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Group 2 innate lymphoid cells (ILC2s) are sentinels of barrier immunity, and their activation by the epithelial alarmins IL-25 and IL-33 is a defining trait. In this study, we identified a role for the chemokine receptor CCR8 in modulating skin ILC2 abundance and activation. CCR8 signaling facilitated IL-25-induced increases in skin and lung ILC2s, ILC2 activation and systemic IL-13 production, and ligand-directed ILC2 entry into skin and lung. CCR8 controlled ILC2 tissue entry in IL-25-treated naive mice, but only transferred bone marrow ILC2 progenitors were equipped to enter the skin, whereas multiple tissue-sourced ILC2s entered the lung. CCR8 selectively regulated IL-33-induced increases in skin ILC2s, their proliferation, and production of IL-13/IL-5, as well as IL-33-responsive transferred ILC2 trafficking only to the skin. Collectively, we illuminate (to our knowledge) novel aspects of CCR8 signaling-regulated ILC2 motility and function, especially in the skin, in response to two hallmark ILC2-activating alarmins.
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Citocinas , Inmunidad Innata , Animales , Ratones , Interleucina-33 , Linfocitos , Interleucina-13 , Alarminas , Pulmón , Movimiento CelularRESUMEN
In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12 + dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19 + IL4I1 + fibroblasts, and clonally expanded IL13 + IL22 + IL26 + T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13 + IL22 + IL26 + T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.
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Leek yellow stripe virus (LYSV) is one of the most important potyviruses, associated with garlic throughout the world, including India. LYSV causes stunting and yellow streaks in garlic and leek leaves and with other coinfecting viruses leading to severe symptom expression and yield reduction. In this study, we have made the first reported attempt to produce specific polyclonal antibodies to LYSV using expressed recombinant coat protein (CP), which would be useful for screening and routine indexing of the garlic germplasm. The CP gene was cloned, sequenced, and further subcloned in pET-28a(+) expression vector, which yielded â¼35 kDa fusion protein. The fusion protein was obtained in insoluble fraction after purification and its identity was confirmed by SDS-PAGE and western blotting. The purified protein was used as immunogen for production of polyclonal antisera in New Zealand white rabbit. Antisera raised, was able to recognize the corresponding recombinant proteins in western blotting, immunosorbent electron microscopy and dot immunobinding assay (DIBA). Developed antisera to LYSV (titer 1:2000) was used for screening of 21 garlic accessions in antigen coated plate enzyme-linked immunosorbent assay (ACP-ELISA) and 16 accessions were found positive for LYSV, indicating its widespread presence within the collection tested. To the best of our knowledge, this is the first report of a polyclonal antiserum against the in-vitro expressed CP of LYSV and its successful application in diagnosis of LYSV in garlic accessions in India.
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Ajo , Potyvirus , Animales , Conejos , Cebollas , Escherichia coli/genética , Secuencia de Bases , Proteínas Recombinantes/genética , Ajo/genética , Potyvirus/genética , Sueros Inmunes/genéticaRESUMEN
Limb transplantation is a life-changing procedure for amputees. However, limb recipients have a 6-fold greater rejection rate than solid organ transplant recipients, related in part to greater immunogenicity of the skin. Here, we report a detailed immunological and molecular characterization of individuals who underwent bilateral limb transplantation at our institution. Circulating Th17 cells are increased in limb transplant recipients over time. Molecular characterization of 770 genes in skin biopsies reveals upregulation of T cell effector immune molecules and chemokines, particularly CCL18. Skin antigen-presenting cells primarily express the chemokine CCL18, which binds to the CCR8 receptor. CCL18 treatment recruits more allo-T cells to the skin xenograft in a humanized skin transplantation model, leading to signs of accelerated graft rejection. Blockade of CCR8 remarkedly decreases CCL18-induced allo-T cell infiltration. Our results suggest that targeting the CCL18:CCR8 pathway could be a promising immunosuppressive approach in transplantation.
