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1.
Genes Dev ; 33(23-24): 1673-1687, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699777

RESUMO

Knockout of the ubiquitously expressed miRNA-17∼92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17∼92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17∼92:Bim interactions to the complex miR-17∼92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3' UTR miR-17∼92 seed matches. Blocking miR-17∼92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17∼92 ablation and generated a skeletal kinky tail. In the hematopoietic system, instead of causing the predicted B cell developmental block, it produced a selective inability of B cells to resist cellular stress; and prevented B and T cell hyperplasia caused by Bim haploinsufficiency. Thus, the interaction of miR-17∼92 with a single target is essential for life, and BIM regulation by miRNAs serves as a rheostat controlling cell survival in specific physiological contexts.


Assuntos
Linfócitos B/citologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Sobrevivência Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Hematopoese/genética , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Linfócitos B/patologia , Proteína 11 Semelhante a Bcl-2/genética , Técnicas de Inativação de Genes , Pulmão/embriologia , Camundongos , MicroRNAs/genética , Mutação , Estresse Fisiológico
2.
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
3.
Immunogenetics ; 71(8-9): 519-530, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31520135

RESUMO

Human CD4+ T lymphocytes play an important role in inducing potent immune responses. T cells are activated and stimulated by peptides presented in human leucocyte antigen (HLA)-class II molecules. These HLA-class II molecules typically present peptides of between 12 and 20 amino acids in length. The region that interacts with the HLA molecule, designated as the peptide-binding core, is highly conserved in the residues which anchor the peptide to the molecule. In addition, as these peptides are the product of proteolytic cleavages, certain conserved residues may be expected at the N- and C-termini outside the binding core. To study whether similar conserved residues are present in different cell types, potentially harbouring different proteolytic enzymes, the ligandomes of HLA-DRB1*03:01/HLA-DRB > 1 derived from two different cell types (dendritic cells and EBV-transformed B cells) were identified with mass spectrometry and the binding core and N- and C-terminal residues of a total of 16,568 peptides were analysed using the frequencies of the amino acids in the human proteome. Similar binding motifs were found as well as comparable conservations in the N- and C-terminal residues. Furthermore, the terminal conservations of these ligandomes were compared to the N- and C-terminal conservations of the ligandome acquired from dendritic cells homozygous for HLA-DRB1*04:01. Again, comparable conservations were evident with only minor differences. Taken together, these data show that there are conservations in the terminal residues of peptides, presumably the result of the activity of proteases involved in antigen processing.


Assuntos
Linfócitos B/metabolismo , Células Dendríticas/metabolismo , Antígenos HLA-DR/classificação , Antígenos HLA-DR/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteoma/metabolismo , Motivos de Aminoácidos , Linfócitos B/citologia , Células Cultivadas , Células Dendríticas/citologia , Humanos , Ligantes , Ligação Proteica
4.
Nat Commun ; 10(1): 3353, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350389

RESUMO

The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRß locus, Setd2 deficiency reduces TCRß H3K36me3 and suppresses TCRß V(D)J rearrangement by impairing RAG1 binding to TCRß loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Recombinação V(D)J , Motivos de Aminoácidos , Animais , Linfócitos B/citologia , Linfócitos B/enzimologia , Diferenciação Celular , Pré-Escolar , Epigênese Genética , Histona-Lisina N-Metiltransferase/genética , Histonas/química , Histonas/metabolismo , Humanos , Lactente , Lisina/genética , Lisina/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , /genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/citologia
5.
Immunology ; 158(2): 104-120, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31318442

RESUMO

Activation of B and T lymphocytes leads to major remodelling of the metabolic landscape of the cells enabling their post-activation functions. However, naive B and T lymphocytes also show metabolic differences, and the genesis, nature and functional significance of these differences are not yet well understood. Here we show that resting B-cells appeared to have lower energy demands than resting T-cells as they consumed lower levels of glucose and fatty acids and produced less ATP. Resting B-cells are more dependent on OXPHOS, while T-cells show more dependence on aerobic glycolysis. However, despite an apparently higher energy demand, T lineage cells showed lower rates of protein synthesis than equivalent B lineage stages. These metabolic differences between the two lineages were established early during lineage differentiation, and were functionally significant. Higher levels of protein synthesis in B-cells were associated with increased synthesis of MHC class II molecules and other proteins associated with antigen internalization, transport and presentation. The combination of higher energy demand and lower protein synthesis in T-cells was consistent with their higher ATP-dependent motility. Our data provide an integrated perspective of the metabolic differences and their functional implications between the B and T lymphocyte lineages.


