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1.
Front Immunol ; 12: 645277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335563

RESUMO

Circulating T helper cells with a type 17-polarized phenotype (TH17) and expansion of aquaporin-4 (AQP4)-specific T cells are frequently observed in patients with neuromyelitis optica spectrum disorder (NMOSD). However, naive T cell populations, which give rise to T helper cells, and the primary site of T cell maturation, namely the thymus, have not been studied in these patients. Here, we report the alterations of naive CD4 T cell homeostasis and the changes in thymic characteristics in NMOSD patients. Flow cytometry was performed to investigate the naive CD4+ T cell subpopulations in 44 NMOSD patients and 21 healthy controls (HC). On immunological evaluation, NMOSD patients exhibited increased counts of CD31+thymic naive CD4+ T cells and CD31-cental naive CD4+ T cells along with significantly higher fraction and absolute counts of peripheral blood CD45RA+ CD62L+ naive CD4+ T cells. Chest computed tomography (CT) images of 60 NMOSD patients and 65 HCs were retrospectively reviewed to characterize the thymus in NMOSD. Thymus gland of NMOSD patients exhibited unique morphological characteristics with respect to size, shape, and density. NMOSD patients showed exacerbated age-dependent thymus involution than HC, which showed a significant association with disease duration. These findings broaden our understanding of the immunological mechanisms that drive severe disease in NMOSD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Neuromielite Óptica/imunologia , Timo/imunologia , Adulto , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologia , Estudos Retrospectivos , Timo/patologia
2.
Ann R Coll Surg Engl ; 103(7): e212-e215, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34192501

RESUMO

We present a case of a man with a background of myasthenia gravis who presented with a neck lump, which was diagnosed as thyrolipomatosis in continuity with a very large thymolipoma. Following removal of these lesions, the patient's myaesthenic symptoms improved. While thymolipomas are often seen in the context of myasthenia gravis, thyrolipomatosis is a rare entity and to our knowledge the concurrent finding of both lesions with myasthenia gravis has never been reported. We highlight the important imaging features of both entities and the clinical importance of recognising them.


Assuntos
Lipoma/cirurgia , Lipomatose/cirurgia , Miastenia Gravis/terapia , Neoplasias do Timo/cirurgia , Doenças da Glândula Tireoide/cirurgia , Adulto , Humanos , Lipoma/diagnóstico , Lipoma/patologia , Lipomatose/diagnóstico , Lipomatose/patologia , Masculino , Miastenia Gravis/etiologia , Prednisolona/uso terapêutico , Brometo de Piridostigmina/uso terapêutico , Timectomia , Timo/diagnóstico por imagem , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/patologia , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/patologia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Tireoidectomia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Front Immunol ; 12: 669893, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140950

RESUMO

Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased ß-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.


Assuntos
Proliferação de Células , Senescência Celular , Síndrome de Down/metabolismo , Células Epiteliais/metabolismo , Imunossenescência , Estresse Oxidativo , Timócitos/metabolismo , Timo/metabolismo , Fatores Etários , Estudos de Casos e Controles , Proliferação de Células/genética , Senescência Celular/genética , Criança , Pré-Escolar , Síndrome de Down/genética , Síndrome de Down/imunologia , Síndrome de Down/patologia , Epigênese Genética , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunossenescência/genética , Lactente , Masculino , Estresse Oxidativo/genética , Timócitos/imunologia , Timócitos/patologia , Timo/imunologia , Timo/patologia , Transcriptoma
4.
J Occup Health ; 63(1): e12235, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34089209

