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1.
Artigo em Chinês | MEDLINE | ID: mdl-34979610

RESUMO

Objective:To investigate the clinical features of diffuse large B-cell lymphoma (DLBCL) of head and neck. Methods:A retrospective study was conducted among patients with DLBCL in the Department of otolaryngology and head and neck surgery of the Second Affiliated Hospital of Xi'an Jiaotong University from July 2011 to September 2021. The disease location, clinical manifestations, diagnosis, treatment and prognosis of DLBCL patients in head and neck were analyzed retrospectively. Results:Oropharynx(27 cases, including 25 cases in tonsil), neck(29 cases), nasopharynx and nasal cavity (7 cases)were included in 63 cases of DLBCL in head and neck. Pharyngalgia, pharyngeal foreign body sensation and dysphagia were the most common manifestations of oropharyngeal DLBCL, while nasal obstruction, runny nose and hyposmia were the initial manifestations of nasal and nasopharyngeal DLBCL.Under the NBI endoscopy, locally uplifted neoplasm with rough surface mucosa was observed in 34 cases DLBCL patients of oropharynx, nasopharynx and nasal cavity. Among them, 16 cases were covered with yellow-white and patchy pseudomembrane on the surface of the neoplasm, and 5 cases were detected with abnormal new vessels, including 3 cases of tonsils, 1 case of root of tongue, and 1 case of nasopharynx. Painless progressive lymphadenectasis was the common manifestation of DLBCL in head and neck, and the maximum diameter([21.3±6.7]mm) of neck lymph nodes in the same side of DLBCL was significantly larger than that in the opposite side([16.0±7.2]mm, P=0.009). Sixty-three cases of DLBCL in head and neck, including 27 cases of germinal center type(GCB), 33 cases of nongerminal center type(non-GCB), and 3 cases of non-specific DLBCL, were confirmed the diagnosis by needle biopsy(33 cases, 52.4%) and surgical resection(30 cases, 47.6%). The imaging features of DLBCL in head and neck were mostly showed as local soft tissue masses with uniform density and uneven enhancement, and the surrounding structures were often compressed and displaced. All the patients were treated with standard R-CHOP chemotherapy regimens, and overall survival was longer in normal LDH, and overall survival of the patients at low risk of IPI was longer than those at medium-high or high risk of IPI(PLDH=0.011, PIPI=0.022, P<0.05). Conclusion:DLBCL mainly occurs in oropharynx, especially the unilateral tonsil. When flake yellow-white pseudomembrane adhesion and abnormal neovessels on the surface of the mass are detected under endoscopy, and the ultrasound suggested multiple enlarged lymph nodes in the neck with large iplateral lymph nodes, the possibility of DLBCL should be considered. Surgical resection could be performed for diagnosis if necessary, and early diagnosis would have a better prognosis.


Assuntos
Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Centro Germinativo , Humanos , Pescoço , Prognóstico , Estudos Retrospectivos
2.
Methods Mol Biol ; 2380: 3-13, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802117

RESUMO

Long-lasting immunity depends on generation of antibody forming cells in germinal centers (GCs). Conventional methods such as immunohistology and intravital live imaging have been used extensively to investigate the location of cellular assemblies within tissues as well as their dynamic motility and cellular interactions. Two photon laser scanning microscopy (TPLSM) intravital imaging allows scanning of large areas within tissues and reveals multiple immune cell niches. Nonetheless, this type of imaging is limited by the depth of penetration and cannot capture effectively all of the GC niches within lymphoid organs. Here we describe a method to visualize antigen-specific T and B cells in multiple microanatomical locations and niches at the level of a whole organ. This large-scale imaging approach can greatly increase our understanding of the spatial distribution of immune cells and help obtain detailed 3D maps of their locations and quantities.