Assuntos
Linfócitos B/metabolismo , Glicólise/imunologia , Fosforilação Oxidativa , Linfócitos T/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Ácidos Graxos/metabolismo , Expressão Gênica , Glucose/metabolismo , Glicólise/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Especificidade de Órgãos , Cultura Primária de Células , Biossíntese de Proteínas/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 552-556, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292060

RESUMO

Objective To investigate the effect of diabetes mellitus on lymphocytes in rheumatic heart valve tissue and its mechanism. Methods Valve tissues of 40 patients undergoing heart valve replacement were collected, including 20 patients in rheumatic heart disease group (without diabetes) and 20 patients in diabetic group (rheumatic heart disease combined with diabetes). In addition, 20 cases of valve tissue from control group were collected. HE staining was used to observe the damage of valve tissue and the area of collagen degeneration. CD4+ T cells, CD8+ T cells, B cells and plasma cells were detected by immunohistochemical staining. Flow cytometry was used to detect the proportion of regulatory T cells (Tregs) in peripheral blood. Results Compared with the rheumatic heart disease group, the damage of valve tissue in the diabetic group was further aggravated, the number of infiltrating inflammatory cells increased, and the area of collagen degeneration was enlarged. Compared with the control group, the number of T cells, CD4+ T cells, CD8+ T cells, B cells and plasma cells in valve tissue of patients with rheumatic heart disease increased significantly. Diabetes mellitus further increased the number of T cells, CD4+ T cells, B cells and plasma cells in valve tissue, but had no significant effect on CD8+ T cells. The proportion of Tregs in the peripheral blood of patients with rheumatic heart disease was significantly reduced. Diabetes mellitus could further reduce the proportion of Tregs. Conclusion The number of T cells, CD4+T cells, B cells and plasma cells in heart valves of rheumatic heart disease patients with diabetes mellitus go up significantly, and Treg ratio goes down.


Assuntos
Linfócitos B/citologia , Linfócitos T CD8-Positivos/citologia , Diabetes Mellitus/patologia , Valvas Cardíacas/citologia , Cardiopatia Reumática/complicações , Linfócitos T Reguladores/citologia , Estudos de Casos e Controles , Humanos
7.
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
8.
Cells ; 8(6)2019 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181729

RESUMO

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and currently the second most common cause of cancer-related deaths worldwide with increasing incidence and poor prognosis. Exosomes are now considered as important mediators of host anti-tumor immune response as well as tumor cell immune escape. HCC-derived exosomes have been shown to attenuate the cytotoxicity of T-cells and NK cells, and promote the immuno-suppressive M2 macrophages, N2 neutrophils, and Bregs. These exosomes harbor several immune-related non-coding RNAs and proteins that drive immune-escape and tumor progression, and thus may serve as potential diagnostic biomarkers and therapeutic targets for HCC. In a previous study, we identified miR146a as an exosomal factor that promotes M2-polarization and suppresses the anti-HCC function of T-cells. In this review, we summarized the role of tumor-derived exosomes and their key components in mediating tumor immune escape during HCC development.


Assuntos
Carcinoma Hepatocelular/patologia , Exossomos/metabolismo , Neoplasias Hepáticas/patologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Cells ; 8(6)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167518

RESUMO

Fas Apoptosis Inhibitory Molecule (FAIM) is an anti-apoptotic protein that is up-regulated in B cell receptor (BCR)-activated B cells and confers upon them resistance to Fas-mediated cell death. Faim has two alternatively spliced isoforms, with the short isoform ubiquitously expressed in various tissues and the long isoform mainly found in the nervous tissues. FAIM is evolutionarily conserved but does not share any significant primary sequence homology with any known protein. The function of FAIM has been extensively studied in the past 20 years, with its primary role being ascribed to be anti-apoptotic. In addition, several other functions of FAIM were also discovered in different physiological and pathological conditions, such as cell growth, metabolism, Alzheimer's disease and tumorigenesis. However, the detailed molecular mechanisms underlying FAIM's role in these conditions remain unknown. In this review, we summarize comprehensively the functions of FAIM in these different contexts and discuss its potential as a diagnostic, prognostic or therapeutic target.


Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Metabolismo Energético , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 296-301, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167687

RESUMO

Objective To investigate the role of CD161+ regulatory T cells (Treg) in reducing valve injury in rheumatic heart disease rats and the underlying mechanism. Methods CD161- and CD161+ regulatory T cells (Tregs) were separated by flow cytometry and then cultured. The concentrations of interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß) in the supernates were detected by ELISA. Rat models of rheumatic heart disease were established by mixing A type hemolytic streptococcus suspension with Freund's complete adjuvant. They were divided into control group, CD161-Treg group and CD161+Treg group. One week later, heart blood and mitral valve were taken from the model rats. The proportion of follicular helper T (Tfh) cells, B cells and plasma cells was detected by flow cytometry. Histopathological changes were detected by HE staining and the number of B cells and plasma cells by immunohistochemical staining. ELISA was used to detect the level of IL-21 in serum. Results The ability of CD161+Tregs to secrete IL-10 and TGF-ß was significantly higher than that of CD161-Tregs. Compared with the rats injected with CD161-Tregs, CD161+Tregs could significantly reduce the damage of valve tissue and the proportion of B cells and plasma cells in valve tissue. Moreover, CD161+Tregs injection could reduce the proportion of Tfh cells, B cells and plasma cells in rat blood and decrease the content of IL-21 in serum. Conclusion CD161+Tregs can reduce the valve injury of rheumatic heart disease by inhibiting the proliferation and differentiation of Tfh cells and B cells.


Assuntos
Valvas Cardíacas/patologia , Cardiopatia Reumática/imunologia , Linfócitos T Reguladores/citologia , Animais , Linfócitos B/citologia , Interleucina-10/metabolismo , Interleucinas/sangue , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Plasmócitos/citologia , Ratos , Fator de Crescimento Transformador beta/metabolismo
11.
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
12.
MAbs ; 11(6): 1025-1035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31185801

RESUMO

Accelerated development of monoclonal antibody (mAb) tool reagents is an essential requirement for the successful advancement of therapeutic antibodies in today's fast-paced and competitive drug development marketplace. Here, we describe a direct, flexible, and rapid nanofluidic optoelectronic single B lymphocyte antibody screening technique (NanOBlast) applied to the generation of anti-idiotypic reagent antibodies. Selectively enriched, antigen-experienced murine antibody secreting cells (ASCs) were harvested from spleen and lymph nodes. Subsequently, secreted mAbs from individually isolated, single ASCs were screened directly using a novel, integrated, high-content culture, and assay platform capable of manipulating living cells within microfluidic chip nanopens using structured light. Single-cell polymerase chain reaction-based molecular recovery on select anti-idiotypic ASCs followed by recombinant IgG expression and enzyme-linked immunosorbent assay (ELISA) characterization resulted in the recovery and identification of a diverse and high-affinity panel of anti-idiotypic reagent mAbs. Combinatorial ELISA screening identified both capture and detection mAbs, and enabled the development of a sensitive and highly specific ligand binding assay capable of quantifying free therapeutic IgG molecules directly from human patient serum, thereby facilitating important drug development decision-making. The ASC import, screening, and export discovery workflow on the chip was completed within 5 h, while the overall discovery workflow from immunization to recombinantly expressed IgG was completed in under 60 days.


Assuntos
Anticorpos Monoclonais Murinos/imunologia , Linfócitos B/imunologia , Imunoglobulina G/imunologia , Animais , Linfócitos B/citologia , Células CHO , Cricetulus , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos
13.
Genes Dev ; 33(13-14): 763-781, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123064

RESUMO

Coordinated induction, but also repression, of genes are key to normal differentiation. Although the role of lineage-specific transcription regulators has been studied extensively, their functional integration with chromatin remodelers, one of the key enzymatic machineries that control chromatin accessibility, remains ill-defined. Here we investigate the role of Mi-2ß, a SNF-2-like nucleosome remodeler and key component of the nucleosome remodeling and histone deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2ß arrested differentiation at the large pre-B-cell stage and caused derepression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2ß also supported IL-7R signaling, survival, and proliferation by repressing negative effectors of this pathway. Importantly, overexpression of Bcl2, a mitochondrial prosurvival gene and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2ß loss. Mi-2ß stably associated with chromatin sites that harbor binding motifs for IKAROS and EBF1 and physically associated with these transcription factors both on and off chromatin. Notably, Mi-2ß shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1, albeit in a distinct fashion. Thus, the nucleosome remodeler Mi-2ß promotes pre-B-cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.