RESUMO

OBJECTIVE: To evaluate the immunotoxicity and effects of noise and/or low-concentration carbon monoxide (CO) exposure on immune organs and immune functions in rats. METHODS: Male Wistar rats exposed to 98 dB(A) white noise and/or 100 ppm CO 4 h/d for 30 d were used to determine the pathological changes in the thymus and spleen, and variations in leukocyte counts, inflammatory factors, and immunoglobulin (Ig) concentrations. RESULTS: The boundaries of the cortex and medulla of the thymus were unclear following noise and combined exposure. The pathological changes in spleen after CO and combined exposure included blurred boundaries of red-pulp and white-pulp, disappearance of normal splenic nodules and neutrophil infiltration. After exposure to noise and in combination, leukocyte and lymphocyte counts decreased significantly. After exposure to low-concentration CO and in combination, serum IgM and IgG levels decreased significantly, but the levels of tumor necrosis factor-α and interferon-γ levels increased significantly. Eosinophils and IgA levels decreased significantly following exposure to noise and/or low concentration of CO, while the level of interleukin-1 increased significantly. Monocytes increased significantly only under noise or CO exposure, but not under combined exposure. CONCLUSIONS: Noise and/or low-concentration CO exposure may suppress innate and adaptive immune functions and induce inflammatory responses. Noise exposure mainly affected the innate immune function of rats, whereas low-concentration CO exposure mainly affected adaptive immune functions. Combined exposure presented higher immunotoxicity than noise or CO alone, suggesting that exposure to noise and low-concentration CO in the living and working environments can affect the immune system.


Assuntos
Monóxido de Carbono/toxicidade , Exposição Ambiental/efeitos adversos , Imunidade , Imunotoxinas/toxicidade , Ruído/efeitos adversos , Imunidade Adaptativa , Animais , Imunidade Inata , Imunoglobulinas/sangue , Mediadores da Inflamação/sangue , Contagem de Leucócitos , Masculino , Ratos , Ratos Wistar , Baço/patologia , Timo/patologia
5.
Front Immunol ; 12: 652538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113341

RESUMO

The thymus is a vital organ of the immune system that plays an essential role in thymocyte development and maturation. Thymic atrophy occurs with age (physiological thymic atrophy) or as a result of viral, bacterial, parasitic or fungal infection (pathological thymic atrophy). Thymic atrophy directly results in loss of thymocytes and/or destruction of the thymic architecture, and indirectly leads to a decrease in naïve T cells and limited T cell receptor diversity. Thus, it is important to recognize the causes and mechanisms that induce thymic atrophy. In this review, we highlight current progress in infection-associated pathogenic thymic atrophy and discuss its possible mechanisms. In addition, we discuss whether extracellular vesicles/exosomes could be potential carriers of pathogenic substances to the thymus, and potential drugs for the treatment of thymic atrophy. Having acknowledged that most current research is limited to serological aspects, we look forward to the possibility of extending future work regarding the impact of neural modulation on thymic atrophy.


Assuntos
Doenças Transmissíveis/complicações , Doenças Linfáticas/etiologia , Doenças Linfáticas/patologia , Timo/patologia , Animais , Atrofia , Doenças Transmissíveis/etiologia , Interações Hospedeiro-Parasita , Interações Hospedeiro-Patógeno , Humanos
6.
Histochem Cell Biol ; 156(2): 133-146, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33993340

RESUMO

Immunosuppressive drugs such as cyclosporine A (CSA) can disrupt thymic structure and functions, ultimately inducing syngeneic/autologous graft-versus-host disease together with involuted medullas. To elucidate the effects of CSA on the thymus more precisely, we analyzed the effects of CSA on the thymus and T cell system using rats. In addition to confirming the phenomena already reported, we newly found that the proportion of recent thymic emigrants also greatly decreased, suggesting impaired supply. Immunohistologically, the medullary thymic epithelial cells (mTECs) presented with a relative decrease in the subset with a competent phenotype and downregulation of class II major histocompatibility complex molecules. In control rats, thymic dendritic cells (DCs) comprised two subsets, XCR1+SIRP1α-CD4- and XCR1-SIRP1α+CD4+. The former had a tendency to selectively localize in the previously-reported epithelium-containing areas of the rat medullas, and the number was significantly reduced by CSA treatment. The epithelium-free areas, another unique domains in the rat medullas, contained significantly more Foxp3+ thymic Tregs. With CSA treatment, the epithelium-free areas presented strong involution, and the number and distribution of Tregs in the medulla were greatly reduced. These results suggest that CSA inhibits the production of single-positive thymocytes, including Tregs, and disturbs the microenvironment of the thymic medulla, with a decrease of the competent mTECs and disorganization of epithelium-free areas and DC subsets, leading to a generation of autoreactive T cells with selective medullary involution.