Assuntos
Células T Auxiliares Foliculares , Linfócitos B , Centro Germinativo , Microscopia de Fluorescência , Linfócitos T Auxiliares-Indutores
3.
Methods Mol Biol ; 2380: 15-27, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802118

RESUMO

Germinal centers (GCs) are microanatomical structures in secondary lymphoid organs where B cells undergo affinity maturation for antigen during the course of an immune response. This process is driven by a subset of T cells termed T follicular helper cells (Tfh) that through a multistep process gain access to the GC niche within the B cell follicle. This protocol details how to study Tfh behavior in vivo, on a single cell level, using two-photon intravital microscopy of the murine popliteal lymph node.


Assuntos
Células T Auxiliares Foliculares , Animais , Linfócitos B , Centro Germinativo , Linfonodos , Camundongos , Linfócitos T Auxiliares-Indutores
4.
Methods Mol Biol ; 2380: 41-46, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802120

RESUMO

T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells are crucially involved in the regulation of germinal center reactions. Thus, as key players, the assessment of these cell subsets is necessary for a better understanding of the humoral immune response. Flow cytometry (FC) is one of the most used techniques to perform immunophenotypic analysis, allowing the simultaneous study of different proteins by using multicolor fluorescent panels. Here, we describe an approach to identify Tfr cells from human blood and tissues, namely tonsil and lymph node, by flow cytometry.


Assuntos
Citometria de Fluxo , Centro Germinativo/imunologia , Humanos , Imunidade Humoral , Imunofenotipagem , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia
5.
Methods Mol Biol ; 2380: 99-109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802125

RESUMO

Follicular T-helper cells play a key role in orchestrating the germinal center response. Cellular dynamics revealed by intravital imaging have helped deepen our understanding of how follicular T-helper cells develop and function in vivo. Here we describe routine methods to image T-cell dynamics during germinal center responses. Methods for quantitative analysis of imaging data are detailed using published examples.


Assuntos
Comunicação Celular , Linfócitos B , Diferenciação Celular , Centro Germinativo , Microscopia Intravital , Linfócitos T Auxiliares-Indutores
6.
Methods Mol Biol ; 2380: 111-123, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802126

RESUMO

Germinal centers (GC) are dynamic, short-lived anatomical structures generated within lymphoid follicles during immune responses to protein-containing antigens. There, follicular dendritic cells, antigen-specific B cells, and follicular T helper cells engage with each other in an antigen dependent way, setting into play a mini-evolutionary ecosystem that ultimately lead to antibody affinity maturation, with the resulting GC reaction following a rise-and-fall dynamics. The complexity of the cell-to-cell interaction processes makes very difficult to mechanistically understand the GC dynamics. Different mathematical or computational models have been or can be developed to help clarify the mechanisms driving and regulating the GC dynamics. However, the very important question of which are the dominant model parameters is not frequently studied for most of those models. Here we describe in detail one method to perform such a parameter analysis-known as parameter sensitivity analysis-which can be applied to many models of the GC dynamics.


Assuntos
Centro Germinativo , Antígenos , Linfócitos B , Células Dendríticas Foliculares , Ecossistema , Linfócitos T Auxiliares-Indutores
7.
Methods Mol Biol ; 2380: 149-163, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802129

RESUMO

Every T cell clone has its unique T cell receptor that results from somatic recombination of V(D)J genes in developing T cells. This process leads to a highly diverse TCR repertoire of naïve T cells, which is selected, upon antigenic recognition, to form the repertoires of effector and memory T cells. The advent of next-generation sequencing (NGS) technology allows for the high-throughput analysis of the TCR repertoires in the different T cell populations. TFH cells, since their initial discovery in human tonsils and in mouse lymphoid organs, have become the subject of intense investigations due to their essential role in regulating B cell responses and the process of antibody affinity maturation. Circulating follicular helper T cells (cTFH) are considered a helper T cell linage in the blood that to some extent relates with bona fide TFH cells in the germinal centers of secondary lymphoid organs. Due to the limited access to the secondary lymphoid organs, cTFH have become a more accessible immunological readout. The assessment of the TCR repertoires of TFH and of cTFH cells is of both fundamental and clinical importance being instrumental to define the linage relationship of cTFH with other T cell subsets and to monitor response to infections or vaccination or disease states. In this chapter, we will provide detailed methods for isolation of antigen-specific cTFH cells in vitro and subsequent protocols for the high-throughput TCR sequencing, followed by repertoire data analysis.