Assuntos
Linfócitos B/citologia , Diferenciação Celular/genética , Cromatina/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Animais , Linhagem da Célula , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Camundongos , Fatores de Transcrição
14.
Cells ; 8(5)2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086070

RESUMO

Tumor-infiltrating lymphocytes are known to be critical in controlling tumor progression. While the role of T lymphocytes has been extensively studied, the function of B cells in this context is still ill-defined. In this review, we propose to explore the role of B cells in tumor immunity. First of all we define their dual role in promoting and inhibiting cancer progression depending on their phenotype. To continue, we describe the influence of different tumor microenvironment factors such as hypoxia on B cells functions and differentiation. Finally, the role of B cells in response to therapy and as potential target is examined. In accordance with the importance of B cells in immuno-oncology, we conclude that more studies are required to throw light on the precise role of B cells in the tumor microenvironment in order to have a better understanding of their functions, and to design new strategies that efficiently target these cells by immunotherapy.


Assuntos
Linfócitos B/imunologia , Carcinogênese/imunologia , Neoplasias , Microambiente Tumoral , Animais , Linfócitos B/citologia , Linhagem Celular , Humanos , Imunoterapia , Oncologia , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Ratos
15.
Nanoscale ; 11(21): 10493-10503, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31112199

RESUMO

Carbon-based nanomaterials represent a new tool in future medical applications. Thus, focusing on the evaluation of the degree of their safety has been growing in the last years. In this study we were particularly interested in understanding the impact of few layer graphene (FLG) on primary murine lymphocytes. These B and T cells, that are the second, but specialized, line of defense of the immune system, rely on various mechanisms to ensure their efficient function and maintenance. One of these mechanisms is autophagy that can be triggered by various nanomaterials in some types of cells. For these reasons, we were interested in evaluating the way FLG could affect this process in lymphocytes. Our results point out that FLG neither impacts the viability and activation of T and B cells nor their autophagic activity. Using confocal microscopy, we were also able to see that FLG does not appear to cause any membrane damage and does not penetrate inside of these cells. Overall, our data do not show any effect of this material on lymphocyte homeostasis, which is one more argument in favor of the continuation of studies investigating the potential of FLG for therapeutic applications.


Assuntos
Autofagia/efeitos dos fármacos , Linfócitos B/metabolismo , Grafite , Nanoestruturas/química , Linfócitos T/metabolismo , Animais , Linfócitos B/citologia , Grafite/química , Grafite/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/citologia
16.
J Food Sci ; 84(6): 1577-1585, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31120637

RESUMO

A mixture of multiple ingredients is often more effective than the individual ingredients. The functions of Lycium barbarum polysaccharide (LBP) glycoconjugate and grape seed procyanidins (GSP) are widely known. Here, we investigated the synergistic immune-enhancing activity of LBP and GSP. Atomic force microscopy results suggested that the mixture of LBP and GSP exhibited circular structure unlike LBP alone, and the addition of polyphenols may change the spatial conformation of the sugar chain. The changes in the structure were related to the synergistic effect of the two functional agents on immune recovery. In vitro, the proliferation rate of splenocytes was higher in LBP + GSP group (64.16%), rather than the sum of LBP group (13.01%) and GSP group (43.61%) individually used. This synergistical proliferation of splenocytes may be correlated to the increasing intracellular free calcium levels. Furthermore, the mixture significantly enhanced the immunity in vivo, as evident from the recovery of peripheral white blood cell counts in LBP + GSP group (18.535 × 109 /L) to normal group levels (18.115 × 109 /L) and higher B cell proliferation than normal group (P < 0.05). These results highlight the immune-enhancing activity of the combination of LBP and GSP associated with the structural changes, which may facilitate the development of functional foods with fewer resources but enhanced activities. PRACTICAL APPLICATION: The synergistic effects of LBP and GSP on immunomodulatory were better than the sum of the effects of the individual agents both in vitro and in vivo. Our results may provide a research-based support for the development of related functional products and an insight into the production of food resources with a fewer but more effective functional agents for better results.


