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1.
Immunity ; 48(6): 1144-1159.e5, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29884460

RESUMO

PKCß-null (Prkcb-/-) mice are severely immunodeficient. Here we show that mice whose B cells lack PKCß failed to form germinal centers and plasma cells, which undermined affinity maturation and antibody production in response to immunization. Moreover, these mice failed to develop plasma cells in response to viral infection. At the cellular level, we have shown that Prkcb-/- B cells exhibited defective antigen polarization and mTORC1 signaling. While altered antigen polarization impaired antigen presentation and likely restricted the potential of GC development, defective mTORC1 signaling impaired metabolic reprogramming, mitochondrial remodeling, and heme biosynthesis in these cells, which altogether overwhelmingly opposed plasma cell differentiation. Taken together, our study reveals mechanistic insights into the function of PKCß as a key regulator of B cell polarity and metabolic reprogramming that instructs B cell fate.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Plasmócitos/imunologia , Proteína Quinase C beta/imunologia , Animais , Heme/biossíntese , Camundongos , Camundongos Knockout , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Plasmócitos/citologia
2.
EMBO Rep ; 24(7): e56131, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37184882

RESUMO

In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8+ T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter "instructs" the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8+ T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.


Assuntos
Linfócitos T CD8-Positivos , Células Dendríticas , Apresentação de Antígeno , Apresentação Cruzada , Antígenos de Bactérias
3.
Nat Immunol ; 10(8): 880-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19561613

RESUMO

T cell antigen receptors (TCRs) and B cell antigen receptors (BCRs) transmit low-grade signals necessary for the survival and maintenance of mature cell pools. We show here that TC21, a small GTPase encoded by Rras2, interacted constitutively with both kinds of receptors. Expression of a dominant negative TC21 mutant in T cells produced a rapid decrease in cell viability, and Rras2(-/-) mice were lymphopenic, possibly as a result of diminished homeostatic proliferation and impaired T cell and B cell survival. In contrast, TC21 was overexpressed in several human lymphoid malignancies. Finally, the p110delta catalytic subunit of phosphatidylinositol-3-OH kinase (PI(3)K) was recruited to the TCR and BCR in a TC21-dependent way. Consequently, we propose TC21 directly links antigen receptors to PI(3)K-mediated survival pathways.


Assuntos
Linfócitos B/imunologia , Proteínas de Membrana/fisiologia , Proteínas Monoméricas de Ligação ao GTP/fisiologia , Receptores de Antígenos de Linfócitos B/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Animais , Sobrevivência Celular , Homeostase , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Proteínas de Membrana/imunologia , Camundongos , Proteínas Monoméricas de Ligação ao GTP/imunologia , Fosfatidilinositol 3-Quinases/fisiologia , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais
4.
Immunity ; 35(2): 208-22, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21820331

RESUMO

The immunological synapse (IS) serves a dual role for sustained T cell receptor (TCR) signaling and for TCR downregulation. TC21 (Rras2) is a RRas subfamily GTPase that constitutively associates with the TCR and is implicated in tonic TCR signaling by activating phosphatidylinositol 3-kinase. In this study, we demonstrate that TC21 both cotranslocates with the TCR to the IS and is necessary for TCR internalization from the IS through a mechanism dependent on RhoG, a small GTPase previously associated with phagocytosis. Indeed, we found that the TCR triggers T cells to phagocytose 1-6 µm beads through a TC21- and RhoG-dependent pathway. We further show that TC21 and RhoG are necessary for the TCR-promoted uptake of major histocompatibility complex (MHC) from antigen-presenting cells. Therefore, TC21 and RhoG dependence underlie the existence of a common phagocytic mechanism that drives TCR internalization from the IS together with its peptide-MHC ligand.


