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1.
Immunity ; 55(7): 1250-1267.e12, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35709757

RESUMEN

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.


Asunto(s)
Enfermedades Transmisibles , Microbiota , Animales , Eosinófilos , Homeostasis , Mucosa Intestinal , Intestino Delgado , Ratones
2.
Trends Immunol ; 36(8): 460-70, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26169256

RESUMEN

The immune system has developed strategies to maintain a homeostatic relationship with the resident microbiota. IgA is central in holding this relationship, as the most dominant immunoglobulin isotype at the mucosal surface of the intestine. Recent studies report a role for IgA in shaping the composition of the intestinal microbiota and exploit strategies to characterise IgA-binding bacteria for their inflammatory potential. We review these findings here, and place them in context of the current understanding of the range of microorganisms that contribute to the IgA repertoire and the pathways that determine the quality of the IgA response. We examine why only certain intestinal microbes are coated with IgA, and discuss how understanding the determinants of this specific responsiveness may provide insight into diseases associated with dysbiosis.


Asunto(s)
Inmunoglobulina A/inmunología , Intestinos/inmunología , Intestinos/microbiología , Animales , Microbioma Gastrointestinal/inmunología , Humanos
3.
J Allergy Clin Immunol ; 136(6): 1653-1663.e7, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26025126

RESUMEN

BACKGROUND: Group 2 innate lymphoid cells (ILC2) have been implicated in the pathogenesis of allergic lung diseases. However, the upstream signals that regulate ILC2 function during pulmonary inflammation remain poorly understood. ILC2s have been shown to respond to exogenous IL-2, but the importance of endogenous IL-2 in ILC2 function in vivo remains unclear. OBJECTIVE: We sought to understand the role of IL-2 in the regulation of ILC2 function in the lung. METHODS: We used histology, flow cytometry, immunohistochemistry, ELISA, and quantitative PCR with knockout and reporter mice to dissect pulmonary ILC2 function in vivo. We examined the role of ILC2s in eosinophilic crystalline pneumonia, an idiopathic type 2 inflammatory lung condition of mice, and the effect of IL-2 deficiency on this disease. We determined the effect of IL-2 administration on pulmonary ILC2 numbers and function in mice in the steady state and after challenge with IL-33. RESULTS: We discovered an unexpected role for innate cell-derived IL-2 as a major cofactor of ILC2 function during pulmonary inflammation. Specifically, we found that IL-2 was essential for the development of eosinophilic crystalline pneumonia, a type 2 disease characterized by increased numbers of activated ILC2s. We show that IL-2 signaling serves 2 distinct functions in lung ILC2s, namely promoting cell survival/proliferation and serving as a cofactor for the production of type 2 cytokines. We further demonstrate that group 3 innate lymphoid cells are an innate immune source of IL-2 in the lung. CONCLUSION: Innate cell-derived IL-2 is a critical cofactor in regulating ILC2 function in pulmonary type 2 pathology.


Asunto(s)
Interleucina-2/inmunología , Linfocitos/inmunología , Neumonía/inmunología , Eosinofilia Pulmonar/inmunología , Animales , Citocinas/sangre , Citocinas/inmunología , Proteínas de Unión al ADN/genética , Femenino , Proteínas de Homeodominio/genética , Inmunidad Innata/inmunología , Interleucina-2/genética , Pulmón/citología , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Noqueados , Neumonía/sangre , Eosinofilia Pulmonar/sangre , Bazo/inmunología
4.
Clin Immunol ; 159(2): 170-6, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25988860

RESUMEN

The increase in allergic diseases over the past several decades is correlated with changes in the composition and diversity of the intestinal microbiota. Microbial-derived signals are critical for instructing the developing immune system and conversely, immune regulation can impact the microbiota. Perturbations in the microbiota composition may be especially important during early-life when the immune system is still developing, resulting in a critical window of opportunity for instructing the immune system. This review highlights recent studies investigating the role of the microbiome in susceptibility or development of allergic diseases with a focus on animal models that provide insight into the mechanisms and pathways involved. Identification of a causal link between reduced microbial diversity or altered microbial composition and increased susceptibility to immune-mediated diseases will hopefully pave the way for better preventive therapies.