Assuntos
Células T Auxiliares Foliculares , Animais , Centro Germinativo , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Auxiliares-Indutores
8.
Methods Mol Biol ; 2380: 175-185, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802131

RESUMO

T Follicular helper (Tfh) cells stimulate, whereas T follicular regulatory (Tfr) cells inhibit, effector B cell responses. Although new tools have been developed to assess the functional roles of Tfh and Tfr cells in vivo, methods to assess mechanisms have been limited. One such limitation has been the ability of in vitro functional assays to recapitulate robust germinal center-like responses. Although previous in vitro Tfh-mediated and Tfr-suppressed assays to assess antibody regulation have been developed, these classically have relied on polyclonal stimulation. To understand Tfh and Tfr cell functionality, more robust assays that utilize specific antigen are needed. Here we describe an in vitro approach for sensitively and quantitatively assessing the capacity of Tfh and Tfr cells to regulate B cell responses in an antigen-driven system. These assays allow the study of Tfh and Tfr cells in specific disease contexts, such as IgG production after vaccination or IgE responses during allergic airway disease.


Assuntos
Células T Auxiliares Foliculares , Antígenos , Centro Germinativo , Imunoglobulina E , Imunoglobulina G , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores
9.
Methods Mol Biol ; 2380: 225-233, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802135

RESUMO

T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are the two T cell subsets able to interact with B cells driving germinal center (GC) reactions. These T-B interactions are important for protective immune responses within secondary lymphoid tissue. However, the pathological emergence of ectopic lymphoid structures (ELS) that characterize several autoimmune diseases also involves Tfh and Tfr cells. ELS, often with ectopic GCs, can be identified through biopsies. Sjögren's syndrome (SS) is an example of an autoimmune disease where minor salivary gland (MSG) biopsies are often performed for diagnosis and where ELS can be found. Here, we describe a protocol to identify and isolate T follicular cells from MSGs by flow cytometry and immunohistochemistry.


Assuntos
Síndrome de Sjogren , Células T Auxiliares Foliculares , Doenças Autoimunes , Linfócitos B , Centro Germinativo , Humanos , Síndrome de Sjogren/diagnóstico , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores
10.
Methods Mol Biol ; 2380: 255-265, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802137

RESUMO

T follicular helper (Tfh) cells are a subset of specialized CD4+ T cell residing in B cell follicles and confer essential support for germinal center responses, which lead to the generation of long-lived humoral immunity. A great deal of evidence from the past 15 years indicate that excessive differentiation and dysregulated function of Tfh cells often promote autoimmunity by inducing autoantibody production. Interleukin-2 was identified as a major suppressor to inhibit Tfh differentiation. Therefore, IL-2 treatment was applied in suppressing Tfh function in mouse models and more recently in a clinical trial of patients with systemic lupus erythematosus. Here we describe a protocol for low-dose IL-2 treatment in a murine immunization model and on the assessment of the suppression of Tfh response using flow cytometry.


Assuntos
Células T Auxiliares Foliculares , Animais , Autoimunidade , Linfócitos B , Diferenciação Celular , Centro Germinativo , Humanos , Interleucina-2 , Camundongos , Linfócitos T Auxiliares-Indutores
11.
Methods Mol Biol ; 2380: 267-288, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802138

RESUMO

Research on the human immune system is often restricted to peripheral blood cells. However, these cells can be different from those found in secondary lymphoid organs. For instance, specialized T and B cells that are localized in germinal centers (GCs), which are complex anatomical structures being required for the generation of potent antibodies, are not found in peripheral blood. Most T helper cells located in GCs belong to the T follicular helper (Tfh) cell subset, which provides critical support to B cells. Bona fide human GC Tfh cells can be obtained from secondary lymphoid tissues such as tonsils, which are routinely removed by surgery. We here describe a method that is based on human lymphoid histoculture (HLH) and human lymphoid aggregate culture (HLAC) to culture human adenoid (pharyngeal tonsil) tissue ex vivo, followed by deep Tfh cell phenotyping by flow cytometry. This method allows studying Tfh cells in a versatile explant culture system that preserves many aspects of the original in vivo three-dimensional (3D) structure, in parallel to single-cell suspension organoid cultures in which the original tissue structure is disintegrated. We also describe how this versatile platform can be used for drug testing or manipulation of human Tfh cells in vitro for mechanistic studies.


