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1.
Medicine (Baltimore) ; 98(50): e18300, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852109

RESUMO

RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD. PATIENT CONCERNS: A 56-year-old Japanese man who exhibited painless swelling in the left parotid region. DIAGNOSES: Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels. INTERVENTIONS: The patient underwent corticosteroid therapy and had been followed for 2 years. OUTCOMES: We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches. LESSONS: The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.


Assuntos
Hiperplasia Angiolinfoide com Eosinofilia/imunologia , Linfócitos B/imunologia , Eosinófilos/imunologia , Imunoglobulina E/sangue , Mastócitos/imunologia , Hiperplasia Angiolinfoide com Eosinofilia/sangue , Hiperplasia Angiolinfoide com Eosinofilia/diagnóstico , Linfócitos B/patologia , Biópsia , Eosinófilos/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade
2.
Medicine (Baltimore) ; 98(39): e17311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574860

RESUMO

Immune infiltration of nasopharyngeal carcinoma (NPC) is closely associated with the patients' prognosis. However, previous studies have not interpreted the difference of infiltrating immune cells in NPC.We comprehensively analyzed the tumor-infiltrating immune cells present in NPC for the first time, which was based on a scientific deconvolution algorithm (CIBERSORT) and the gene expression data of GSE64634. The fractions of 22 immune cells were assessed to reveal the associations between normal samples and NPC samples.Profiles of immune infiltration vary significantly between normal samples and NPC samples, and the variation could characterize the individual differences. NPC samples contained a higher proportion for M1 macrophages, whereas memory B cells and CD4 memory resting T cells were relatively lower.Our data suggest that the differences in the infiltrating immune cells in NPC and these differences would probably facilitate patient consultation and individualized treatment.


Assuntos
Linfócitos do Interstício Tumoral , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Algoritmos , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , China , Correlação de Dados , Feminino , Expressão Gênica , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Prognóstico , Reprodutibilidade dos Testes
3.
Cancer Immunol Immunother ; 68(12): 1921-1934, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637475

RESUMO

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Fezes/microbiologia , Células Matadoras Naturais/imunologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Bacteroides , Humanos , Masculino , Microbiota , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Ribossômico 16S/análise
4.
J Biol Regul Homeost Agents ; 33(5): 1437-1449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637902

RESUMO

Influenza has frequently been epidemic in recent years. However, the mechanisms of severe pneumonia with postinfluenza Streptococcus pneumoniae (SP) secondary infection have not been fully understood. In this study, we explored the mechanisms of pneumonia in postinfluenza A virus (IAV) infection via a mouse model. Mice were intranasally inoculated with SP three days after IAV inoculation. We then collected samples at three time points to dynamically observe the pathological progression. In IAV infection alone, lymphocyte infiltration and widened alveolar intervals were observed. In the blood, levels of the CD19+, CD19+CD21+ and CD19+CD79ß+B lymphocyte subpopulations were reduced, and IFN-γ and IL-10 were elevated. Slight atrophy was seen in the spleen, which was due to splenic B lymphocyteinitiated apoptosis through the mitochondrial pathway. When SP infection occurred after IAV infection, the pulmonary inflammation was significantly aggravated; a fair number of lymphocytes and neutrophils infiltrated simultaneously with exfoliated bronchial epithelial cells, vascular endothelial cells, widened alveolar septum and hemorrhaging. Increasing edema fluid and bacteria accumulated in the alveolar cavity. Decreased CD19+, CD19+CD21+ and CD19+CD79ß+B lymphocyte subpopulations and increased interferon gamma (IFN-γ) or interleukin 10 (IL-10) were more prominent compared to those with viral infection alone. Spleen atrophy resulting from coinfection was more obvious because of massive splenic B lymphocyte apoptosis through the mitochondrial pathway compared to viral infection alone. This study shows that although inflammation caused by SP infection alone was temporary, preceding IAV infection provided favorable conditions for SP colonization and multiplication by destroying lung structure and suppressing humoral immunity. Synergistic IAV-SP coinfection is likely to facilitate more SP colonization and promote B lymphocyte-suppression and reduction. Eventually, the pneumonia worsened.