Assuntos
Ciclosporina/farmacologia , Células Epiteliais/efeitos dos fármacos , Fatores de Transcrição Forkhead/análise , Imunossupressores/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Ciclosporina/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Células Epiteliais/patologia , Fatores de Transcrição Forkhead/metabolismo , Imuno-Histoquímica , Imunossupressores/administração & dosagem , Injeções Subcutâneas , Masculino , Imagem Óptica , Ratos , Ratos Endogâmicos Lew , Receptores de Quimiocinas/análise , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/patologia , Timócitos/efeitos dos fármacos , Timócitos/patologia , Timo/patologia
7.
Front Immunol ; 12: 640595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936055

RESUMO

Treating premature infants with high oxygen is a routine intervention in the context of neonatal intensive care. Unfortunately, the increase in survival rates is associated with various detrimental sequalae of hyperoxia exposure, most notably bronchopulmonary dysplasia (BPD), a disease of disrupted lung development. The effects of high oxygen exposure on other developing organs of the infant, as well as the possible impact such disrupted development may have on later life remain poorly understood. Using a neonatal mouse model to investigate the effects of hyperoxia on the immature immune system we observed a dramatic involution of the thymic medulla, and this lesion was associated with disrupted FoxP3+ regulatory T cell generation and T cell autoreactivity. Significantly, administration of mesenchymal stromal cell-derived extracellular vesicles (MEx) restored thymic medullary architecture and physiological thymocyte profiles. Using single cell transcriptomics, we further demonstrated preferential impact of MEx treatment on the thymic medullary antigen presentation axis, as evidenced by enrichment of antigen presentation and antioxidative-stress related genes in dendritic cells (DCs) and medullary epithelial cells (mTECs). Our study demonstrates that MEx treatment represents a promising restorative therapeutic approach for oxygen-induced thymic injury, thus promoting normal development of both central tolerance and adaptive immunity.


Assuntos
Vesículas Extracelulares/transplante , Hiperóxia/complicações , Células-Tronco Mesenquimais/metabolismo , Linfócitos T , Timo , Animais , Animais Recém-Nascidos , Vesículas Extracelulares/metabolismo , Xenoenxertos , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/patologia , Timo/imunologia , Timo/patologia , Cordão Umbilical
8.
J Toxicol Sci ; 46(5): 223-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952799

RESUMO

Sodium carboxy methyl cellulose (SCMC) is an important absorbable biomaterial for anti-adhesion and hemostasis medical devices used in the abdominal cavity. However, the systemic toxicity of SCMC following intraperitoneal route has not been revealed sufficiently. Three SCMC solutions with gradient concentrations were intraperitoneally injected into 3 groups of rats with the doses of 50 mg/kg, 320 mg/kg and 2000 mg/kg respectively all at once to observe the dose-dependence of systemic reactions of SCMC and 10 rats (5 rats per sex) of each group were sacrificed 3 days, 7 days, 28 days and 90 days after injection to evaluate the time-dependence of the reactions. A range of adverse effects were shown in rats of the high-dose group which were found varied with time extending and virtually disappeared 90 days after injection. Slight reactions were observed in the medium-dose group while negligible effects were found in the low-dose group. The intraperitoneal application of SCMC can induce reversible systemic adverse effects to rats at the dose higher than 320 mg/kg and it is essential to take both dose- and time-dependent effects into account while designing a systemic toxicity study for absorbable biomaterials.


Assuntos
Carboximetilcelulose Sódica/toxicidade , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia , Útero/efeitos dos fármacos , Útero/patologia
9.
Eur J Cardiothorac Surg ; 60(4): 881-887, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34023891

RESUMO

OBJECTIVES: Resection of thymic tumours including the removal of both the tumour and the thymus gland (thymothymectomy; TT) is the procedure of choice and is recommended in most relevant articles in the literature. Nevertheless, in recent years, some authors have suggested that resection of the tumour (simple thymomectomy; ST) may suffice from an oncological standpoint in patients with early-stage thymoma who do not have myasthenia gravis (MG) (non-MG). The goal of our study was to compare the short- and long-term outcomes of ST versus TT in non-MG early-stage thymomas using the European Society of Thoracic Surgeons thymic database. METHODS: A total of 498 non-MG patients with pathological stage I thymoma were included in the study. TT was performed in 466 (93.6%) of 498 patients who had surgery with curative intent; ST was done in 32 (6.4%). The completeness of resection, the rate of complications, the 30-day mortality, the overall recurrence and the freedom from recurrence were compared. We performed crude and propensity score-adjusted comparisons by surgical approach (ST vs TT). RESULTS: TT showed the same rate of postoperative complications, 30-day mortality and postoperative length of stay as ST. The 5-year overall survival rate was 89% in the TT group and 55% in the ST group. The 5-year freedom from recurrence was 96% in the TT group and 79% in the ST group. CONCLUSION: Patients with early-stage thymoma without MG who have a TT show significantly better freedom from recurrence than those who have an ST, without an increase in postoperative morbidity rate.