Assuntos
Células T Auxiliares Foliculares , Centro Germinativo , Humanos , Organoides , Tonsila Palatina , Preparações Farmacêuticas , Linfócitos T Auxiliares-Indutores , Técnicas de Cultura de Tecidos
12.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34901992

RESUMO

In this issue of JEM, He et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211004) associate novel P2RY8 genetic variants to lupus, expanding the field of monogenic autoimmunity. The authors demonstrate that P2RY8 prevents the expansion of DNA-reactive B cells by restraining B cell mobility and activation within the germinal center.


Assuntos
Centro Germinativo , Lúpus Eritematoso Sistêmico , Linfócitos B , DNA , Humanos , Lúpus Eritematoso Sistêmico/genética , Núcleo Familiar , Receptores Purinérgicos P2Y
13.
Front Immunol ; 12: 776933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34917089

RESUMO

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.


Assuntos
Linfócitos B/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Seleção Clonal Mediada por Antígeno/imunologia , Centro Germinativo/imunologia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/imunologia , Antígenos/imunologia , Linfócitos B/metabolismo , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Relação Dose-Resposta Imunológica , Centro Germinativo/metabolismo , Humanos , Imunização Secundária , Modelos Teóricos , Vacinação
14.
Front Immunol ; 12: 688493, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621263

RESUMO

The cohesin complex plays critical roles in genomic stability and gene expression through effects on 3D architecture. Cohesin core subunit genes are mutated across a wide cross-section of cancers, but not in germinal center (GC) derived lymphomas. In spite of this, haploinsufficiency of cohesin ATPase subunit Smc3 was shown to contribute to malignant transformation of GC B-cells in mice. Herein we explored potential mechanisms and clinical relevance of Smc3 deficiency in GC lymphomagenesis. Transcriptional profiling of Smc3 haploinsufficient murine lymphomas revealed downregulation of genes repressed by loss of epigenetic tumor suppressors Tet2 and Kmt2d. Profiling 3D chromosomal interactions in lymphomas revealed impaired enhancer-promoter interactions affecting genes like Tet2, which was aberrantly downregulated in Smc3 deficient lymphomas. Tet2 plays important roles in B-cell exit from the GC reaction, and single cell RNA-seq profiles and phenotypic trajectory analysis in Smc3 mutant mice revealed a specific defect in commitment to the final steps of plasma cell differentiation. Although Smc3 deficiency resulted in structural abnormalities in GC B-cells, there was no increase of somatic mutations or structural variants in Smc3 haploinsufficient lymphomas, suggesting that cohesin deficiency largely induces lymphomas through disruption of enhancer-promoter interactions of terminal differentiation and tumor suppressor genes. Strikingly, the presence of the Smc3 haploinsufficient GC B-cell transcriptional signature in human patients with GC-derived diffuse large B-cell lymphoma (DLBCL) was linked to inferior clinical outcome and low expression of cohesin core subunits. Reciprocally, reduced expression of cohesin subunits was an independent risk factor for worse survival int DLBCL patient cohorts. Collectively, the data suggest that Smc3 functions as a bona fide tumor suppressor for lymphomas through non-genetic mechanisms, and drives disease by disrupting the commitment of GC B-cells to the plasma cell fate.