Assuntos
Linfócitos B/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Pneumocócicas/imunologia , Pneumonia Bacteriana/imunologia , Animais , Apoptose , Linfócitos B/citologia , Coinfecção/microbiologia , Coinfecção/virologia , Células Endoteliais , Vírus da Influenza A , Pulmão , Camundongos , Infecções por Orthomyxoviridae/microbiologia , Infecções Pneumocócicas/virologia , Streptococcus pneumoniae
5.
Cancer Sci ; 110(10): 3038-3048, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385405

RESUMO

Retroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas and lacks effective treatment. This study aimed to provide a thorough profile of immune characteristics of RLPS. This study included 56 RLPS patients. Multisite tumor tissues were collected from 16 patients. Immunohistochemistry was carried out to identify CD4+ , CD8+ , FoxP3+ , CD20+ , or programmed cell death-1 (PD-1)+ tumor infiltrating lymphocytes (TILs) and  Programmed cell death ligand-1 (PD-L1) expression in tumor tissues. Ultradeep sequencing of T-cell receptor (TCR) ß-chain gene was carried out in 42 tumor samples as well as peripheral blood samples collected from 6 patients. In RLPS, TILs were distributed in 3 patterns and T cells were more prevalent than B cells. Generally, the proportion of TILs decreased and PD-L1 expression increased with tumor progression. Patients with higher PD-1/PD-L1 expression tended to have poorer prognosis, whereas patients with tertiary lymphoid structure tended to have a favorable disease-free survival. Although T-cell clones in tumors were quite different from those in peripheral blood, TCR sequencing showed low TCR repertoire reads as well as polyclonal status within tumors, which indicated limited T cell response in the tumors. Both TILs distribution and TCR repertoires suggested spatial immune heterogeneity in RLPS. Our research described the immune landscape of RLPS, and suggested RLPS might be a kind of tumor with low T cell infiltration as well as great immune heterogeneity. Therefore, strategies that can facilitate lymphocytic infiltration and immune reactivity need to be developed in the future to improve the efficacy of immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Lipossarcoma/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Neoplasias Retroperitoneais/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lipossarcoma/genética , Lipossarcoma/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/mortalidade , Análise de Sequência de DNA , Linfócitos T/imunologia , Regulação para Cima
6.
Clin Exp Rheumatol ; 37 Suppl 118(3): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464681

RESUMO

Despite the well-established role of B cells in the pathogenesis of primary Sjögren's syndrome (pSS), the beneficial role of B-cell depletion therapy with rituximab remains elusive in this condition, contrary to other autoimmune diseases. Although early, small-scale studies showed promising results, two recent large randomised controlled trials did not meet their primary end-points. It is evident from most trials that rituximab has a positive impact on B-cell numbers and activity, both in the peripheral blood and in salivary glands, but clinical outcomes vary among studies. We review here the evidence to date of B-cell depletion in pSS, analysing the underlying causes for the discrepancies in different studies and their limitations. We also discuss the potential use of peripheral and salivary gland biomarkers for patient stratification and targeted patient selection. Overall, rituximab remains a plausible treatment for pSS provided future studies address the shortfalls that emerged from our current knowledge of the use of B-cell depletion in this condition.


