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1.
bioRxiv ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39345367

RESUMEN

Mechanisms that restrict class switch recombination (CSR) to IgE limit the subsequent production of IgE antibodies and therefore the development of allergic disease. Mice with impaired B cell receptor (BCR) signaling have significantly increased IgE responses, consistent with a role for BCR signaling in IgE regulation. While prior work focused on BCR signaling in IgE-expressing cells to explain these findings, it has been reported that BCR signaling can reduce CSR. Therefore, we investigated the possibility that IgE CSR might be particularly sensitive to inhibition by BCR signaling in unswitched B cells. We found that immunization of mice with high-affinity antigen resulted in reduced representation of IgE-expressing cells among germinal center B cells and plasma cells relative to a low-affinity antigen. Mechanistic experiments with cultured mouse B cells demonstrated that BCR ligands selectively inhibited IgE CSR in a dose-, affinity-, and avidity-dependent manner. Signaling via Syk was required for the inhibition of IgE CSR following BCR stimulation, whereas inhibition of the PI3K subunit p110δ increased IgE CSR independently of BCR ligation. The inhibition of IgE CSR by BCR ligands synergized with IL-21 or TGFß1. BCR ligation also inhibited CSR to IgE in human tonsillar B cells, and this inhibition was also synergistic with IL-21. These findings establish that IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.

2.
J Exp Med ; 220(4)2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-36880536

RESUMEN

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.


Asunto(s)
Hipersensibilidad , Células Plasmáticas , Animales , Ratones , Apoptosis , Núcleo Celular , Supervivencia Celular , Inmunosupresores , Receptores de Antígenos de Linfocitos B/inmunología
3.
Elife ; 112022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36173678

RESUMEN

In allergic asthma, allergen inhalation leads to local Th2 cell activation and peribronchial inflammation. However, the mechanisms for local antigen capture and presentation remain unclear. By two-photon microscopy of the mouse lung, we established that soluble antigens in the bronchial airway lumen were efficiently captured and presented by a population of CD11c+ interstitial macrophages with high CX3CR1-GFP and MHC class II expression. We refer to these cells as Bronchus-Associated Macrophages (BAMs) based on their localization underneath the bronchial epithelium. BAMs were enriched in collagen-rich regions near some airway branchpoints, where inhaled antigens are likely to deposit. BAMs engaged in extended interactions with effector Th2 cells and promoted Th2 cytokine production. BAMs were also often in contact with dendritic cells (DCs). After exposure to inflammatory stimuli, DCs migrated to draining lymph nodes, whereas BAMs remained lung resident. We propose that BAMs act as local antigen presenting cells in the lung and also transfer antigen to DCs.


Asunto(s)
Células Dendríticas , Células Th2 , Alérgenos , Animales , Bronquios , Citocinas , Pulmón/patología , Macrófagos , Ratones
4.
Front Immunol ; 13: 880887, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35634278

RESUMEN

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of P2rx4 in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.


Asunto(s)
Conexina 43 , Fibrosis Pulmonar Idiopática , Adenosina Trifosfato/metabolismo , Animales , Bleomicina/farmacología , Calcio/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Noqueados
5.
Science ; 375(6581): eabi5965, 2022 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-35143305

RESUMEN

Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on Gα13 and adhesion G protein-coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s.


Asunto(s)
Células Dendríticas/fisiología , Eritrocitos/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Bazo/citología , Bazo/inmunología , Actinas/metabolismo , Animales , Presentación de Antígeno , Antígenos/inmunología , Circulación Sanguínea , Antígenos CD55/sangre , Antígenos CD55/metabolismo , Movimiento Celular , Células Dendríticas/inmunología , Eritrocitos/metabolismo , Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo , Homeostasis , Factores Reguladores del Interferón/metabolismo , Ligandos , Ratones , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Bazo/irrigación sanguínea , Bazo/metabolismo , Transcripción Genética , Transcriptoma
6.
J Immunol ; 208(2): 257-266, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-35017215

RESUMEN

This Brief Review delves into B cell responses in the context of allergy. The primary contribution of B cells to allergy is the production of IgE, the Ab isotype that triggers immediate hypersensitivity reactions through the release of mediators from mast cells and basophils. B cells may also have protective roles in allergy, such as through the production of IgG or as regulatory B cells. In this review, I focus on the basic principles of B cell differentiation and discuss features relevant to allergic immune responses. In particular, I discuss: (1) class-switch recombination; (2) plasma cell differentiation; (3) germinal centers and affinity maturation; and (4) memory B cells and recall responses, with an emphasis on IgE, IgG1, and IgG4. I also consider how B cells may contribute to allergic responses independent of Ab production-for example, by serving as APCs.