Assuntos
Linfócitos B/imunologia , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Proteínas Cromossômicas não Histona/genética , Dosagem de Genes , Centro Germinativo/imunologia , Haploinsuficiência , Linfoma Difuso de Grandes Células B/genética , Plasmócitos/imunologia , Animais , Linfócitos B/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Células Cultivadas , Proteoglicanas de Sulfatos de Condroitina/imunologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Cromossômicas não Histona/imunologia , Proteínas Cromossômicas não Histona/metabolismo , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Genéticas , Dioxigenases/genética , Dioxigenases/metabolismo , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Centro Germinativo/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Fenótipo , Plasmócitos/metabolismo , Transcrição Genética
15.
Front Immunol ; 12: 731100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603308

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious infectious disease that has led to a global pandemic with high morbidity and mortality. High-affinity neutralizing antibody is important for controlling infection, which is closely regulated by follicular helper T (Tfh) cells. Tfh cells play a central role in promoting germinal center reactions and driving cognate B cell differentiation for antibody secretion. Available studies indicate a close relationship between virus-specific Tfh cell-mediated immunity and SARS-CoV-2 infection progression. Although several lines of evidence have suggested that Tfh cells contribute to the control of SARS-CoV-2 infection by eliciting neutralizing antibody productions, further studies are needed to elucidate Tfh-mediated effector mechanisms in anti-SARS-CoV-2 immunity. Here, we summarize the functional features and roles of virus-specific Tfh cells in the immunopathogenesis of SARS-CoV-2 infection and in COVID-19 vaccines, and highlight the potential of targeting Tfh cells as therapeutic strategy against SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , COVID-19/patologia , Vacinas contra COVID-19/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Ativação Linfocitária/imunologia , Células T Auxiliares Foliculares/citologia
16.
Immunity ; 54(10): 2182-2185, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644552

RESUMO

High levels of cholesterol and diets high in fat are associated with immune dysfunction and inflammatory disease. In this issue of Immunity, Trindade et al. (2021) report how the cholesterol metabolite 25-hydroxycholesterol restrains IgA plasma cell differentiation from germinal-center B cells in the Peyer's patches through regulation of the sterol-sensing transcription factor SREBP2, independently of EBI2-mediated migration.


Assuntos
Imunoglobulina A , Nódulos Linfáticos Agregados , Linfócitos B , Centro Germinativo , Hidroxicolesteróis
17.
J Immunol ; 207(9): 2255-2264, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599081

RESUMO

MHC class II (MHC II) Ag presentation by dendritic cells (DCs) is critical for CD4+ T cell immunity. Cell surface levels of MHC II loaded with peptide is controlled by ubiquitination. In this study, we have examined how MHC II ubiquitination impacts immunity using MHC IIKRKI/KI mice expressing mutant MHC II molecules that are unable to be ubiquitinated. Numbers of conventional DC (cDC) 1, cDC2 and plasmacytoid DCs were significantly reduced in MHC IIKRKI/KI spleen, with the remaining MHC IIKRKI/KI DCs expressing an altered surface phenotype. Whereas Ag uptake, endosomal pH, and cathepsin protease activity were unaltered, MHC IIKRKI/KI cDC1 produced increased inflammatory cytokines and possessed defects in Ag proteolysis. Immunization of MHC IIKRKI/KI mice identified impairments in MHC II and MHC class I presentation of soluble, cell-associated and/or DC-targeted OVA via mAb specific for DC surface receptor Clec9A (anti-Clec9A-OVA mAb). Reduced T cell responses and impaired CTL killing was observed in MHC IIKRKI/KI mice following immunization with cell-associated and anti-Clec9A-OVA. Immunization of MHC IIKRKI/KI mice failed to elicit follicular Th cell responses and generated barely detectable Ab to anti-Clec9A mAb-targeted Ag. In summary, MHC II ubiquitination in DCs impacts the homeostasis, phenotype, cytokine production, and Ag proteolysis by DCs with consequences for Ag presentation and T cell and Ab-mediated immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Centro Germinativo/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Animais , Apresentação do Antígeno/genética , Células Cultivadas , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe II/genética , Imunidade Celular , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Ubiquitinação
18.
Microbiome ; 9(1): 198, 2021 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-34602091