Assuntos
Miastenia Gravis , Cirurgiões , Timoma , Neoplasias do Timo , Humanos , Miastenia Gravis/epidemiologia , Miastenia Gravis/patologia , Miastenia Gravis/cirurgia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Timectomia/efeitos adversos , Timoma/patologia , Timoma/cirurgia , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/patologia , Neoplasias do Timo/cirurgia
10.
Diabetes ; 70(8): 1729-1737, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34035042

RESUMO

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen specificity of Treg plays an important role in their in vivo activity. We therefore assessed the diversity of the T-cell receptors (TCRs) for antigen expressed by Treg newly developed in the thymus of autoimmune type 1 diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that use of the TCRα and TCRß variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRα and TCRß chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type 1 diabetes in the NOD mouse.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Reguladores/patologia , Timo/patologia , Animais , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Timo/imunologia
11.
Front Immunol ; 12: 655354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815417

RESUMO

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.


Assuntos
Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/metabolismo , Células Estromais/metabolismo , Timo/anormalidades , Timo/metabolismo , Alelos , Animais , Terapia Combinada , Suscetibilidade a Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Fenótipo , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/terapia , Células Estromais/patologia , Timo/patologia , Resultado do Tratamento
12.
FASEB J ; 35(5): e21535, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33817835

RESUMO

Thymic epithelial cells (TECs) are indispensable for T cell development, T cell receptor (TCR) repertoire selection, and specific lineage differentiation. Medullary thymic epithelial cells (mTECs), which account for the majority of TECs in adults, are critical for thymocyte selection and self-tolerance. CD74 is a nonpolymorphic transmembrane glycoprotein of major histocompatibility complex class II (MHCII) that is expressed in TECs. However, the exact role of CD74 in regulating the development of mTEC is poorly defined. In this research, we found that loss of CD74 resulted in a significant diminution in the medulla, a selective reduction in the cell number of mature mTECs expressing CD80 molecules, which eventually led to impaired thymic CD4+ T cell development. Moreover, RNA-sequence analysis showed that CD74 deficiency obviously downregulated the canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in mTECs. Our results suggest that CD74 positively controls mTEC cellularity and maturation partially by activating the canonical NF-κB signaling pathway.


Assuntos
Antígenos de Diferenciação de Linfócitos B/fisiologia , Diferenciação Celular , Células Epiteliais/patologia , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/fisiologia , Ativação Linfocitária/imunologia , NF-kappa B/metabolismo , Timo/patologia , Animais , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Transdução de Sinais , Timo/imunologia , Timo/metabolismo
13.
Nat Commun ; 12(1): 2099, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833239

RESUMO

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-ß and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.


Assuntos
Tolerância Imunológica/imunologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Distrofia Muscular Animal/patologia , Timo/patologia , Animais , Autofagia/fisiologia , Grelina/biossíntese , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Nus , Distrofia Muscular de Duchenne/patologia , Linfócitos T/transplante , Linfócitos T Reguladores/imunologia , Timo/transplante , Fatores de Transcrição/biossíntese
14.
Oncol Rep ; 45(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33907842