Assuntos
Sinapses Imunológicas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fagocitose , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Apresentação de Antígeno , Antígenos/metabolismo , Comunicação Celular , Antígenos de Histocompatibilidade Classe II , Humanos , Sinapses Imunológicas/patologia , Células Jurkat , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Monoméricas de Ligação ao GTP/imunologia , Fragmentos de Peptídeos/imunologia , Fagocitose/imunologia , Transporte Proteico , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Proteínas rho de Ligação ao GTP/imunologia
5.
EMBO Rep ; 19(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29987136

RESUMO

Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen-coated particles, a process thought to be exclusive of specialized antigen-presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR-driven and mechanistically dependent on the GTPase RhoG. Using Rhog-/- mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high-affinity class-switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum-antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1-3 µm size antigen particles to follicular B cells.


Assuntos
Antígenos/imunologia , Linfócitos B/imunologia , Imunidade Humoral , Fagocitose/imunologia , Actinas/metabolismo , Adjuvantes Imunológicos , Compostos de Alúmen/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , GTP Fosfo-Hidrolases/genética , Centro Germinativo/citologia , Centro Germinativo/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Microesferas , Fagocitose/genética , Vacinação/métodos , Proteínas rho de Ligação ao GTP
6.
Nat Commun ; 15(1): 2569, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519473

RESUMO

The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.


Assuntos
Linfócitos B , Mitocôndrias , Camundongos , Animais , Mitocôndrias/genética , Centro Germinativo , Camundongos Knockout , Ativação Linfocitária
7.
Biomed J ; : 100630, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37459965

RESUMO

Trogocytosis is an active process whereby fragments of plasma membrane proteins and cytoplasm are transferred from one cell to another in a cell-cell contact-dependent manner. T cells trogocytose pieces of the cells presenting antigen to them at the site of the immunological synapse. Fragments of the antigen-presenting cell membrane rich in antigen/major histocompatibility (MHC) complexes are internalized by the T cell. Those complexes are redirected to the plasma membrane of the T cell, which becomes an antigen-presenting cell to other T cells. Removing antigen/MHC complexes from professional and tumoral cells has consequences for the intensity and duration of the immune response. However, the acquired capacity of T cells to present the acquired cognate antigen/MHC complexes also affects the properties of the antigen-presenting trogocytotic T cells. Acting as antigen-presenting cells, trogocytotic CD4 T cells influence the differentiation of cytotoxic T cells and the differentiation of other CD4 T cells into pro-inflammatory effector T cells. Furthermore, trogocytosis of antigen/MHC complexes promotes the differentiation of the trogocytotic CD4 T cells towards regulatory T cells and Th2 effector cells. Trogoctyosis is, therefore, a parallel mechanism to signal transduction by membrane receptors, including the T cell antigen receptor, at the plane of the plasma membrane.

8.
Methods Mol Biol ; 2675: 109-115, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37258759

RESUMO

The study of immunometabolism is an important and emerging field in immunology. B-cell activation upon antigen recognition induces profound metabolic changes in the cell, leading to an increase in ATP production to sustain cell proliferation and differentiation. Current methods available to determine the amount of ATP are time-consuming, require extensive sample processing, and need a large amount of starting material. We set up an easy follow-up protocol to determine the relative amount of ATP in living cells, combining cell surface staining with quinacrine. This acridine dye emits a green fluorescent signal in the presence of intracellular ATP. This protocol allows us to determine ATP in small populations of cells using flow cytometry, such as the germinal center.


Assuntos
Linfócitos B , Centro Germinativo , Ativação Linfocitária , Diferenciação Celular , Citometria de Fluxo , Trifosfato de Adenosina/metabolismo
9.
Front Immunol ; 14: 1200259, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37475858

RESUMO

Introduction: Macrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming. Methods: Here we use biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy. Results: We demonstrate that growth hormone (GH) reprograms inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ) by functioning as a metabolic modulator. We found that exogenous treatment of GM-MØ with recombinant human GH reduced glycolysis and lactate production to levels similar to those found in anti-inflammatory M-MØ. Moreover, GH treatment of GM-MØ augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae. Conclusions: Our data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered as a new target to intervene in inflammatory diseases.


