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1.
Cell ; 172(3): 517-533.e20, 2018 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-29249358

RESUMEN

B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Inmunidad Innata , Gripe Humana/inmunología , Interleucina-4/genética , Células Asesinas Naturales/inmunología , Infección por el Virus Zika/inmunología , Animales , Pollos , Perros , Centro Germinal/citología , Humanos , Interleucina-4/metabolismo , Macaca , Macrófagos/inmunología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL
2.
Nat Immunol ; 21(6): 684-694, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32231301

RESUMEN

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citotoxicidad Inmunológica , Perfilación de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Células Asesinas Naturales/metabolismo , Transducción de Señal , Fiebre Amarilla/genética , Fiebre Amarilla/inmunología , Fiebre Amarilla/metabolismo , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/inmunología
3.
Nat Immunol ; 19(8): 859-870, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30013146

RESUMEN

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.


Asunto(s)
Linfocitos B/fisiología , Carcinoma de Células Escamosas/inmunología , Células Epiteliales/fisiología , Inmunoglobulina E/metabolismo , Linfocitos Intraepiteliales/fisiología , Neoplasias Experimentales/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de IgE/metabolismo , Animales , Antracenos/toxicidad , Carcinoma de Células Escamosas/diagnóstico , Muerte Celular , Células Cultivadas , Regiones Determinantes de Complementariedad/genética , Daño del ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/genética , Vigilancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Experimentales/inducido químicamente , Piperidinas/toxicidad , Pronóstico , Receptores de Antígenos de Linfocitos T gamma-delta/genética
4.
Nature ; 620(7974): 634-642, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37438525

RESUMEN

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1-3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.


Asunto(s)
Alérgenos , Reacción de Prevención , Hipersensibilidad , Mastocitos , Animales , Ratones , Alérgenos/inmunología , Reacción de Prevención/fisiología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Estómago/inmunología , Vagotomía , Inmunidad Innata/inmunología , Inmunidad Mucosa/inmunología , Células Th2/inmunología , Citocinas/inmunología , Leucotrienos/biosíntesis , Leucotrienos/inmunología , Intestino Delgado/inmunología
5.
Nature ; 607(7919): 585-592, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35732737

RESUMEN

The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate1. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms2. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration3. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.


Asunto(s)
Indoles , Regeneración Nerviosa , Propionatos , Cicatrización de Heridas , Animales , Ratones , Axones/efectos de los fármacos , Axones/fisiología , Quimiotaxis de Leucocito , Clostridium/metabolismo , Ayuno , Ganglios Espinales/metabolismo , Microbioma Gastrointestinal , Indoles/sangre , Indoles/metabolismo , Indoles/farmacología , Compresión Nerviosa , Factores de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa/efectos de los fármacos , Neutrófilos/citología , Neutrófilos/inmunología , Propionatos/sangre , Propionatos/metabolismo , Propionatos/farmacología , Recuperación de la Función , Nervio Ciático/lesiones , Análisis de Secuencia de ARN , Cicatrización de Heridas/efectos de los fármacos
6.
Nature ; 590(7844): 151-156, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33442055

RESUMEN

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.


Asunto(s)
Dolor Abdominal/inmunología , Dolor Abdominal/patología , Alérgenos/inmunología , Hipersensibilidad a los Alimentos/inmunología , Alimentos/efectos adversos , Intestinos/inmunología , Síndrome del Colon Irritable/inmunología , Dolor Abdominal/etiología , Dolor Abdominal/microbiología , Adulto , Animales , Citrobacter rodentium/inmunología , Diarrea/inmunología , Diarrea/microbiología , Diarrea/patología , Infecciones por Enterobacteriaceae/complicaciones , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/microbiología , Femenino , Hipersensibilidad a los Alimentos/complicaciones , Hipersensibilidad a los Alimentos/microbiología , Hipersensibilidad a los Alimentos/patología , Glútenes/inmunología , Humanos , Inmunoglobulina E/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/microbiología , Intestinos/patología , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/microbiología , Síndrome del Colon Irritable/patología , Masculino , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Leche/inmunología , Ovalbúmina/inmunología , Calidad de Vida , Receptores Histamínicos H1/metabolismo , Proteínas de Soja/inmunología , Triticum/inmunología
8.
J Immunol ; 207(12): 2976-2991, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34810221