Assuntos
Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Imunidade/efeitos dos fármacos , Lycium/química , Extratos Vegetais/administração & dosagem , Proantocianidinas/administração & dosagem , Vitis/química , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biflavonoides/química , Catequina/química , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Feminino , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Proantocianidinas/química , Sementes/química
17.
Int J Exp Pathol ; 100(3): 184-191, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31090156

RESUMO

The expression of microRNA in eukaryotic cells is subject to tightly regulated processing. The altered expression of microRNAs in a number of cancers suggests their contribution to disease pathogenesis, where processing pathways may be involved in disease pathogenesis. In the present study, we evaluated changes in the profile of two main components of microRNA biogenesis, AGO2 and DICER, and assessed their correlation with disease progression in childhood acute lymphoblastic leukaemia (ALL). To achieve this aim, 25 patients afflicted with ALL were included in the study along with 25 healthy subjects as control. The expression level of AGO2 and DICER was evaluated by real-time PCR. The results revealed an increase in the expression of DICER and a decrease in AGO2 in patients. The correlation between the alteration levels of these genes with pathologic events was also studied. This increase or decrease proved to be directly correlated with the progression of the disease particularly in L1 to L2. According to the obtained results, it can be deduced that dysregulation in transcription of DICER and AGO2, involved in the formation of mature microRNAs in cytoplasm of ALL cancer cells, is a part of the pathological molecular mechanism implicated in the exacerbation of this malignancy. Therefore, the genes involved in microRNAs biogenesis that have been studied here could be considered as candidate prognostic markers especially in childhood ALL which will help towards a better understanding of the molecular basis of ALL.


Assuntos
Proteínas Argonauta/metabolismo , Linfócitos B/citologia , Linhagem da Célula/imunologia , RNA Helicases DEAD-box/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Ribonuclease III/metabolismo , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos
18.
Tissue Cell ; 58: 112-120, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133238

RESUMO

Apoptosis inhibitor of macrophages (AIM) is a protein which plays important roles in controlling the immune response and inflammation in human and mice. In dogs, AIM is reported to be expressed in cancerated macrophages and regulate the survival of these tumor cells. In this study, to elucidate the physiological expression pattern of AIM in dogs, systemic expression and distribution of AIM of dogs were investigated. Mature healthy Beagles were used. Various tissues, peripheral blood cells, and bone marrow cells of normal dogs were collected for in situ hybridization, real-time RT-PCR, and immunohistochemistry. AIM mRNA and protein were expressed in tissue macrophages of the spleen, liver, lungs, and lymph nodes, but not in the microglia of the cerebrum. Proximal tubules in the kidney also expressed AIM protein. Monocytes and B lymphocytes in circulating blood and a part of microvasculature endothelial cells showed AIM expression at both the mRNA and protein levels. In the bone marrow, early-stage monocyte progenitor-like cells expressed AIM mRNA and protein. These results clarified that AIM is expressed in more cell types than previously reported in human and mice. These data spread the possibility of AIM physiological functions and implies the relationship of AIM to the maturation of macrophage-strain cells in dogs and other species.


Assuntos
Linfócitos B/metabolismo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Macrófagos/metabolismo , Receptores Depuradores/biossíntese , Animais , Linfócitos B/citologia , Cães , Células Endoteliais/citologia , Humanos , Macrófagos/citologia , Camundongos , Especificidade de Órgãos , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie
19.
Immunity ; 50(5): 1172-1187.e7, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31076359

RESUMO

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.


Assuntos
Linfócitos B/imunologia , Interferon gama/imunologia , Receptores de Interferon/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Produtoras de Anticorpos/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Cromatina/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nematospiroides dubius/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Proteínas com Domínio T/genética
20.
Nat Commun ; 10(1): 2201, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101814

RESUMO

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Criança , Modelos Animais de Doenças , Feminino , Frequência do Gene , Células HEK293 , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma , Quinases da Família src/metabolismo
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