Assuntos
Hormônio do Crescimento , Macrófagos , Humanos , Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/metabolismo , Glicólise , Homeostase , Mitocôndrias/metabolismo
10.
Immunology ; 133(4): 420-5, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21631496

RESUMO

The immunological synapse forms as a result of the tight apposition of a T cell with an antigen-presenting cell (APC) and it is the site where the T-cell receptor (TCR) is triggered by its antigen ligand, the peptide-MHC complex present in the APC membrane. The immunological synapse was initially characterized in the T-cell membrane as three concentric rings of membrane receptors and their underlying cytoskeletal and signalling proteins. The inner circle, or central supramolecular activation cluster (cSMAC), concentrates most of the TCR and CD28, and it is surrounded by the peripheral SMAC that is formed by integrins. Finally, the most external ring or distal SMAC (dSMAC) is where proteins with large ectodomains are located, such as CD43 and CD45, far from the cSMAC. This arrangement was initially thought to be responsible for maintaining sustained TCR signalling, however, this typical concentric bull's-eye pattern is not found in the immunological synapses formed with the APCs of dendritic cells. Interestingly, TCR signalling has been detected in microclusters formed in the dSMAC area and it extinguishes as the TCRs reach the cSMAC. Hence, it appears that TCR signalling and full T-cell activation do not require the formation of the cSMAC and that this structure may rather play a role in TCR down-regulation, as well as participating in the polarized secretion of lytic granules. Here, we shall review the historical evolution of the role of the cSMAC in T-cell activation, finally discussing our most recent data indicating that the cSMAC serves to internalize exhausted TCRs by phagocytosis.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Sinapses Imunológicas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Células Apresentadoras de Antígenos/citologia , Humanos , Transdução de Sinais/imunologia , Linfócitos T/citologia
11.
J Nerv Ment Dis ; 199(9): 666-71, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21878780

RESUMO

This study assessed the relationship between self-perceived clinical and social needs and aggressive behavior in outpatients with schizophrenia. A total of 895 outpatients with schizophrenia were enrolled. The presence of aggressive episodes was assessed using the Modified Overt Aggression Scale. Self-perceived needs were assessed using the Camberwell Assessment of Need in six areas of needs (food, household skills, self-care, daytime activities, psychotic symptoms, satisfaction with treatment, and company). The most common areas of needs were "psychotic symptoms" (81.6%), "daytime activities" (60.6%), and "household skills" (57.5%). More needs were expressed by patients who had more severe illnesses (p < 0.001) and more aggressive behavior (p < 0.001). Multivariate analysis showed that, in schizophrenia outpatients, self-perceived needs were associated with aggressive behavior (adjusted odds ratio, 11.43; 95% confidence interval, 5.11 to 25.56). Appropriate compliance with antipsychotic treatment was related with lower aggressive behavior (p < 0.001).


Assuntos
Necessidades e Demandas de Serviços de Saúde , Pacientes Ambulatoriais/psicologia , Psicologia do Esquizofrênico , Violência/psicologia , Adulto , Agressão/psicologia , Antipsicóticos/uso terapêutico , Serviços Comunitários de Saúde Mental , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação das Necessidades , Escalas de Graduação Psiquiátrica , Fatores de Risco , Esquizofrenia/tratamento farmacológico
13.
Nat Metab ; 1(8): 775-789, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31579886

RESUMO

The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbor point, activating mutations in RRAGC, an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent RRAGC mutations in B cell function and lymphoma is unexplored. RRAGC mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, Rragc mutations sustain induced germinal centers and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Ativação Linfocitária , Linfoma Folicular/tratamento farmacológico , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Humanos , Linfoma Folicular/patologia , Camundongos , Camundongos Transgênicos
14.
Life Sci Alliance ; 1(5): e201800060, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30456377