RESUMEN

RUNX1 is a transcription factor that plays key roles in hematopoietic development and in hematopoiesis and lymphopoiesis. In this article, we report that RUNX1 regulates a gene expression program in naive mouse B cells that affects the dynamics of cell cycle entry in response to stimulation of the BCR. Conditional knockout of Runx1 in mouse resting B cells resulted in accelerated entry into S-phase after BCR engagement. Our results indicate that Runx1 regulates the cyclin D2 (Ccnd2) gene, the immediate early genes Fosl2, Atf3, and Egr2, and the Notch pathway gene Rbpj in mouse B cells, reducing the rate at which transcription of these genes increases after BCR stimulation. RUNX1 interacts with the chromatin remodeler SNF-2-related CREB-binding protein activator protein (SRCAP), recruiting it to promoter and enhancer regions of the Ccnd2 gene. BCR-mediated activation triggers switching between binding of RUNX1 and its paralog RUNX3 and between SRCAP and the switch/SNF remodeling complex member BRG1. Binding of BRG1 is increased at the Ccnd2 and Rbpj promoters in the Runx1 knockout cells after BCR stimulation. We also find that RUNX1 exerts positive or negative effects on a number of genes that affect the activation response of mouse resting B cells. These include Cd22 and Bank1, which act as negative regulators of the BCR, and the IFN receptor subunit gene Ifnar1 The hyperresponsiveness of the Runx1 knockout B cells to BCR stimulation and its role in regulating genes that are associated with immune regulation suggest that RUNX1 could be involved in regulating B cell tolerance.


Asunto(s)
Linfocitos B , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Animales , Linfocitos B/metabolismo , Ciclo Celular/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Hematopoyesis , Ratones , Regiones Promotoras Genéticas
9.
Nat Immunol ; 9(2): 146-54, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18176566

RESUMEN

The self-encoded ligands MICA (human) and Rae-1 (mouse) for the cytotoxic lymphocyte activating receptor NKG2D are highly expressed in carcinomas and inflammatory lesions and have been linked to immunosurveillance and graft rejection. However, whether NKG2D ligands have an intrinsic ability to acutely regulate tissue-associated immune compartments is not known. Here we show that epidermis-specific upregulation of Rae-1 induced rapid, coincident and reversible changes in the organization of tissue-resident V(gamma)5V(delta)1 TCRgammadelta+ intraepithelial T cells and Langerhans cells, swiftly followed by epithelial infiltration by unconventional alphabeta T cells. Whereas local V(gamma)5V(delta)1+ T cells limited carcinogenesis, Langerhans cells unexpectedly promoted it. These results provide unique insight into the early phases of tissue immunosurveillance and indicate that acute changes in NKG2D ligands may alone initiate a rapid, multifaceted immunosurveillance response in vivo.


Asunto(s)
Transformación Celular Neoplásica/inmunología , Epidermis/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Vigilancia Inmunológica , Células de Langerhans/inmunología , Neoplasias Cutáneas/inmunología , Animales , Ligandos , Ratones , Ratones Endogámicos , Subfamilia K de Receptores Similares a Lectina de Células NK , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Receptores Inmunológicos/metabolismo , Receptores de Células Asesinas Naturales , Linfocitos T/inmunología , Regulación hacia Arriba
10.
Semin Immunol ; 21(3): 110-20, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19369094

RESUMEN

Although studies of the skin have provided fundamental models for innate and adaptive immune surveillance of body surfaces, there remains relatively little understanding of the role that epithelial cells play in sensing infection and/or organ dysfunction, and the pathways available to them to communicate with local and systemic immune cells. In particular, evidence is emerging for a novel stress response initiated by local lymphocytes, rather than dendritic cells, and based on their recognition of epithelial stress-induced antigens. Its consequences are to sustain tissue integrity by providing immunoprotection and novel modes of immunoregulation, whereas its dysregulation may promote body surface immunopathologies.