Assuntos
Linfócitos B , Rituximab/uso terapêutico , Síndrome de Sjogren , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Humanos , Depleção Linfocítica , Glândulas Salivares , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
7.
Vet Immunol Immunopathol ; 215: 109913, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420069

RESUMO

The development of a rapid and efficient system to generate porcine monoclonal antibodies (mAbs) is an important step toward the discovery of critical neutralizing targets for designing rational vaccines against porcine viruses. In this study, we established a platform for producing porcine mAbs based on single cell technologies. First, we singled out an optimal donor from 507 pigs based on serum antibody neutralizing activity against porcine reproductive and respiratory syndrome virus (PRRSV). After identifying the contribution of IgG to the neutralizing activity, single CD45R+IgG+Ag+ B cells were sorted from peripheral blood mononuclear cells (PBMCs). Single B cell RT-PCR was performed using primers designed to cover the germline repertoire of the porcine VH/VL gene segments. Paired VH/VLs were cloned into a eukaryotic expression vector and transfected into 293T cells. We demonstrate that full-length porcine mAbs were produced, and antigen-specific mAbs were obtained after further validation. The approach reported in this study can be applied to generate porcine mAbs against any given antigen and may help with the screening of neutralizing antibodies against porcine pathogens.


Assuntos
Anticorpos Monoclonais/biossíntese , Anticorpos Antivirais/biossíntese , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Suínos/imunologia , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Especificidade de Anticorpos , Linfócitos B/imunologia , Células HEK293 , Humanos , Região Variável de Imunoglobulina/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Transfecção , Recombinação V(D)J
8.
Life Sci ; 231: 116688, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348950

RESUMO

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Infecções por Helicobacter/terapia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocinas CXC/imunologia , Quimiocinas CXC/metabolismo , Mucosa Gástrica/metabolismo , Gastrite , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Receptores CXCR/imunologia , Receptores CXCR/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Estômago/patologia , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Medicine (Baltimore) ; 98(29): e16390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335688

RESUMO

INTRODUCTION: Sjögren's syndrome (SS) often causes lymphoproliferative disorders such as malignant lymphoma and macroglobrinemia. Approximately 5% of long-term follow-up SS patients develop malignant lymphoma. Recently, the tumor necrosis factor receptor superfamily cluster of differentiation 30 (CD30) has been thought to be implicated in malignant cells in organs affected by Hodgikin lymphoma or in a prognostic marker of diffuse large B cell lymphoma. In this study, we investigated CD30 expression in lacrimal gland and conjunctiva in patients with SS. METHODS: We examined lacrimal gland and conjunctival tissues for the diagnosis from 3 female SS patients with a median age of 51 and 3 female chronic graft-versus-host disease (cGVHD) patients with a median age of 41. Histological analysis of these tissues of the remaining samples was conducted by methods including immunohistochemistry and electron microscopy (#20090277). We analyzed the expression and localization of cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), cluster of differentiation 20 (CD20), CD30, and Interferon-γ in tissue sections prepared from lacrimal glands and conjunctiva in 3 each of SS and cGVHD patients. RESULTS: There were more B cells and plasma cells in lobules of SS-affected lacrimal glands than in those of their cGVHD-affected counterparts. Interferon-γ was expressed on endothelia of capillaries in SS-affected lacrimal gland and conjunctival tissues whereas it was expressed on fibroblasts in their GVHD-affected equivalents. Furthermore, lacrimal glands and conjunctiva disordered by SS had a greater number of CD30 cells than those disordered by cGVHD. CONCLUSION: Our results suggest that CD30 cells are increased in lacrimal glands and conjunctiva affected by SS and that a subset of SS patients are thereby at risk of development malignant lymphoma.