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Quimiocinas , Trasplante de Piel , Quimiocinas CC/genética , Humanos , Inmunosupresores , PielRESUMEN
When a sessile droplet of a complex mixture evaporates, its nonvolatile components may deposit into various patterns. One such phenomena, the coffee ring effect, has been a topic of interest for several decades. Here, we identify what we believe to be a fascinating phenomenon of droplet pattern deposition for another well-known beverage-what we have termed a "whiskey web". Nanoscale agglomerates were generated in diluted American whiskeys (20-25% alcohol by volume), which later stratified as microwebs on the liquid-air interface during evaporation. The web's strandlike features result from monolayer collapse, and the resulting pattern is a function of the intrinsic molecular constituents of the whiskey. Data suggest that, for our conditions (diluted 1.0 µL drops evaporated on cleaned glass substrates), whiskey webs were unique to diluted American whiskey; however, similar structures were generated with other whiskeys under different conditions. Further, each product forms their own distinct pattern, demonstrating that this phenomenon could be used for sample analysis and counterfeit identification.
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Ionomer polyesters have polymer backbones functionalized with charged groups that make them water-dispersible. Despite the widespread use of ionomer polymers in environmentally friendly coatings without volatile organic solvents, the fundamental understanding of their film formation properties is still limited. In the study, we deposited polyester nanofilms of brilliant structural colors and correlated the macroscale optical properties to the microscale thickness of the thin films. We found that sessile water droplets deposited on these films drive the formation of a rich variety of structures by an evaporation-induced effect of "coffee-ring erosion". The ionomers spontaneously get partially re-dispersed in the form of nanoparticles in the sessile droplets and driven by convective evaporation flows, become redistributed in multiple colorful ring patterns. By using the structural colors as means to follow the polymer redistribution, we characterized further the coffee-ring patterns and found that the generated patterns are dictated by polymer composition but are mostly independent on molecular weight. As expected by colloidal theory, this phenomenon was suppressed in presence of electrolytes. Furthermore, we show that the integrity of these thin polyester films can be significantly improved by thermal densification without any further chemical curing.
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The present study was undertaken to know the genetics of purple color of cauliflower curds using a Sicilian purple 'PC-1' and a white curding mid-late group genotype of Indian cauliflower. For this, a cross was attempted between 'DC-466' (white curd) and 'PC-1' (purple curd) and observed intermediate level of purple pigmentation on curds in F1 plants. Segregation of F2 population (173) revealed that the purple color of the curd was governed by a single gene dominant over white, but the expression of trait was incomplete. It was substantiated by segregation of plants of BC1 and F2:3(intermediate) generations into 1(white):1(intermediate) and 1(white):2(intermediate):1(intense), respectively. The F2, B1, and B2 generations segregated into purple(intermediate to intense): white curding plants in the ratio of 126: 47, 26:24, and 40:0, respectively fitting well with the Mendelian ratio of single gene for purple curds. However, purple pigmentation on curds ranged from very light to intense, which corroborated with the wide range of anthocyanin content in F2 (3.81-48.21 mg/100 g fw). Out of three molecular markers from high resolution map of Pr gene in purple color cauliflower 'Graffiti', only BoMYB3 marker could distinguish purple and white curding parents but did not show co-segregation while investigated in F2 population. Expression of BoMYB1 gene was up regulated in both the purple curd genotypes 'PC-1' and 'Graffiti' in comparison to white curded 'DC-466', while BoMYB2 gene was slightly upregulated in 'PC-1' but down regulated in 'Graffiti'. Occurrence of 'broccoli type' F2 individuals and their genetic stability in F2:3 support the intermediate position of 'Sicilian purple' between broccoli (Calabrese) and cauliflower. There was not any correlation between curd coloration and pigmentation on apical leaf and stem portion, indicating difference of expression in 'PC-1' than 'Graffiti'. The information obtained is useful for breeding anthocyanin rich attractive purple curding 'specialty cauliflower' for better consumer health and growers' earnings.