RESUMO

Due to the lack of specific symptoms in early thymic epithelial tumours (TETs), patients are mostly in the advanced stage at the time of presentation. The aim of the present study was to explore the mechanism by which the long noncoding RNA (lncRNA) LOXL1­AS1 affects thymoma and thymic carcinoma progression by targeting the miR­525­5p­HSPA9 axis. Bioinformatics was used to analyse the process of LOXL1­AS1 targeting miR­525­5p­HSPA9 and its expression characteristics in TET. The relationships between LOXL1­AS1, miR­525­5p, HSPA9 and prognosis were analysed. The dual luciferase reporter assay was applied to verify targeting. The gene was knocked down or overexpressed by plasmid transfection. Cell counting kit 8 (CCK­8) assay, flow cytometry and Transwell assay were used to detect cell viability, apoptosis and invasion ability, respectively. Proteins and RNAs were examined by western blot analysis and qPCR, respectively. A tumour­burdened assay was used to perform in vivo verification. LOXL1­AS1 and HSPA9 were overexpressed in thymoma and thymic carcinoma; high levels of LOXL1­AS1 and HSPA9 were associated with poor prognosis, and there was a significant positive correlation between their levels. Downregulation of miR­525­5p expression was also associated with poor prognosis of patients. Clinical trials also demonstrated the same trends. miR­525­5p inhibited the expression of HSPA9 protein by targeting the 3'­untranslated region (UTR) of HSPA9 mRNA. LOXL1­AS1 promoted the expression of HSPA9 as a sponge targeting miR­525­5p. Animal experiment results also showed that knockdown of miR­525­5p promoted cancer by promoting the expression of HSPA9. In conclusion, LOXL1­AS1 and HSPA9 are highly expressed in thymoma and thymic carcinoma; miR­525­5p is expressed at low levels in thymoma and thymic carcinoma; and downregulation of miR­525­5p is associated with poor prognosis. In summary, this study demonstrates that LOXL1­AS1 acts as a sponge that targets miR­525­5p to promote HSPA9 expression, thereby promoting the growth and invasion and inhibiting apoptosis of thymoma and thymic carcinoma cells.


Assuntos
Proteínas de Choque Térmico HSP70/genética , MicroRNAs/metabolismo , Proteínas Mitocondriais/genética , RNA Longo não Codificante/metabolismo , Timoma/genética , Neoplasias do Timo/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , MicroRNAs/genética , Invasividade Neoplásica/genética , Prognóstico , Taxa de Sobrevida , Timectomia , Timoma/diagnóstico , Timoma/mortalidade , Timoma/cirurgia , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/mortalidade , Neoplasias do Timo/cirurgia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Front Immunol ; 12: 636072, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746975

RESUMO

The thymus is the primary site of T lymphocyte development, where mutually inductive signaling between lymphoid progenitors and thymic stromal cells directs the progenitors along a well-characterized program of differentiation. Although thymic stromal cells, including thymic epithelial cells (TECs) are critical for the development of T cell-mediated immunity, many aspects of their basic biology have been difficult to resolve because they represent a small fraction of thymus cellularity, and because their isolation requires enzymatic digestion that induces broad physiological changes. These obstacles are especially relevant to the study of metabolic regulation of cell function, since isolation procedures necessarily disrupt metabolic homeostasis. In contrast to the well-characterized relationships between metabolism and intracellular signaling in T cell function during an immune response, metabolic regulation of thymic stromal cell function represents an emerging area of study. Here, we review recent advances in three distinct, but interconnected areas: regulation of mTOR signaling, reactive oxygen species (ROS), and autophagy, with respect to their roles in the establishment and maintenance of the thymic stromal microenvironment.


Assuntos
Metabolismo Energético , Células Epiteliais/metabolismo , Timo/metabolismo , Animais , Autofagia , Microambiente Celular , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Estresse Oxidativo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Timo/imunologia , Timo/patologia
16.
BMC Cancer ; 21(1): 279, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726691

RESUMO

BACKGROUND: Thymic tumors are unusual neoplasms, representing 0.2 to 1.5% of tumors in humans, but correspond to 20% of mediastinal tumors and 50% of those that occur in the anterior mediastinum. They tend to appear around the fourth and fifth decades of life without gender predilection. Up to 30% of patients are asymptomatic, therefore many are incidentally diagnosed. Radical thymectomy is the treatment of choice with high survival rates when detected in the early stages. METHODS: This was a retrospective descriptive study, including 18 adult patients' diagnosis of thymic neoplasm, who were managed with surgical resection from 2011 to 2019. Information about demographics, clinical characteristics, imaging findings, surgical and medical management, plus histological findings was obtained and reported. RESULTS: 18 patients with thymic tumors were included, of which specific histologic studies reveled thymomas, carcinomas, neuroendocrine tumors, thymolipoma and thymic cyst. Mean age was 52.7 years, with a predominance of male population. The main symptom was dyspnea, followed by cough and chest pain. Paraneoplastic syndromes such as myasthenia gravis, aplastic anemia and Cushing syndrome were reported. 89% of cases were treated by radical thymectomy alone, while only 2 cases required chemotherapy and radiotherapy. There were no surgical complications. Mean hospital stay length was 11. 9 days, with only 1 mortality during hospital admission. 5-year survival rate was 81%. CONCLUSIONS: The treatment of choice is radical thymectomy, which has been shown to positively impact patient mortality. Early detection is key to improve patient outcomes.