Assuntos
Túnica Conjuntiva , Doença Enxerto-Hospedeiro , Antígeno Ki-1 , Aparelho Lacrimal , Linfoma/diagnóstico , Síndrome de Sjogren , Adulto , Linfócitos B/imunologia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Imuno-Histoquímica , Interferon gama/sangue , Antígeno Ki-1/análise , Antígeno Ki-1/imunologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Plasmócitos/imunologia , Prognóstico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia
10.
Scand J Immunol ; 90(5): e12809, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322747

RESUMO

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome de DiGeorge/imunologia , Imunoglobulina M/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Lactente , Contagem de Linfócitos , Masculino
11.
Nat Commun ; 10(1): 2935, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270335

RESUMO

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Histonas/química , Histonas/imunologia , Imunidade Humoral , Lisina/imunologia , Animais , Linfócitos B/química , Linfócitos B/citologia , Ciclo Celular , Células Cultivadas , Ciclina E/genética , Ciclina E/imunologia , Desmetilação , Proteínas F-Box/genética , Proteínas F-Box/imunologia , Histonas/genética , Ferro/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/imunologia , Ativação Linfocitária , Lisina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia
12.
Nat Immunol ; 20(8): 963-969, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285625

RESUMO

Over the past several decades, B cell antigen receptor (BCR)-induced signaling pathways have been described in extraordinary molecular detail, mainly from studies of B cell responses to antigens in vitro. BCR signaling has been shown to govern the initiation of transcriptional programs associated with B cell activation and fate decisions, as well as the BCR-dependent processing of antigen and presentation of antigen to T cells. However, although the potential of the BCR to orchestrate B cell behavior was known, there was no clear appreciation of the context in which B cells signal in secondary lymphoid organs in vivo or how that context influences signaling. In this Review, we describe the current view of the cellular consequences of BCR signaling and advances in the understanding of B cell signaling in context in vivo.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Humanos , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
13.
Arerugi ; 68(6): 661-667, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31308331
14.
Scand J Immunol ; 90(5): e12807, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31282004

RESUMO

Exosomes are a potent means for intercellular communication. However, exosomes have received intensive research focus in immunobiology only relatively recently. Because they transport proteins, lipids and genetic material between cells, they are especially suited to amplify their parental cell's message and overcome the physical constraints of cell-to-cell contact, that is exosome release gives cells the ability to alter distant, non-contiguous cells. As progress is made in this field, it has become increasingly obvious that exosomes are involved in most biological processes. In the immune system, exosomes are fundamental tools used by every immune cell type to fulfil its function and promote inflammation or tolerance. In this review, we first summarize key aspects of immune cell-specific exosomes and their functions. Then, we describe how exosomes have been shown to be indispensable orchestrators of the immune response in two immunological scenarios, namely transplant rejection or tolerance, and tumour evasion or initiation of anti-tumour immune responses.


Assuntos
Exossomos/metabolismo , Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Neoplasias/imunologia , Evasão Tumoral/imunologia , Linfócitos B/imunologia , Transporte Biológico/fisiologia , Comunicação Celular/fisiologia , Células Dendríticas/imunologia , Humanos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia
15.
Vet Microbiol ; 235: 86-92, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282383

RESUMO

Although PCV2 infections generally cause mild disease in pigs, concurrent co-infections with other pathogens can damage the immune system and cause more severe diseases, collectively termed porcine circovirus associated diseases (PCVAD). Involvement of porcine parvovirus (PPV, a common cause of reproductive failure in naïve dams) in PCVAD caused by PCV2, has been reported. As this co-infection can be difficult to eliminate, there is a critical need to develop an effective vaccine to protect against PPV or synergistic effects of PCV2 and PPV under field conditions. In this study, we designed chimeric PCV2 virus-like particles (cVLPs) displaying a B-cell epitope derived from PPV1 structural protein around the surface of the 2-fold axes of PCV2 VLPs, based on 3D-structure analysis of the PCV2 capsid. The cVLPs were successfully prepared, verified by transmission electron microscopy and chromatography, with robust antibody titers against PCV2 and PPV1 produced in mice and guinea pigs. In addition, in guinea pigs challenged with 106 TCID50 PCV2, cVLPs conferred more effective immune protection (based on viral load) than a commercial PCV2 vaccine. Finally, antibody responses and immune protection against PPV were also evaluated. In guinea pigs vaccinated with cVLPs, although PPV antibodies detected by a hemagglutination inhibition (HI) assay appeared later after vaccination in the PCV2 cVLPs group than in the commercial PPV vaccine group, there were fewer PPV genomic DNA copies in the PCV2 cVLPs group than in a PBS group. In conclusion, guinea pigs vaccinated with cVLPs developed effective protective immunity against PCV2 challenge, with some protective immunity against PPV. This study provided valuable research data to pursue molecular design of chimeric epitopes PCV2 VLPs.