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Water-dispersible sulfopolyesters are a major class of film-forming and solution-modifying polymers, which are routinely used in applications such as inks, adhesives, coatings, and personal care products. Since these polyesters are designed to be used as waterborne dispersions, understanding their colloidal interactions in dispersions is critical for their application. By using a range of commercially available water-dispersible sulfopolyesters as a model system, we investigated the relationship between their molecular composition, colloidal interactions, and phase equilibria. We established how these polyesters undergo different molecular configurations and nanoaggregated states, depending on the nature of the liquid medium. For example, the polyesters are in a solvated molecular form in certain organic solvents, whereas they self-assemble into compact nanoaggregates in water. We found that the interactions of these nanoaggregates follow the classical DLVO theory of critical colloidal coagulation where the stability of these nanoparticles is extremely sensitive to multivalent electrolytes (i.e., Ccrit â z-6). By using static, dynamic, and electrophoretic light scattering, we correlate their nanoscale intermolecular and interparticle interactions with corresponding macroscale phase behavior in both organic medium and water, based on the theoretical framework of second virial coefficients. We present a model for nanoaggregate formation in water based on the critical surface charge density of these nanoparticles. Such fundamental understanding of colloidal interactions could be used to efficiently control and improve the colloidal stability and film-formation ability of these polyesters and may enable the design of novel high-performance surfactant-free waterborne dispersion systems.
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Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.
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Alérgenos/inmunología , Asma/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Inflamación/patología , Células Th2/inmunología , Adulto , Asma/complicaciones , Asma/patología , Citocinas , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/patología , Inflamación/complicaciones , Pulmón/patología , Moco/metabolismo , Músculo Liso/inmunología , Músculo Liso/patología , FenotipoRESUMEN
The availability of nutrient components in the environment was identified as a critical regulator of virulence and biofilm formation in Pseudomonas aeruginosa. This work proposes the first systems-biology approach to quantify microbial biofilm formation upon the change of nutrient availability in the environment. Specifically, the change of fluxes of metabolic reactions that were positively associated with P. aeruginosa biofilm formation was used to monitor the trend for P. aeruginosa to form a biofilm. The uptake rates of nutrient components were changed according to the change of the nutrient availability. We found that adding each of the eleven amino acids (Arg, Tyr, Phe, His, Iso, Orn, Pro, Glu, Leu, Val, and Asp) to minimal medium promoted P. aeruginosa biofilm formation. Both modeling and experimental approaches were further developed to quantify P. aeruginosa biofilm formation for four different availability levels for each of the three ions that include ferrous ions, sulfate, and phosphate. The developed modeling approach correctly predicted the amount of biofilm formation. By comparing reaction flux change upon the change of nutrient concentrations, metabolic reactions used by P. aeruginosa to regulate its biofilm formation are mainly involved in arginine metabolism, glutamate production, magnesium transport, acetate metabolism, and the TCA cycle.
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Aminoácidos/administración & dosificación , Biopelículas/crecimiento & desarrollo , Pseudomonas aeruginosa/metabolismo , Biología de Sistemas , Acetatos/metabolismo , Aminoácidos/metabolismo , Arginina/metabolismo , Biopelículas/efectos de los fármacos , Ciclo del Ácido Cítrico , Humanos , Magnesio/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/patogenicidadRESUMEN
Toxin/antitoxin (TA) systems are nearly universal in prokaryotes; toxins are paired with antitoxins which inactivate them until the toxins are utilized. Here we explore whether toxins may function alone; i.e., whether a toxin which lacks a corresponding antitoxin (orphan toxin) is physiologically relevant. By focusing on a homologous protein of the membrane-damaging toxin GhoT of the Escherichia coli GhoT/GhoS type V TA system, we found that YdcX (renamed OrtT for orphan toxin related to tetrahydrofolate) is toxic but is not part of TA pair. OrtT is not inactivated by neighboring YdcY (which is demonstrated to be a protein), nor is it inactivated by antitoxin GhoS. Also, OrtT is not inactivated by small RNA upstream or downstream of ortT. Moreover, screening a genomic library did not identify an antitoxin partner for OrtT. OrtT is a protein and its toxicity stems from membrane damage as evidenced by transmission electron microscopy and cell lysis. Furthermore, OrtT reduces cell growth and metabolism in the presence of both antimicrobials trimethoprim and sulfamethoxazole; these antimicrobials induce the stringent response by inhibiting tetrahydrofolate synthesis. Therefore, we demonstrate that OrtT acts as an independent toxin to reduce growth during stress related to amino acid and DNA synthesis.