Asunto(s)
Linfocitos B/inmunología , Diferenciación Celular/inmunología , Hipersensibilidad Inmediata/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina E/inmunología , Linfocitos B Reguladores/inmunología , Basófilos/inmunología , Centro Germinal/inmunología , Humanos , Hipersensibilidad Inmediata/patología , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Memoria Inmunológica/inmunología , Activación de Linfocitos/inmunología , Mastocitos/inmunología , Células B de Memoria/inmunología , Células Plasmáticas/citología , Células Plasmáticas/inmunología
7.
J Exp Med ; 218(11)2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34586363

RESUMEN

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222-deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.


Asunto(s)
Cambio de Clase de Inmunoglobulina/genética , MicroARNs/genética , Recombinación Genética/genética , Animales , Linfocitos B/inmunología , Femenino , Expresión Génica/genética , Expresión Génica/inmunología , Redes Reguladoras de Genes/genética , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina E/genética , Inmunoglobulina G/genética , Masculino , Ratones , MicroARNs/inmunología , Recombinación Genética/inmunología
8.
Curr Opin Immunol ; 72: 221-229, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34216934

RESUMEN

Stringent regulation of IgE antibody production is critical for constraining allergic responses. This review discusses recent advances in understanding cell-intrinsic and extrinsic mechanisms that regulate the genesis and fate of IgE B cells. B cell-intrinsic regulation of IgE is orchestrated by the IgE B Cell Receptor (BCR). Through its antigen-independent signaling and low surface expression, the IgE BCR drives IgE B cells to differentiate into short-lived plasma cells and/or undergo apoptosis, restricting IgE-expressing cells from entering long-lived compartments. The pivotal extrinsic regulators of IgE responses are T follicular helper cells (TFH). TFH produce IL-4 and IL-21, which, respectively, are the major activating and inhibitory cytokines for IgE class-switching. Other newly identified T follicular subsets also contribute to IgE regulation. Although IgE responses are normally constrained, recent studies suggest that specific conditions can induce the formation of IgE responses with enhanced affinity or longevity, effectively 'breaking the rules' of IgE regulation.


Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Inmunoglobulina E/inmunología , Inmunomodulación , Animales , Formación de Anticuerpos/genética , Apoptosis/genética , Apoptosis/inmunología , Linfocitos B/metabolismo , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Memoria Inmunológica , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo
9.
J Exp Med ; 217(5)2020 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-32130409

RESUMEN

IgE antibodies may elicit potent allergic reactions, and their production is tightly controlled. The tendency to generate IgE has been thought to reflect the balance between type 1 and type 2 cytokines, with the latter promoting IgE. Here, we reevaluated this paradigm by a direct cellular analysis, demonstrating that IgE production was not limited to type 2 immune responses yet was generally constrained in vivo. IL-21 was a critical negative regulator of IgE responses, whereas IFN-γ, IL-6, and IL-10 were dispensable. Follicular helper T cells were the primary source of IL-21 that inhibited IgE responses by directly engaging the IL-21 receptor on B cells and triggering STAT3-dependent signaling. We reconciled previous discordant results between mouse and human B cells and revealed that the inhibition of IgE class switch recombination by IL-21 was attenuated by CD40 signaling, whereas IgG1 class switch recombination was potentiated by IL-21 in the context of limited IL-4. These findings establish key features of the extrinsic regulation of IgE production by cytokines.


Asunto(s)
Linfocitos B/inmunología , Cambio de Clase de Inmunoglobulina/genética , Inmunoglobulina E/genética , Interleucinas/metabolismo , Animales , Apoptosis , Antígenos CD40/metabolismo , Recuento de Células , Centro Germinal/citología , Humanos , Inmunidad , Inmunoglobulina G/metabolismo , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ganglios Linfáticos/citología , Ratones , Modelos Biológicos , Células Plasmáticas/metabolismo , Receptores de Interleucina-21/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células T Auxiliares Foliculares/metabolismo
10.
Cell ; 177(3): 524-540, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-31002794

RESUMEN

B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.


Asunto(s)
Linfocitos B/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/metabolismo , Antígenos/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Memoria Inmunológica , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Vacunas/inmunología
12.
Methods Mol Biol ; 1799: 247-264, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29956157

RESUMEN

Immunoglobulin E (IgE) is the least abundant antibody isotype in mammalians, yet it plays a critical role in allergy and asthma. IgE-producing (IgE+) B cells are rare and difficult to detect, which have hindered progress to understand their generation and differentiation. Recently developed new fluorescent IgE reporter mice have enabled better understanding of the biology of IgE+ B cells. We here describe the usage of the Verigem IgE reporter mouse to study IgE+ B cells and plasma cells by flow cytometry and microscopy.


Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Inmunoglobulina E/biosíntesis , Inmunoglobulina E/inmunología , Animales , Formación de Anticuerpos/genética , Técnicas de Cultivo de Célula , Citometría de Flujo , Expresión Génica , Genes Reporteros , Sitios Genéticos , Centro Germinal/inmunología , Centro Germinal/metabolismo , Inmunización , Inmunoglobulina E/genética , Ratones , Microscopía , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo
13.
J Immunol Methods ; 457: 33-40, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29614266

RESUMEN

Genome editing in human cells with targeted nucleases now enables diverse experimental and therapeutic genome engineering applications, but extension to primary human B cells remains limited. Here we report a method for targeted genetic engineering in primary human B cells, utilizing electroporation of CRISPR-Cas9 ribonucleoproteins (RNPs) to introduce gene knockout mutations at protein-coding loci with high efficiencies that in some cases exceeded 80%. Further, we demonstrate knock-in editing of targeted nucleotides with efficiency exceeding 10% through co-delivery of oligonucleotide templates for homology directed repair. We delivered Cas9 RNPs in two distinct in vitro culture systems to achieve editing in both undifferentiated B cells and activated B cells undergoing differentiation, reflecting utility in diverse experimental conditions. In summary, we demonstrate a powerful and scalable research tool for functional genetic studies of human B cell biology that may have further applications in engineered B cell therapeutics.


Asunto(s)
Linfocitos B/citología , Sistemas CRISPR-Cas , Ingeniería Genética , Ribonucleoproteínas/genética , Adolescente , Adulto , Linfocitos B/inmunología , Línea Celular , Técnicas de Inactivación de Genes , Humanos , Mutación , Tonsila Palatina/citología , Reparación del ADN por Recombinación , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Adulto Joven
14.
Dev Biol ; 444 Suppl 1: S252-S261, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29501457

RESUMEN

To move directionally, cells can bias the generation of protrusions or select among randomly generated protrusions. Here we use 3D two-photon imaging of chick branchial arch 2 directed neural crest cells to probe how these mechanisms contribute to directed movement, whether a subset or the majority of cells polarize during movement, and how the different classes of protrusions relate to one another. We find that, in contrast to Xenopus, cells throughout the stream are morphologically polarized along the direction of overall stream movement and do not exhibit contact inhibition of locomotion. Instead chick neural crest cells display a progressive sharpening of the morphological polarity program. Neural crest cells have weak spatial biases in filopodia generation and lifetime. Local bursts of filopodial generation precede the generation of larger protrusions. These larger protrusions are more spatially biased than the filopodia, and the subset of protrusions that are productive for motility are the most polarized of all. Orientation rather than position is the best correlate of the protrusions that are selected for cell guidance. This progressive polarity refinement strategy may enable neural crest cells to efficiently explore their environment and migrate accurately in the face of noisy guidance cues.


Asunto(s)
Movimiento Celular/fisiología , Cresta Neural/embriología , Cresta Neural/fisiología , Animales , Región Branquial/embriología , Polaridad Celular/fisiología , Embrión de Pollo , Pollos , Inhibición de Contacto , Cresta Neural/metabolismo , Seudópodos/fisiología , Cráneo/embriología
15.
Methods Mol Biol ; 1707: 39-49, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29388098

RESUMEN

B cells, after activation, can undergo class-switch recombination and somatic hypermutation of their immunoglobulin genes, and can differentiate into memory cells and plasma cells. Expressing genes in altered versions in primary B cells and B cell lines is an important approach to understanding how B cell receptor signaling leads to B cell activation and differentiation. Recombinant retrovirus-based transduction is the most efficient method to deliver exogenous genes for expression in B cells. In this chapter, we describe streamlined protocols for using recombinant retroviral vectors to transduce both murine primary B cells and B cell lines.


Asunto(s)
Linfocitos B/metabolismo , Expresión Génica , Vectores Genéticos/genética , Retroviridae/genética , Transducción Genética/métodos , Animales , Linfocitos B/citología , Línea Celular , Humanos , Ratones , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética
16.
J Exp Med ; 214(3): 639-649, 2017 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-28143955

RESUMEN

Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1+ GC B cells increases during the course of an immune response with Ephrin-B1+ GC B cells displaying elevated levels of Bcl6, S1pr2, and Aicda relative to their Ephrin-B1- counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1+ GC B cells that have begun to down-regulate Bcl6 and S1pr2 and express markers associated with memory B cells, such as CD38 and EBI2. Transcriptional analysis indicates that these cells are developmentally related to memory B cells, and likely represent a population of GC memory precursor (PreMem) B cells. GC PreMem cells display enhanced survival relative to bulk GC B cells, localize near the edge of the GC, and are predominantly found within the light zone. These findings offer insight into the significant heterogeneity that exists within the GC B cell population and provide tools to further dissect signals regulating the differentiation of GC B cells.


