1R, cell migration ability decreased and the proportion of cells in S phase significantly increased (both P<0.05). The expression levels of MHCII, CD80, and CD86 were all increased in DC2.4 cells (all <0.05). CONCLUSIONS Silencing the expression of 4.1R in dendritic cells resulted in inhibition of migration ability, cell cycle arrest, and increase in surface antigens, which suggest that 4.1R participates in MG autoimmunity.


Assuntos
Células Dendríticas/imunologia , Proteínas dos Microfilamentos/metabolismo , Miastenia Gravis/imunologia , Animais , Antígenos de Superfície/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Células Dendríticas/metabolismo , Humanos , Camundongos , Proteínas dos Microfilamentos/genética , Miastenia Gravis/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Timo/imunologia , Timo/patologia , Regulação para Cima/imunologia
14.
Sci Immunol ; 5(44)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111619

RESUMO

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.


Assuntos
Fatores de Transcrição Box Pareados/imunologia , Timo/imunologia , Síndrome Brânquio-Otorrenal/genética , Síndrome Brânquio-Otorrenal/imunologia , Síndrome Brânquio-Otorrenal/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Lactente , Masculino , Fatores de Transcrição Box Pareados/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Timo/patologia
15.
PLoS One ; 15(3): e0230668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208448

RESUMO

The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival. This study was designed to assess the histopathologic changes that occur in postnatal human thymus slices when cultured according to protocols used for transplanted tissues. Results showed that as thymic organ cultures progressed from days 0 through 21, slices developed increasing amounts of necrosis, increasing condensation of thymic epithelium, and decreasing numbers of residual T cells. The architecture of the thymic epithelial network remained generally well-preserved throughout the 21 days of culture, with focal expression of cytokeratin 14, a putative biomarker of thymic epithelial cells with long-term organ-repopulating potential. All organ slices derived from the same donor thymus closely resembled one another, with minor differences in size, shape, and relative content of cortex versus medulla. Similarly, slices derived from different donors showed similar histopathologic characteristics when examined at the same culture time point. Taken together, these results demonstrate that diagnostic criteria based on structural features of the tissue identifiable via hematoxylin and eosin staining and cytokeratin immunohistochemistry can be used to evaluate the quality of slices transplanted into patients with congenital athymia.


Assuntos
Timo/patologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Hospedeiro Imunocomprometido , Lactente , Queratina-14/metabolismo , Técnicas de Cultura de Órgãos , Linfócitos T/citologia , Linfócitos T/patologia , Timo/metabolismo , Fatores de Tempo
16.
J Radiol Case Rep ; 14(1): 1-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32184929

RESUMO

Primary neuroendocrine tumors of the thymus are extremely rare. In this report, we describe a case of a 69 year-old man with an intermediate grade thymic neuroendocrine tumor. The radiologic and histopathologic features of thymic neuroendocrine tumors are discussed with reference to relevant literature.


Assuntos
Diagnóstico por Imagem/métodos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/patologia , Idoso , Humanos , Imagem por Ressonância Magnética , Masculino , Tumores Neuroendócrinos/cirurgia , Radiografia , Timo/diagnóstico por imagem , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/cirurgia , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
17.
Proc Natl Acad Sci U S A ; 117(10): 5420-5429, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094187

RESUMO

Chronic infection provokes alterations in inflammatory and suppressive pathways that potentially affect the function and integrity of multiple tissues, impacting both ongoing immune control and restorative immune therapies. Here we demonstrate that chronic lymphocytic choriomeningitis virus infection rapidly triggers severe thymic depletion, mediated by CD8 T cell-intrinsic type I interferon (IFN) and signal transducer and activator of transcription 2 (Stat2) signaling. Occurring temporal to T cell exhaustion, thymic cellularity reconstituted despite ongoing viral replication, with a rapid secondary thymic depletion following immune restoration by anti-programmed death-ligand 1 (PDL1) blockade. Therapeutic hematopoietic stem cell transplant (HSCT) during chronic infection generated new antiviral CD8 T cells, despite sustained virus replication in the thymus, indicating an impairment in negative selection. Consequently, low amounts of high-affinity self-reactive T cells also escaped the thymus following HSCT during chronic infection. Thus, by altering the stringency and partially impairing negative selection, the host generates new virus-specific T cells to replenish the fight against the chronic infection, but also has the potentially dangerous effect of enabling the escape of self-reactive T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Interferon Tipo I/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica , Timo/patologia , Timo/virologia , Animais , Atrofia/virologia , Antígeno B7-H1/antagonistas & inibidores , Doença Crônica , Transplante de Células-Tronco Hematopoéticas , Interferon Tipo I/genética , Coriomeningite Linfocítica/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais , Replicação Viral
18.
Lupus ; 29(3): 290-302, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32041506