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Toxinas Bacterianas/genética , Proteínas de Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Antibacterianos/farmacología , Antitoxinas/genética , Antitoxinas/metabolismo , Toxinas Bacterianas/metabolismo , Carbenicilina/farmacología , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Sulfametoxazol/farmacología , Tetrahidrofolatos/biosíntesis , Trimetoprim/farmacologíaRESUMEN
The transcriptional repressor B lymphocyte-induced maturation protein 1 (BLIMP1) is a master regulator of B and T cell differentiation. To examine the role of BLIMP1 in innate immunity, we used a conditional knockout (CKO) of Blimp1 in myeloid cells and found that Blimp1 CKO mice were protected from lethal infection induced by Listeria monocytogenes. Transcriptome analysis of Blimp1 CKO macrophages identified the murine chemokine (C-C motif) ligand 8, CCL8, as a direct target of Blimp1-mediated transcriptional repression in these cells. BLIMP1-deficient macrophages expressed elevated levels of Ccl8, and consequently Blimp1 CKO mice had higher levels of circulating CCL8, resulting in increased neutrophils in the peripheral blood, promoting a more aggressive antibacterial response. Mice lacking the Ccl8 gene were more susceptible to L. monocytogenes infection than were wild-type mice. Although CCL8 failed to recruit neutrophils directly, it was chemotactic for γ/δ T cells, and CCL8-responsive γ/δ T cells were enriched for IL-17F. Finally, CCL8-mediated enhanced clearance of L. monocytogenes was dependent on γ/δ T cells. Collectively, these data reveal an important role for BLIMP1 in modulating host defenses by suppressing expression of the chemokine CCL8.
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Quimiocina CCL8/inmunología , Regulación de la Expresión Génica/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Macrófagos/inmunología , Factores de Transcripción/inmunología , Animales , Quimiocina CCL8/genética , Regulación de la Expresión Génica/genética , Listeriosis/genética , Macrófagos/patología , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Factores de Transcripción/genética , Transcripción Genética/genética , Transcripción Genética/inmunologíaRESUMEN
Toxin/antitoxin (TA) systems perhaps enable cells to reduce their metabolism to weather environmental challenges although there is little evidence to support this hypothesis. Escherichia coliâ GhoT/GhoS is a TA system in which toxin GhoT expression is reduced by cleavage of its messenger RNA (mRNA) by antitoxin GhoS, and TA system MqsR/MqsA controls GhoT/GhoS through differential mRNA decay. However, the physiological role of GhoT has not been determined. We show here through transmission electron microscopy, confocal microscopy and fluorescent stains that GhoT reduces metabolism by damaging the membrane and that toxin MqsR (a 5'-GCU-specific endoribonuclease) causes membrane damage in a GhoT-dependent manner. This membrane damage results in reduced cellular levels of ATP and the disruption of proton motive force (PMF). Normally, GhoT is localized to the pole and does not cause cell lysis under physiological conditions. Introduction of an F38R substitution results in loss of GhoT toxicity, ghost cell production and membrane damage while retaining the pole localization. Also, deletion of ghoST or ghoT results in significantly greater initial growth in the presence of antimicrobials. Collectively, these results demonstrate that GhoT reduces metabolism by reducing ATP and PMF and that this reduction in metabolism is important for growth with various antimicrobials.