Asunto(s)
Linfocitos B/inmunología , Efrina-B1/fisiología , Centro Germinal/inmunología , Memoria Inmunológica , Animales , Biomarcadores , Efrina-B1/análisis , Ratones , Ratones Endogámicos C57BL , Receptores de Lisoesfingolípidos/análisis , Receptores de Esfingosina-1-Fosfato , Sindecano-1/análisis
17.
J Immunol ; 198(5): 1815-1822, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28115531

RESUMEN

Polymorphisms in genes involved in IL-4 responses segregate with allergic disease risk and correlate with IgE levels in humans, and IL-4 promotes IgE and IgG1 Ab production against allergens in mice. We report that mice with only one intact Il4 gene copy are significantly impaired in their ability to make specific IgE responses against allergens, whereas IgG1 responses to allergens remain unaffected. Il4-hemizygosity also resulted in a modest but detectable drop in IL-4 production by CD4+ T cells isolated from lymph nodes and prevented IgE-dependent oral allergen-induced diarrhea. We conclude that a state of haploinsufficiency for the Il4 gene locus is specifically relevant for IL-4-dependent IgE responses to allergens with the amount of IL-4 produced in the hemizygous condition falling close to the threshold required for switching to IgE production. These results may be relevant for how polymorphisms in genes affecting IL-4 responses influence the risk of IgE-mediated allergic disease in humans.


Asunto(s)
Alérgenos/inmunología , Haploinsuficiencia , Inmunoglobulina E/inmunología , Interleucina-4/genética , Animales , Linfocitos T CD4-Positivos/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/inmunología , Interleucina-4/inmunología , Ratones , Polen/inmunología , Polimorfismo Genético
18.
Elife ; 52016 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-27935477

RESUMEN

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.


Asunto(s)
Linfocitos B/inmunología , Inmunoglobulina E/metabolismo , Activación de Linfocitos , Receptores de IgE/metabolismo , Animales , Apoptosis , Proliferación Celular , Células Cultivadas , Ratones Endogámicos C57BL
19.
Immunity ; 42(5): 783-5, 2015 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-25992852

RESUMEN

Fas is a cell surface death receptor critical for immune regulation. In this issue of Immunity, Butt et al. (2015) show that Fas eliminates B cells that have become uncoupled from positive and negative selection in the germinal center.


Asunto(s)
Autoanticuerpos/inmunología , Linfocitos B/citología , Centro Germinal/citología , Centro Germinal/inmunología , Inmunoglobulina E/inmunología , Receptor fas/inmunología , Animales , Humanos
20.
J Exp Med ; 212(4): 513-24, 2015 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-25779634

RESUMEN

Vertebrate immunity has evolved a modular architecture in response to perturbations. Allergic inflammation represents such a module, with signature features of antigen-specific IgE and tissue eosinophilia, although the cellular and molecular circuitry coupling these responses remains unclear. Here, we use genetic and imaging approaches in models of IgE-dependent eosinophilic dermatitis to demonstrate a requisite role for basophils. After antigenic inflammation, basophils initiate transmigration like other granulocytes but, upon activation via their high-affinity IgE receptor, alter their migratory kinetics to persist at the endothelium. Prolonged basophil-endothelial interactions, in part dependent on activation of focal adhesion kinases, promote delivery of basophil-derived IL-4 to the endothelium and subsequent induction of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is required for eosinophil accumulation. Thus, basophils are gatekeepers that link adaptive immunity with innate effector programs by altering access to tissue sites by activation-induced interactions with the endothelium.


Asunto(s)
Basófilos/inmunología , Células Endoteliales/inmunología , Eosinófilos/inmunología , Inmunoglobulina E/inmunología , Migración Transendotelial y Transepitelial/inmunología , Animales , Basófilos/patología , Comunicación Celular , Dermatitis/inmunología , Dermatitis/patología , Células Endoteliales/metabolismo , Eosinófilos/patología , Inmunidad Innata/genética , Interleucina-4/genética , Interleucina-4/inmunología , Ratones , Ratones Noqueados , Migración Transendotelial y Transepitelial/genética , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunología
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