Asunto(s)
Células de Langerhans/inmunología , Células de Langerhans/metabolismo , Piel/inmunología , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Autoantígenos/inmunología , Comunicación Celular , Movimiento Celular , Citocinas/metabolismo , Humanos , Vigilancia Inmunológica , Queratinocitos/inmunología , Queratinocitos/metabolismo , Queratinocitos/patología , Activación de Linfocitos , Piel/patología , Estrés Fisiológico
11.
Elife ; 122023 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-37566453

RESUMEN

Monocytes are heterogeneous innate effector leukocytes generated in the bone marrow and released into circulation in a CCR2-dependent manner. During infection or inflammation, myelopoiesis is modulated to rapidly meet the demand for more effector cells. Danger signals from peripheral tissues can influence this process. Herein we demonstrate that repetitive TLR7 stimulation via the epithelial barriers drove a potent emergency bone marrow monocyte response in mice. This process was unique to TLR7 activation and occurred independently of the canonical CCR2 and CX3CR1 axes or prototypical cytokines. The monocytes egressing the bone marrow had an immature Ly6C-high profile and differentiated into vascular Ly6C-low monocytes and tissue macrophages in multiple organs. They displayed a blunted cytokine response to further TLR7 stimulation and reduced lung viral load after RSV and influenza virus infection. These data provide insights into the emergency myelopoiesis likely to occur in response to the encounter of single-stranded RNA viruses at barrier sites.


Asunto(s)
Mielopoyesis , Receptor Toll-Like 7 , Virosis , Animales , Ratones , Citocinas , Pulmón , Ratones Endogámicos C57BL , Monocitos , Receptor Toll-Like 7/genética , Virosis/inmunología
12.
J Immunother Cancer ; 10(9)2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36162919

RESUMEN

Type 1 conventional dendritic cells (cDC1) play a critical role in priming anticancer cytotoxic CD8+ T cells. DNGR-1 (a.k.a. CLEC9A) is a cDC1 receptor that binds to F-actin exposed on necrotic cancer and normal cells. DNGR-1 signaling enhances cross-presentation of dead-cell associated antigens, including tumor antigens. We have recently shown that secreted gelsolin (sGSN), a plasma protein, competes with DNGR-1 for binding to dead cell-exposed F-actin and dampens anticancer immunity. Here, we investigated the effects of loss of sGSN on various anticancer therapies that are thought to induce cell death and provoke an immune response to cancer. We compared WT (wildtype) with Rag1-/- , Batf3-/- , Clec9agfp/gfp , sGsn-/- or sGsn-/- Clec9agfp/gfp mice implanted with transplantable tumor cell lines, including MCA-205 fibrosarcoma, 5555 BrafV600E melanoma and B16-F10 LifeAct (LA)-ovalbumin (OVA)-mCherry melanoma. Tumor-bearing mice were treated with (1) doxorubicin (intratumoral) chemotherapy for MCA-205, (2) BRAF-inhibitor PLX4720 (oral gavage) targeted therapy for 5555 BrafV600E, and (3) X-ray radiotherapy for B16 LA-OVA-mCherry. We confirmed that efficient tumor control following each therapy requires an immunocompetent host as efficacy was markedly reduced in Rag1-/- compared with WT mice. Notably, across all the therapeutic modalities, loss of sGSN significantly enhanced tumor control compared with treated WT controls. This was an on-target effect as mice deficient in both sGSN and DNGR-1 behaved no differently from WT mice following therapy. In sum, we find that mice deficient in sGsn display enhanced DNGR-1-dependent responsiveness to chemotherapy, targeted therapy and radiotherapy. Our findings are consistent with the notion some cancer therapies induce immunogenic cell death (ICD), which mobilizes anticancer T cells. Our results point to cDC1 and DNGR-1 as decoders of ICD and to sGSN as a negative regulator of such decoding, highlighting sGSN as a possible target in cancer treatment. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function.