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Adenosina Trifosfato/metabolismo , Membrana Celular/metabolismo , Proteínas de Escherichia coli/fisiología , Escherichia coli/crecimiento & desarrollo , Antibacterianos/farmacología , Compuestos de Bifenilo/farmacología , Carbenicilina/farmacología , Cefoxitina/farmacología , Cloroquinolinoles/farmacología , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Transporte de Proteínas , Fuerza Protón-Motriz , ARN Mensajero/metabolismoRESUMEN
The CC chemokine ligand 18 (CCL18) is one of the most highly expressed chemokines in human chronic inflammatory diseases. An appreciation of the role of CCL18 in these diseases has been hampered by the lack of an identified chemokine receptor. We report that the human chemokine receptor CCR8 is a CCL18 receptor. CCL18 induced chemotaxis and calcium flux of human CCR8-transfected cells. CCL18 bound with high affinity to CCR8 and induced its internalization. Human CCL1, the known endogenous CCR8 ligand, and CCL18 competed for binding to CCR8-transfected cells. Further, CCL1 and CCL18 induced heterologous cross-desensitization of CCR8-transfected cells and human Th2 cells. CCL18 induced chemotaxis and calcium flux of human activated highly polarized Th2 cells through CCR8. Wild-type but not Ccr8-deficient activated mouse Th2 cells migrated in response to CCL18. CCL18 and CCR8 were coexpressed in esophageal biopsy tissue from individuals with active eosinophilic esophagitis (EoE) and were present at markedly higher levels compared with esophageal tissue isolated from EoE patients whose disease was in remission or in normal controls. Identifying CCR8 as a chemokine receptor for CCL18 will help clarify the biological role of this highly expressed chemokine in human disease.
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Quimiocinas CC/metabolismo , Receptores CCR8/metabolismo , Animales , Calcio/metabolismo , Línea Celular , Quimiocinas CC/inmunología , Quimiotaxis/inmunología , Eosinófilos/inmunología , Expresión Génica , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Ligandos , Antígeno-1 Asociado a Función de Linfocito/inmunología , Ratones , Filogenia , Unión Proteica , Receptores CCR8/genética , Células Th2/inmunología , Células Th2/metabolismo , TransfecciónRESUMEN
Allergic inflammation develops in tissues that have large epithelial surface areas that are exposed to the environment, such as the lung, skin and gut. In the steady state, antigen-experienced memory T cells patrol these peripheral tissues to facilitate swift immune responses against invading pathogens. In at least two allergy-prone organs, the skin and the gut, memory T cells are programmed during the initial antigen priming to express trafficking receptors that enable them to preferentially home to these organs. In this review we propose that tissue-specific memory and inflammation-specific T cell trafficking facilitates the development of allergic disease in these organs. We thus review recent advances in our understanding of tissue-specific T cell trafficking and how regulation of T cell trafficking by the chemokine system contributes to allergic inflammation in mouse models and in human allergic diseases of the skin, lung and gut. Inflammation- and tissue-specific T lymphocyte trafficking pathways are currently being targeted as new treatments for non-allergic inflammatory diseases and may yield effective new therapeutics for allergic diseases.
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Epitelio/inmunología , Hipersensibilidad/inmunología , Linfocitos T/fisiología , Alérgenos/inmunología , Animales , Asma/inmunología , Movimiento Celular , Quimiocinas/fisiología , Hipersensibilidad a los Alimentos/inmunología , Humanos , Memoria Inmunológica , Ratones , Células Th2/fisiologíaRESUMEN
Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation.
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Quimiocina CCL1/metabolismo , Quimiocina CCL8/metabolismo , Dermatitis Atópica/inmunología , Piel/patología , Células Th2/metabolismo , Traslado Adoptivo , Animales , Señalización del Calcio/inmunología , Células Cultivadas , Quimiocina CCL1/genética , Quimiocina CCL1/inmunología , Quimiocina CCL8/genética , Quimiocina CCL8/inmunología , Quimiotaxis/genética , Quimiotaxis/inmunología , Clonación Molecular , Modelos Animales de Enfermedad , Humanos , Interleucina-5/inmunología , Interleucina-5/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Mensajeros de Linfocitos/inmunología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
Bangladesh represents one of the few countries in south Asia where the pace of fertility decline has been unprecedented over the last three decades. Although there has been significant reduction in fertility levels at the national level, regional variations continue to persist, especially in Sylhet and Chittagong where the total fertility rates are well above the country average. Using data from three consecutive Bangladesh Demographic and Health Surveys (BDHSs) this paper assesses how fertility patterns in Sylhet and Chittagong differ from the rest of Bangladesh through a marriage cohort analysis of the parity progression ratios, and examines the factors determining the transition rates to higher parity in these two regions. Three cohorts of women are identified: those married during 1965-1974, 1975-84 and 1985-94. The results show that the probability that a woman from the recent cohort in Sylhet or Chittagong who had a third birth will have a fourth birth is nearly twice that of her counterpart in other regions. Social characteristics such as education, occupation, religion and residence have no effect on fertility in Sylhet and Chittagong. Additional period-specific analyses using the 2007 BDHS data show that women in Sylhet are considerably more likely to have a third or fourth birth sooner than those in other divisions, especially Khulna. The findings call for specific family planning policy interventions in Sylhet and Chittagong ensuring gender equity, promoting female education and delaying entry into marriage and childbearing.