Assuntos
Síndromes Paraneoplásicas/epidemiologia , Timectomia , Timo/patologia , Neoplasias do Timo/cirurgia , Idoso , Carcinoma/complicações , Carcinoma/diagnóstico , Carcinoma/mortalidade , Carcinoma/cirurgia , Colômbia/epidemiologia , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Lipoma/complicações , Lipoma/diagnóstico , Lipoma/mortalidade , Lipoma/cirurgia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Síndromes Paraneoplásicas/etiologia , Estudos Retrospectivos , Taxa de Sobrevida , Timoma/complicações , Timoma/diagnóstico , Timoma/mortalidade , Timoma/cirurgia , Timo/diagnóstico por imagem , Timo/cirurgia , Neoplasias do Timo/complicações , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/mortalidade
17.
Immunology ; 163(4): 478-492, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33786850

RESUMO

Age-related thymic atrophy results in reduced output of naïve conventional T (Tcon) cells. However, its impact on regulatory T (Treg) cells is insufficiently understood. Given evidence that thymic Treg (tTreg) cell generation is enhanced in the aged, atrophy thymus and that the aged periphery accumulates peripheral Treg (pTreg) cells, we asked why these Treg cells are unable to effectively attenuate increased autoreactivity-induced chronic inflammation in the elderly. We designed a mock-self-antigen chimera mouse model, in which membrane-bound ovalbumin (mOVA) transgenic mice, bearing a FoxN1-floxed gene for induction of conditional thymic atrophy, received OVA-specific (OT-II) T-cell receptor (TCR) transgenic progenitor cells. The chimeric mice with thymic atrophy exhibited a significant decrease in OVA-specific tTreg and pTreg cells but not polyclonal (pan)-Treg cells. These OVA-specific pTreg cells were significantly less able to suppress OVA-specific stimulation-induced proliferation in vitro and exhibited lower FoxP3 expression. Additionally, we conducted preliminary TCR repertoire diversity sequencing for Treg cells among recent thymic emigrants (RTEs) from RagGFP -FoxP3RFP dual-reporter mice and observed a trend for decreased diversity in mice with thymic atrophy compared to littermates with normal thymus. These data indicate that although the effects of age-related thymic atrophy do not affect pan-Treg generation, certain tissue-specific Treg clones may experience abnormal agonist selection. This, combined with enhanced pan-pTreg cells, may greatly contribute to age-related chronic inflammation, even in the absence of acute autoimmune disease in the elderly.


Assuntos
Envelhecimento/fisiologia , Doenças Autoimunes/imunologia , Inflamação/imunologia , Linfócitos T Reguladores/imunologia , Timo/patologia , Idoso , Animais , Atrofia , Autoantígenos/imunologia , Seleção Clonal Mediada por Antígeno , Células Clonais , Humanos , Imunomodulação , Camundongos , Camundongos Transgênicos , Ovalbumina/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Quimeras de Transplante
18.
Vet Microbiol ; 255: 109033, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33711568