Asunto(s)
Gelsolina , Melanoma Experimental , Actinas/metabolismo , Animales , Antígenos de Neoplasias/metabolismo , Linfocitos T CD8-positivos , Doxorrubicina/metabolismo , Gelsolina/genética , Gelsolina/metabolismo , Proteínas de Homeodominio , Lectinas Tipo C , Ratones , Ovalbúmina , Proteínas Proto-Oncogénicas B-raf/metabolismo , Receptores Inmunológicos/metabolismo
13.
Science ; 376(6594): eabd5926, 2022 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-35549409

RESUMEN

Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice. Lymphotoxin activated the transcription factor NF-κB, which induced expression of the chemokine CXCL13 by neurons. This in turn recruited CXCR5+CD8+ T cells to injured DRG neurons overexpressing major histocompatibility complex class I. CD8+ T cells repressed the axonal regeneration of DRG neurons via caspase 3 activation. CXCL13 neutralization prevented CXCR5+CD8+ T cell recruitment to the DRG and reversed aging-dependent regenerative decline, thereby promoting neurological recovery after SNI. Thus, axonal regeneration can be facilitated by antagonizing cross-talk between immune cells and neurons.


Asunto(s)
Envejecimiento , Axones , Linfocitos T CD8-positivos , Ganglios Espinales , Regeneración Nerviosa , Neuronas , Nervio Ciático , Envejecimiento/metabolismo , Animales , Axones/fisiología , Linfocitos T CD8-positivos/metabolismo , Ganglios Espinales/metabolismo , Ratones , Neuronas/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/fisiología
14.
J Invest Dermatol ; 141(2): 404-414.e6, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32682912

RESUMEN

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.


Asunto(s)
Carcinoma de Células Escamosas/inmunología , Complemento C3/metabolismo , Neoplasias Experimentales/inmunología , Neoplasias Cutáneas/inmunología , 9,10-Dimetil-1,2-benzantraceno/administración & dosificación , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Carcinógenos/administración & dosificación , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Activación de Complemento/genética , Activación de Complemento/inmunología , Complemento C3/genética , Complemento C5/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales/sangre , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/metabolismo , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Escape del Tumor
15.
Br J Nutr ; 103(9): 1278-86, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20100372

RESUMEN

The aim of the present systematic review was to evaluate the influence of early life exposure (maternal and childhood) to peanuts and the subsequent development of sensitisation or allergy to peanuts during childhood. Studies were identified using electronic databases and bibliography searches. Studies that assessed the impact of non-avoidance compared with avoidance or reduced quantities of peanuts or peanut products on either sensitisation or allergy to peanuts, or both outcomes, were eligible. Six human studies were identified: two randomised controlled trials, two case-control studies and two cross-sectional studies. In addition, published animal and mechanistic studies, relevant to the question of whether early life exposure to peanuts affects the subsequent development of peanut sensitisation, were reviewed narratively. Overall, the evidence reviewed was heterogeneous, and was limited in quality, for example, through lack of adjustment for potentially confounding factors. The nature of the evidence has therefore hindered the development of definitive conclusions. The systematic review of human studies and narrative expert-led reviews of animal studies do not provide clear evidence to suggest that either maternal exposure, or early or delayed introduction of peanuts in the diets of children, has an impact upon subsequent development of sensitisation or allergy to peanuts. Results from some animal studies (and limited evidence from human subjects) suggest that the dose of peanuts is an important mediator of peanut sensitisation and tolerance; low doses tend to lead to sensitisation and higher doses tend to lead to tolerance.


Asunto(s)
Arachis/inmunología , Hipersensibilidad al Cacahuete/epidemiología , Preescolar , Dieta , Femenino , Humanos , Lactante , Leche Humana , Hipersensibilidad al Cacahuete/etiología
16.
Elife ; 92020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31931959

RESUMEN

IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE antibodies is unclear but it has been suggested that they provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show, in mice, that skin inflammation enhances levels of IgE antibodies that have natural specificities and a repertoire, VDJ rearrangements and CDRH3 characteristics similar to those of IgE antibodies in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and thymic stromal lymphopoietin (TSLP)/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE antibodies support skin barrier defences, but that during chronic tissue inflammation this role may be subverted to promote tumour growth.