RESUMO

During B-cell activation, the dynamic reorganisation of the cytoskeleton is crucial for multiple cellular responses, such as receptor signalling, cell spreading, antigen internalisation, intracellular trafficking, and antigen presentation. However, the role of intermediate filaments (IFs), which represent a major component of the mammalian cytoskeleton, is not well defined. Here, by using multiple super-resolution microscopy techniques, including direct stochastic optical reconstruction microscopy, we show that IFs in B cells undergo drastic reorganisation immediately upon antigen stimulation and that this reorganisation requires actin and microtubules. Although the loss of vimentin in B cells did not impair B-cell development, receptor signalling, and differentiation, vimentin-deficient B cells exhibit altered positioning of antigen-containing and lysosomal associated membrane protein 1 (LAMP1+) compartments, implying that vimentin may play a role in the fine-tuning of intracellular trafficking. Indeed, vimentin-deficient B cells exhibit impaired antigen presentation and delayed antibody responses in vivo. Thus, our study presents a new perspective on the role of IFs in B-cell activation.

15.
Sci Signal ; 11(532)2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844052

RESUMO

Upon antigen recognition within peripheral lymphoid organs, B cells interact with T cells and other immune cells to transiently form morphological structures called germinal centers (GCs), which are required for B cell clonal expansion, immunoglobulin class switching, and affinity maturation. This process, known as the GC response, is an energetically demanding process that requires the metabolic reprogramming of B cells. We showed that the Ras-related guanosine triphosphate hydrolase (GTPase) R-Ras2 (also known as TC21) plays an essential, nonredundant, and B cell-intrinsic role in the GC response. Both the conversion of B cells into GC B cells and their expansion were impaired in mice lacking R-Ras2, but not in those lacking a highly related R-Ras subfamily member or both the classic H-Ras and N-Ras GTPases. In the absence of R-Ras2, activated B cells did not exhibit increased oxidative phosphorylation or aerobic glycolysis. We showed that R-Ras2 was an effector of both the B cell receptor (BCR) and CD40 and that, in its absence, B cells exhibited impaired activation of the PI3K-Akt-mTORC1 pathway, reduced mitochondrial DNA replication, and decreased expression of genes involved in glucose metabolism. Because most human B cell lymphomas originate from GC B cells or B cells that have undergone the GC response, our data suggest that R-Ras2 may also regulate metabolism in B cell malignancies.


Assuntos
Linfócitos B/fisiologia , Metabolismo Energético , Genes ras , Centro Germinativo/fisiologia , Proteínas de Membrana/fisiologia , Mitocôndrias/metabolismo , Proteínas Monoméricas de Ligação ao GTP/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Linfócitos B/citologia , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Feminino , Centro Germinativo/citologia , Glicólise , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo
16.
Science ; 355(6325): 641-647, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28183981

RESUMO

Autophagy is important in a variety of cellular and pathophysiological situations; however, its role in immune responses remains elusive. Here, we show that among B cells, germinal center (GC) cells exhibited the highest rate of autophagy during viral infection. In contrast to mechanistic target of rapamycin complex 1-dependent canonical autophagy, GC B cell autophagy occurred predominantly through a noncanonical pathway. B cell stimulation was sufficient to down-regulate canonical autophagy transiently while triggering noncanonical autophagy. Genetic ablation of WD repeat domain, phosphoinositide-interacting protein 2 in B cells alone enhanced this noncanonical autophagy, resulting in changes of mitochondrial homeostasis and alterations in GC and antibody-secreting cells. Thus, B cell activation prompts a temporal switch from canonical to noncanonical autophagy that is important in controlling B cell differentiation and fate.


Assuntos
Autofagia/imunologia , Linfócitos B/imunologia , Linfócitos B/virologia , Viroses/imunologia , Animais , Regulação para Baixo , Centro Germinativo/imunologia , Centro Germinativo/virologia , Ativação Linfocitária , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Repetições WD40/genética
17.
Methods Mol Biol ; 1389: 71-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27460238