RESUMO

Tembusu Virus (TMUV), a pathogenic member of Flavivirus family, acts as the causative agent of egg-laying and has severely threatened the duck industry over the past few years. Thus far, the pathogenicity of such virus has been extensively studied, whereas TMUV on immune system has been less comprehensively assessed, especially on ducklings that exhibit more susceptible to TMUV attack. Accordingly, in the present study, 5-day-old ducklings were infected with TMUV-TC2B (104 TCID50) via intravenous injection, and mock ones were inoculated with phosphate-buffered saline (PBS) in identical manner as control. At 1 day-post inoculation (dpi), the innate immunity was strongly activated, and reacted rapidly to TMUV invasion, which was reflected as the significantly up-regulated IFN-stimulated genes (ISGs), especially in immune organs (e.g., thymus, bursa of Fabricius (BF) and spleen). Subsequently, under the continuous monitoring, the levels of IgA, IgM and IgG acting as the representative immunoglobulins (Igs) were constantly higher than those of mock ducklings, demonstrating that humoral immunity also played a major role in anti-virus infection. Despite the immune system activated positively, TMUV still caused systemic infection, and in particular, the immune organs were subject to severe damage in the early infection. With our constant observation, the injury of spleen and BF turned out to be getting more serious, and at 6 dpi, TMUV antigen was widely detected in both of two immune organs by immunohistochemistry (IHC) and main histopathological lesion presented as lymphocytopenia. Moreover, the elevated apoptosis rate of splenic lymphocytes and the alteration of immune organ index also revealed the damage of lymphoid organs and similarly, it is worth noting that severe damages were detected in thymus of TMUV-infected ducklings as well. In brief, the present study systematically described the dynamic damage of immune system after being attacked by TMUV and presented insights into the research of pathogenicity.


Assuntos
Imunidade Adaptativa , Bolsa de Fabricius/patologia , Infecções por Flavivirus/veterinária , Flavivirus , Baço/patologia , Timo/patologia , Animais , Peso Corporal , Encéfalo/patologia , Bolsa de Fabricius/virologia , Patos , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/patologia , Infecções por Flavivirus/virologia , Imunoglobulinas/sangue , Interferons/metabolismo , Rim/patologia , Fígado/patologia , Pulmão/patologia , Miocárdio/patologia , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia , Baço/virologia , Timo/imunologia
19.
J Perinat Med ; 49(5): 604-613, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-33561911

RESUMO

OBJECTIVES: The aim of this study was to investigate the correlation between fetal thymus size measured during first-trimester screening and chromosomal anomalies. METHODS: This study is a retrospective evaluation, in which the anterior-posterior diameter of the thymus in a midsagittal plane was measured in first-trimester ultrasound between 11+0 and 13+6 weeks of gestation in 168 fetuses with chromosomal anomalies (study group) and 593 healthy fetuses (control group). The included cases were subdivided into six groups: (1) trisomy 21, (2) trisomy 18, (3) trisomy 13, (4) Turner syndrome, (5) triploidy and (6) normal controls. Thymus size measurements were adjusted to the week of gestation, which was determined by ultrasound using crown-rump-length (CRL), by calculating a ratio between CRL and thymus size (CRL-thymus-ratio). Each study group was compared with the control group separately. RESULTS: Thymus size in fetuses affected by trisomy 18 or trisomy 13 was noticeably smaller compared to the control group (1.4 mm [1.3, 1.5] and 1.3 mm [1.2, 1.4] vs. 1.8 mm [1.6, 2.1]; all p<0.001; respectively). The thymus size of fetuses with trisomy 21 and Turner syndrome did not differ from healthy fetuses. Between the CRL-thymus-ratios of the separate study groups no statistically noticeable differences could be found. CONCLUSIONS: Fetal thymus size appeared to be smaller in pregnancies affected by trisomy 18 and trisomy 13. The predictive value of fetal thymus size in first-trimester screening should be evaluated prospectively.


Assuntos
Transtornos Cromossômicos , Feto/diagnóstico por imagem , Diagnóstico Pré-Natal , Timo , Ultrassonografia Pré-Natal , Adulto , Transtornos Cromossômicos/classificação , Transtornos Cromossômicos/diagnóstico , Feminino , Humanos , Masculino , Tamanho do Órgão , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricos , Reprodutibilidade dos Testes , Timo/diagnóstico por imagem , Timo/patologia , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Ultrassonografia Pré-Natal/métodos , Ultrassonografia Pré-Natal/estatística & dados numéricos
20.
Eur J Immunol ; 51(5): 1166-1181, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33638148

RESUMO

Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.


Assuntos
Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Timo/patologia , Animais , Atrofia , Biomarcadores , Sobrevivência Celular/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Infecções por Orthomyxoviridae/virologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
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