Asunto(s)
Células Epiteliales/fisiología , Hiperplasia/fisiopatología , Inmunoglobulina E/metabolismo , Inflamación/fisiopatología , Animales , Femenino , Ratones , Ratones Transgénicos , Neoplasias/fisiopatología
17.
Cell Microbiol ; 10(8): 1634-45, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18397383

RESUMEN

Phagocytosis of microbial pathogens is essential for the host immune response to infection. Our previous work has shown that lipooligosaccharide (LOS) expression on the surface of Neisseria meningitidis (Nm) is essential for phagocytosis, but the receptor involved remained unclear. In this study, we show that human CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are phagocytic receptors for Nm as illustrated by the capacity of CR3- and CR4-transfected Chinese hamster ovary (CHO) cells to facilitate Nm uptake. A CR3-signalling mutant failed to internalize Nm, showing that the ability of CR3 to signal is essential for phagocytosis. Internalization of Nm by CR3-transfected CHO cells could be inhibited by the presence of CR3-specific antibodies. Furthermore, dendritic cells from leukocyte adhesion deficiency-1 patients, who have diminished expression of beta2 integrins, showed markedly reduced phagocytosis of Nm. The CR3-mediated phagocytosis required the presence of lipopolysaccharide-binding protein (LBP). Furthermore, the expression of LOS by Nm was essential for LBP binding and phagocytosis via CR3. These results reveal a critical role of CR3 and LBP in the phagocytosis of Nm and provide important insights into the initial interaction meningococci have with the immune system.


Asunto(s)
Proteínas de Fase Aguda/inmunología , Antígenos CD18/inmunología , Proteínas Portadoras/inmunología , Glicoproteínas de Membrana/inmunología , Neisseria meningitidis/inmunología , Fagocitosis , Animales , Antígeno CD11b/inmunología , Cricetinae , Células Dendríticas/inmunología , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/inmunología , Síndrome de Deficiencia de Adhesión del Leucocito/inmunología , Lipopolisacáridos/inmunología , Antígeno de Macrófago-1/genética , Antígeno de Macrófago-1/inmunología
18.
Sci Immunol ; 4(38)2019 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-31444235

RESUMEN

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.


Asunto(s)
Células de Langerhans/inmunología , Monocitos/inmunología , Animales , Células Cultivadas , Humanos , Células de Langerhans/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos
19.
Front Immunol ; 9: 851, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29740448

RESUMEN

Natural killer cell receptors (NKRs) are germline-encoded transmembrane proteins that regulate the activation and homeostasis of NK cells as well as other lymphocytes. For γδ T cells, NKRs play critical roles in discriminating stressed (transformed or infected) cells from their healthy counterparts, as proposed in the "lymphoid stress-surveillance" theory. Whereas the main physiologic role is seemingly fulfilled by natural killer group 2 member D, constitutively expressed by γδ T cells, enhancement of their therapeutic potential may rely on natural cytotoxicity receptors (NCRs), like NKp30 or NKp44, that can be induced selectively on human Vδ1+ T cells. Here, we review the contributions of NCRs, NKG2D, and their multiple ligands, to γδ T cell biology in mouse and human.


Asunto(s)
Citotoxicidad Inmunológica , Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Linfocitos T/inmunología , Animales , Humanos , Activación de Linfocitos , Ratones , Receptor 2 Gatillante de la Citotoxidad Natural/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética
20.
Science ; 360(6388): 558-563, 2018 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-29724957

RESUMEN

Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD8-positivos/metabolismo , Complemento C1q/fisiología , Lupus Eritematoso Sistémico/inmunología , Coriomeningitis Linfocítica/inmunología , Animales , Autoanticuerpos/inmunología , Autoinmunidad/genética , Complemento C1q/genética , Complemento C3/genética , Complemento C3/fisiología , Vía Clásica del Complemento/genética , Vía Clásica del Complemento/inmunología , Modelos Animales de Enfermedad , Inmunoglobulinas/inmunología , Memoria Inmunológica/inmunología , Lupus Eritematoso Sistémico/genética , Coriomeningitis Linfocítica/genética , Ratones , Ratones Mutantes
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