Assuntos
Infecções por Circoviridae/veterinária , Coinfecção/veterinária , Epitopos de Linfócito B/imunologia , Imunidade Humoral , Infecções por Parvoviridae/veterinária , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Infecções por Circoviridae/imunologia , Infecções por Circoviridae/prevenção & controle , Circovirus/imunologia , Coinfecção/virologia , Feminino , Cobaias , Camundongos , Infecções por Parvoviridae/imunologia , Infecções por Parvoviridae/prevenção & controle , Parvovirus Suíno/imunologia , Suínos , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Vacinas Atenuadas/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia
16.
Fish Shellfish Immunol ; 92: 813-820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271840

RESUMO

B cells have been found to have phagocytic activity in recent years, but the studies exploring the regulation mechanisms are still lacking to date. In the present study, the recombinant interleukin-10 (rIL-10) was obtained to study the function of IL-10 on phagocytosis of flounder (Paralichthys olivaceus) mIgM+ B lymphocytes. Flow cytometric analysis showed that IL-10 significantly enhanced the phagocytosis of Edwardsiella tarda but not Lactococcus lactis by mIgM+ B lymphocytes. Moreover, significantly higher intracellular ROS levels were detected in mIgM+ B lymphocytes following rIL-10 stimulation. The qRT-PCR analysis showed that rIL-10 could upregulate the expressions of IL-10Rb and Stat3 in mIgM+ B lymphocytes, suggesting that IL-10 might modulate the phagocytosis of mIgM+ B lymphocytes by activating IL-10R and Stat3. In addition, we also found that the enhancing effect of IL-10 on phagocytosis and intracellular ROS levels of mIgM+ B lymphocytes were suppressed by the administration of niclosamide. These results collectively demonstrated that IL-10 enhanced mIgM+ B lymphocyte-mediated phagocytosis of E. tarda and intracellular bactericidal ability, and IL-10R and Stat3 might play a curial role in the regulation of IL-10-stimulated phagocytosis, which would deepen our understanding of regulation mechanism of B cell phagocytosis.


Assuntos
Linfócitos B/imunologia , Proteínas de Peixes/imunologia , Linguados/imunologia , Interleucina-10/imunologia , Fagocitose/imunologia , Animais , Edwardsiella tarda/fisiologia , Lactococcus lactis/fisiologia , Proteínas Recombinantes/imunologia
17.
Cell Host Microbe ; 26(1): 100-113.e8, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31227334

RESUMO

Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen ß2-glycoprotein I (ß2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-ß2GPI IgG autoantibodies. R. int immunization of mice induced ß2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human ß2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Autoimunidade , Linfócitos B/imunologia , Clostridiales/imunologia , Reações Cruzadas , Linfócitos T/imunologia , Adulto , Idoso , Animais , Síndrome Antifosfolipídica/patologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Trato Gastrointestinal/microbiologia , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Adulto Jovem , beta 2-Glicoproteína I/imunologia
18.
Nature ; 571(7763): 122-126, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31189952