RESUMO

BACKGROUND: Intestinal Peyer's patches (PPs) form unique niches for bacteria-immune cell interactions that direct host immunity and shape the microbiome. Here we investigate how peroral administration of probiotic bacterium Limosilactobacillus reuteri R2LC affects B lymphocytes and IgA induction in the PPs, as well as the downstream consequences on intestinal microbiota and susceptibility to inflammation. RESULTS: The B cells of PPs were separated by size to circumvent activation-dependent cell identification biases due to dynamic expression of markers, which resulted in two phenotypically, transcriptionally, and spatially distinct subsets: small IgD+/GL7-/S1PR1+/Bcl6, CCR6-expressing pre-germinal center (GC)-like B cells with innate-like functions located subepithelially, and large GL7+/S1PR1-/Ki67+/Bcl6, CD69-expressing B cells with strong metabolic activity found in the GC. Peroral L. reuteri administration expanded both B cell subsets and enhanced the innate-like properties of pre-GC-like B cells while retaining them in the sub-epithelial compartment by increased sphingosine-1-phosphate/S1PR1 signaling. Furthermore, L. reuteri promoted GC-like B cell differentiation, which involved expansion of the GC area and autocrine TGFß-1 activation. Consequently, PD-1-T follicular helper cell-dependent IgA induction and production was increased by L. reuteri, which shifted the intestinal microbiome and protected against dextran-sulfate-sodium induced colitis and dysbiosis. CONCLUSIONS: The Peyer's patches sense, enhance and transmit probiotic signals by increasing the numbers and effector functions of distinct B cell subsets, resulting in increased IgA production, altered intestinal microbiota, and protection against inflammation. Video abstract.


Assuntos
Subpopulações de Linfócitos B , Probióticos , Centro Germinativo , Nódulos Linfáticos Agregados , Linfócitos T Auxiliares-Indutores
19.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638855

RESUMO

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, affecting approximately 1% of the general population. To alleviate symptoms and ameliorate joint damage, chronic use of immunosuppressives is needed. However, these treatments are only partially effective and may lead to unwanted side effects. Therefore, a more profound understanding of the pathophysiology might lead to more effective therapies, or better still, a cure. The presence of autoantibodies in RA indicates that B cells might have a pivotal role in the disease. This concept is further supported by the fact that a diverse antibody response to various arthritis-related epitopes is associated with arthritis development. In this context, attention has focused in recent years on the role of Germinal Centers (GCs) in RA. Since GCs act as the main anatomic location of somatic hypermutations, and, thus, contributing to the diversity and specificity of (auto) antibodies, it has been speculated that defects in germinal center reactions might be crucial in the initiation and maintenance of auto-immune events. In this paper, we discuss current evidence that various processes within GCs can result in the aberrant production of B cells that possess autoreactive properties and might result in the production of RA related autoantibodies. Secondly, we discuss various (pre-)clinical studies that have targeted various GC processes as novel therapies for RA treatment.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Linfócitos B/imunologia , Epitopos/imunologia , Centro Germinativo/imunologia , Imunidade Adaptativa/imunologia , Animais , Antígenos/imunologia , Apoptose/imunologia , Linfócitos B/metabolismo , Centro Germinativo/citologia , Humanos
20.
Immunity ; 54(9): 2005-2023.e10, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525339

RESUMO

Cell fate decisions during early B cell activation determine the outcome of responses to pathogens and vaccines. We examined the early B cell response to T-dependent antigen in mice by single-cell RNA sequencing. Early after immunization, a homogeneous population of activated precursors (APs) gave rise to a transient wave of plasmablasts (PBs), followed a day later by the emergence of germinal center B cells (GCBCs). Most APs rapidly exited the cell cycle, giving rise to non-GC-derived early memory B cells (eMBCs) that retained an AP-like transcriptional profile. Rapid decline of antigen availability controlled these events; provision of excess antigen precluded cell cycle exit and induced a new wave of PBs. Fate mapping revealed a prominent contribution of eMBCs to the MBC pool. Quiescent cells with an MBC phenotype dominated the early response to immunization in primates. A reservoir of APs/eMBCs may enable rapid readjustment of the immune response when failure to contain a threat is manifested by increased antigen availability.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunidade Humoral/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Animais , Apresentação do Antígeno/imunologia , Diferenciação Celular/imunologia , Camundongos , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia
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