Asunto(s)
Biodiversidad , Parto Obstétrico , Dieta , Microbioma Gastrointestinal/inmunología , Vida Libre de Gérmenes/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Pulmón/microbiología , Animales , Asma/inmunología , Asma/microbiología , Susceptibilidad a Enfermedades , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/microbiología , Humanos , Hipótesis de la Higiene , Hipersensibilidad/microbiología , Intestinos/inmunología , Intestinos/microbiología , Ratones
5.
Atherosclerosis ; 299: 1-8, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32179207

RESUMEN

BACKGROUND AND AIMS: Statin associated muscle symptoms are common and affect adherence to statin treatment. The objective of this study was to assess whether patients with statin-associated myalgia can be successfully treated with Coenzyme Q10 (CoQ10) to improve symptoms and maintain them on statin therapy. METHODS: This systematic review was performed in line with the 2015 PRISMA statement. Relevant studies were identified via a search of MEDLINE, EMBASE and the Cochrane Library. Studies were screened to include randomised controlled trials of oral CoQ10 supplementation versus a placebo in adults with statin-associated myalgia. Continuation of statin therapy was a secondary outcome. Risk of bias was assessed using the Cochrane Risk of Bias tool. Pooled and sensitivity analyses were performed. RESULTS: 413 records were identified by the search strategy. Eight studies were selected for review, and 7 of them (with 321 patients) were included in the meta-analysis. Selected studies were published between 2007 and 2016 with the number of participants ranging from 37 to 76. Only two of these studies demonstrated a positive effect of CoQ10 therapy in relieving muscle pain. The meta-analysis did not demonstrate any benefit of CoQ10 supplementation in improving myalgia symptoms compared to placebo (weighted mean difference -0.42; 95% Confidence Interval [CI] -1.47 to 0.62). Similarly, CoQ10 did not improve the proportion of patients remaining on the statin treatment (RR 0.99; 95%CI, 0.81 to 1.20). CONCLUSIONS: This systematic review and meta-analysis did not demonstrate that CoQ10 supplementation was beneficial for patients with statin-associated muscle pain or improved adherence to statin therapy.


Asunto(s)
Suplementos Dietéticos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Cumplimiento de la Medicación , Mialgia/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adulto , Anciano , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mialgia/inducido químicamente , Mialgia/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Ubiquinona/efectos adversos , Ubiquinona/uso terapéutico
6.
Gut Microbes ; 5(3): 411-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24922519

RESUMEN

The impact of the gut microbiota on immune homeostasis within the gut and, importantly, also at systemic sites has gained tremendous research interest over the last few years. The intestinal microbiota is an integral component of a fascinating ecosystem that interacts with and benefits its host on several complex levels to achieve a mutualistic relationship. Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut while preventing uncontrolled immune responses against the beneficial commensal microbiota potentially leading to chronic inflammatory bowel diseases (IBD). Furthermore, recent studies suggest that the microbiota composition might impact on the susceptibility to immune-mediated disorders such as autoimmunity and allergy. Understanding how the microbiota modulates susceptibility to these diseases is an important step toward better prevention or treatment options for such diseases.


Asunto(s)
Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Sistema Inmunológico/fisiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Microbiota/inmunología , Homeostasis , Humanos
7.
Cell Host Microbe ; 14(5): 559-70, 2013 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-24237701

RESUMEN

Microbial exposure following birth profoundly impacts mammalian immune system development. Microbiota alterations are associated with increased incidence of allergic and autoimmune disorders with elevated serum IgE as a hallmark. The previously reported abnormally high serum IgE levels in germ-free mice suggests that immunoregulatory signals from microbiota are required to control basal IgE levels. We report that germ-free mice and those with low-diversity microbiota develop elevated serum IgE levels in early life. B cells in neonatal germ-free mice undergo isotype switching to IgE at mucosal sites in a CD4 T-cell- and IL-4-dependent manner. A critical level of microbial diversity following birth is required in order to inhibit IgE induction. Elevated IgE levels in germ-free mice lead to increased mast-cell-surface-bound IgE and exaggerated oral-induced systemic anaphylaxis. Thus, appropriate intestinal microbial stimuli during early life are critical for inducing an immunoregulatory network that protects from induction of IgE at mucosal sites.


Asunto(s)
Biodiversidad , Tracto Gastrointestinal/microbiología , Inmunoglobulina E/sangre , Animales , Animales Recién Nacidos , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Vida Libre de Gérmenes , Interleucina-4/inmunología , Ratones
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