RESUMO

Antibodies secreted into mucosal barriers serve to protect the host from a variety of pathogens, and are the basis for successful vaccines1. In type I mucosa (such as the intestinal tract), dimeric IgA secreted by local plasma cells is transported through polymeric immunoglobulin receptors2 and mediates robust protection against viruses3,4. However, owing to the paucity of polymeric immunoglobulin receptors and plasma cells, how and whether antibodies are delivered to the type II mucosa represented by the lumen of the lower female reproductive tract remains unclear. Here, using genital herpes infection in mice, we show that primary infection does not establish plasma cells in the lamina propria of the female reproductive tract. Instead, upon secondary challenge with herpes simplex virus 2, circulating memory B cells that enter the female reproductive tract serve as the source of rapid and robust antibody secretion into the lumen of this tract. CD4 tissue-resident memory T cells secrete interferon-γ, which induces expression of chemokines, including CXCL9 and CXCL10. Circulating memory B cells are recruited to the vaginal mucosa in a CXCR3-dependent manner, and secrete virus-specific IgG2b, IgG2c and IgA into the lumen. These results reveal that circulating memory B cells act as a rapidly inducible source of mucosal antibodies in the female reproductive tract.


Assuntos
Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Movimento Celular/imunologia , Memória Imunológica/imunologia , Vagina/citologia , Vagina/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 2/imunologia , Imunização , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR3/imunologia , Vagina/virologia
19.
Nat Commun ; 10(1): 2423, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160559

RESUMO

The germinal center (GC) reaction in Peyer's patches (PP) requires continuous access to antigens, but how this is achieved is not known. Here we show that activated antigen-specific CCR6+CCR1+GL7- B cells make close contact with M cells in the subepithelial dome (SED). Using in situ photoactivation analysis of antigen-specific SED B cells, we find migration of cells towards the GC. Following antigen injection into ligated intestinal loops containing PPs, 40% of antigen-specific SED B cells bind antigen within 2 h, whereas unspecifc cells do not, indicating B cell-receptor involvment. Antigen-loading is not observed in M cell-deficient mice, but is unperturbed in mice depleted of classical dendritic cells (DC). Thus, we report a M cell-B cell antigen-specific transporting pathway in PP that is independent of DC. We propose that this antigen transporting pathway has a critical role in gut IgA responses, and should be taken into account when developing mucosal vaccines.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Células Epiteliais/imunologia , Nódulos Linfáticos Agregados/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Células Dendríticas/imunologia , Centro Germinativo/imunologia , Imunoglobulina A/imunologia , Ativação Linfocitária , Camundongos
20.
PLoS Negl Trop Dis ; 13(6): e0007474, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194740

RESUMO

During Schistosoma infection, lack of B cells results in more severe granulomas, inflammation, and fibrosis in the liver, but the mechanisms underlying this pathology remain unclear. This study was to clarify the mechanisms underpinning the immunomodulation of B cells in mice infected with Schistosoma japonicum (S. japonicum). We found that B cell deficiency led to aggravated liver pathology, as demonstrated by increases in the size of the egg-associated granulomas, alanine transaminase levels, and collagen deposition. Compared with infected wild-type (WT) mice, infected B cell-deficient (µMT) mice showed increased infiltration of Ly6Chi monocytes and higher levels of proinflammatory cytokines and chemokines. Furthermore, B1 cells were increased significantly in the liver of WT mice following S. japonicum infection. Adoptively transferring B1 cells, but not B2 cells, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. Additionally, secretion of IL-10 from hepatic B cells increased significantly in infected WT mice and this IL-10 was mainly derived from B1 cells. Adoptively transferring B1 cells purified from WT mice, but not from IL-10-deficient mice, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. These reductions were accompanied by decreases in the expression levels of chemokines and inflammatory cytokines. Taken together, these data indicated that after S. japonicum infection, an increased number of hepatic B1 cells secrete IL-10, which inhibits the expression of chemokines and cytokines and suppresses the infiltration of Ly6Chi monocytes into the liver thereby alleviating liver early inflammation and late fibrosis.


Assuntos
Linfócitos B/imunologia , Hepatite/complicações , Hepatite/prevenção & controle , Cirrose Hepática/prevenção & controle , Monócitos/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/complicações , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite/imunologia , Fatores Imunológicos/metabolismo , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL
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