RESUMO

Measuring cellular DNA content by conventional flow cytometry (CFC) and fluorescent DNA-binding dyes is a highly robust method for analysing cell cycle distributions within heterogeneous populations. However, any conclusions drawn from single-parameter DNA analysis alone can often be confounded by the asynchronous nature of cell proliferation. We have shown that by combining fluorescent DNA stains with proliferation tracking dyes and antigenic staining for mitotic cells one can elucidate the division history and cell cycle position of any cell within an asynchronously dividing population. Furthermore if one applies this panel to an imaging flow cytometry (IFC) system then the spatial information allows resolution of the four main mitotic phases and the ability to study molecular distributions within these populations. We have employed such an approach to study the prevalence of asymmetric cell division (ACD) within activated immune cells by measuring the distribution of key fate determining molecules across the plane of cytokinesis in a high-throughput, objective, and internally controlled manner. Moreover the ability to perform high-resolution, temporal dissection of the cell division process lends itself perfectly to investigating the influence chemotherapeutic agents exert on the proliferative capacity of transformed cell lines. Here we describe the method in detail and its application to both ACD and general cell cycle analysis.


Assuntos
Divisão Celular Assimétrica , Ciclo Celular , Proliferação de Células , Citometria de Fluxo/métodos , Citometria por Imagem/métodos , Linfócitos/citologia , Animais , Linhagem Celular , Células Cultivadas , Humanos
19.
J Exp Med ; 212(1): 53-72, 2015 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-25547673

RESUMO

The small Rho GTPase Cdc42, known to interact with Wiskott-Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-deficient mice are incapable of forming germinal centers or generating plasma B cells upon either viral infection or immunization. Such severe immune deficiency is caused by multiple and profound B cell abnormalities, including early blocks during B cell development; impaired antigen-driven BCR signaling and actin remodeling; defective antigen presentation and in vivo interaction with T cells; and a severe B cell-intrinsic block in plasma cell differentiation. Thus, our study presents a new perspective on Cdc42 as key regulator of B cell physiology.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Imunidade Humoral/imunologia , Infecções por Orthomyxoviridae/imunologia , Proteína cdc42 de Ligação ao GTP/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos B/metabolismo , Linfócitos B/ultraestrutura , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Citometria de Fluxo , Expressão Gênica/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunidade Humoral/genética , Vírus da Influenza A/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo
20.
Med Clin (Barc) ; 119(3): 85-9, 2002 Jun 22.
Artigo em Espanhol | MEDLINE | ID: mdl-12106535

RESUMO

BACKGROUND: Nowadays, severe deficiency of vitamin D is not a common finding in most developed countries. However, the prevalence of vitamin D insufficiency is relatively high and it can contribute to the descent of bone mass in osteoporosis risk populations. The objective of our study was to evaluate the prevalence of vitamin D insufficiency in postmenopausal women (PMW), patients with inflammatory bowel disease (IBD) and corticosteroid-dependent asthmatic patients (CAP) and to analyze its relationship with bone mineral density (BMD) and calciotropic hormones. PATIENTS AND METHOD: We studied 299 patients (PMW: 161; IBD: 61; CAP: 77). In all cases, serum levels of PTH and 25OHD were determined and the BMD (DXA, Hologic QDR1000) in lumbar spine (LS) and femoral neck (FN) was measured. RESULTS: Vitamin D insufficiency (25OHD < 15 ng/ml) was observed in 39.1% patients with PMW, 70.7% patients with IBD and 44.2% patients with CAP. 25OHD concentrations were lower in EII patients (p = 0.003) and PTH concentrations were higher in MPM (p < 0.001). We found a negative correlation between PTH and 25OHD in the overall group and this correlation persisted after considering each group separately. After adjusting for remaining variables, 25OHD was found to be significantly associated with BMD at lumbar spine and/or femoral neck in the three groups. CONCLUSIONS: In populations at risk of osteoporosis, there is a high prevalence of vitamin D insufficiency. This insufficiency has a significant effect on bone integrity.


Assuntos
Densidade Óssea/fisiologia , Osteoporose/epidemiologia , Deficiência de Vitamina D/epidemiologia , Adulto , Anti-Inflamatórios/uso terapêutico , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Hormônio Paratireóideo/sangue , Pós-Menopausa , Prevalência , Esteroides , Deficiência de Vitamina D/complicações
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