RESUMO

BACKGROUND: The immune system is one of the most complex regulatory systems in the body and is essential for the maintenance of homeostasis. Despite recent breakthroughs in immunology, the regulation of the immune system and the etiology of autoimmune diseases such as lupus remain unclear. Systemic lupus erythematosus is a systemic autoimmune disease with abnormally and inconsistently expressed pro-inflammatory cytokines. Pyroptosis is a pro-inflammatory form of programmed cell death that is associated with systemic lupus erythematosus. The thymus and spleen are important immune organs involved in systemic lupus erythematosus. Therefore, this study investigated the difference in expression of pyroptosis-inducing pro-inflammatory cytokines between the spleen and thymus in lupus model mice and in control mice, to describe immune regulation at the organ level. OBJECTIVE: To investigate differences in the expression of pyroptosis-inducing cytokines in the spleen and thymus and to explore immune regulatory networks at the organ level. METHODS: Two groups of lupus mice and two groups of control mice were utilized for this study. Using the thymus and spleen of experimental animals, mRNA expression levels of five pyroptosis-inducing cytokines (interleukin 1ß, interleukin 18, NLRP3, caspase-1 and TNF-α) were determined via quantitative polymerase chain reaction. In addition, tissue distribution of these cytokines was investigated via immunohistochemistry. RESULTS: All five pyroptosis-inducing inflammatory cytokines showed higher expression in the spleen than in the thymus (p < 0.05). Moreover, the spleen/thymus expression ratios of all five pyroptosis-inducing cytokines were not statistically different between the four experimental groups. Expression of all five cytokines exhibited a stable ratio (spleen/thymus ratios). This distinctive stable spleen/thymus ratio was consistent in all four experimental groups. The stable spleen/thymus ratios of the five inflammatory cytokines were as follows: interleukin 1ß (2.02 ± 0.9), interleukin 18 (2.07 ± 1.06), caspase-1 (1.93 ± 0.66), NLRP3 (3.14 ± 1.61) and TNF-α (3.16 ± 1.36). Immunohistochemical analysis showed the cytokines were mainly expressed in the red pulp region of the spleen and the medullary region of the thymus, where immune-activated cells aggregated. CONCLUSION: The stable spleen/thymus expression ratios of pyroptosis-inducing cytokines indicated that immune organs exhibit strictly regulated functions to maintain immune homeostasis and adapt to the environment.


Assuntos
Citocinas/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Baço/metabolismo , Timo/metabolismo , Animais , Caspase 1/metabolismo , Células Cultivadas , Feminino , Imuno-Histoquímica , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , RNA Mensageiro/análise , Baço/patologia , Timo/patologia , Fator de Necrose Tumoral alfa/metabolismo
19.
PLoS One ; 15(1): e0227077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929594

RESUMO

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.


Assuntos
Modelos Animais de Doenças , Doença de Gaucher/genética , Glucosilceramidase/genética , Fenótipo , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Glucosilceramidase/metabolismo , Leucócitos/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Mutação , Neurônios/metabolismo , Neurônios/patologia , Baço/metabolismo , Baço/patologia , Timo/metabolismo , Timo/patologia
20.
Am J Forensic Med Pathol ; 41(1): 32-34, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32000220

RESUMO

Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of CD4 and CD8 lymphocytes where CD4+ cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of CD4+ lymphocytes and thymic hypotrophy in this population.


Assuntos
Usuários de Drogas , Abuso de Substâncias por Via Intravenosa , Timo/patologia , Adolescente , Adulto , Envelhecimento/patologia , Atrofia/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Calcinose/patologia , Estudos de Casos e Controles , Feminino , Patologia Legal , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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