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Fertilidad , Matrimonio/estadística & datos numéricos , Paridad , Bangladesh , Estudios de Cohortes , Intervalos de Confianza , Recolección de Datos , Demografía , Servicios de Planificación Familiar , Femenino , Humanos , Lactante , Mortalidad Infantil/tendencias , Recién Nacido , Embarazo , Política Pública , Análisis de RegresiónRESUMEN
The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5-/-) mice were less able to generate an inflammatory response, had decreased chemokine and interferon gamma production, and had higher parasite burden. As a result, CCR5-/- mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5+/+ NK cells into CCR5-/- mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense.
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Movimiento Celular , Células Asesinas Naturales , Receptores CCR5/metabolismo , Toxoplasmosis/fisiopatología , Traslado Adoptivo , Animales , ADN Protozoario/metabolismo , Susceptibilidad a Enfermedades , Hibridación Genética , Inflamación/parasitología , Inflamación/patología , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Células Asesinas Naturales/patología , Ligandos , Ratones , Ratones Endogámicos C57BL/genética , Ratones Endogámicos/genética , Ratones Noqueados/genética , Fenotipo , Receptores CCR5/genética , Sobrevida , Factores de Tiempo , Toxoplasma/genética , Toxoplasmosis/inmunología , Toxoplasmosis/parasitología , Toxoplasmosis/patologíaRESUMEN
We have recently shown that the leukotriene B(4) (LTB(4))-BLT1 pathway is important in early effector T-cell recruitment in mouse models of inflammation. Here we characterize the phenotype and function of human peripheral blood BLT1(+) T cells in health and illustrate their involvement in asthma and acute infection. In healthy individuals, BLT1(+) T cells are a rare peripheral blood T-cell population enriched for the activation markers CD38 and HLA-DR. Compared with BLT1(-) T cells, a larger proportion of peripheral blood BLT1(+) T cells express the effector cytokines IFNgamma and IL-4 and inflammatory chemokine receptors, CCR1, CCR2, CCR6, and CXCR1. Consequently, in healthy individuals peripheral blood BLT1(+) T cells are a rare antigen-primed T-cell subset with unique phenotypic, migratory, and functional properties. BLT1 expression on T cells is tightly regulated by inflammation and only transiently expressed after naive T-cell activation by dendritic cells. Although rare in the peripheral blood of healthy individuals, BLT1(+) T cells are markedly increased in frequency in the peripheral blood in response to acute Epstein-Barr virus (EBV) infection and moderately increased in the airways of asymptomatic allergic asthmatics. Our studies provide novel insights into the LTB(4)-BLT1 lipid chemoattractant pathway in human T-cell responses, and how it may link innate and adaptive immunity.
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ADP-Ribosil Ciclasa 1 , Asma/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos HLA-DR , Receptores de Leucotrieno B4/inmunología , Receptores Purinérgicos P2/inmunología , Linfocitos T/inmunología , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Enfermedad Aguda , Líquido del Lavado Bronquioalveolar/citología , Estudios de Casos y Controles , Células Cultivadas , Infecciones por Virus de Epstein-Barr/metabolismo , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inflamación , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Leucotrieno B4/metabolismo , Activación de Linfocitos , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores CCR2 , Receptores CCR6 , Receptores de Quimiocina/metabolismo , Receptores de Interleucina-8A/metabolismo , Receptores de Leucotrieno B4/genética , Receptores de Leucotrieno B4/metabolismo , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Linfocitos T/metabolismoRESUMEN
Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.