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1.
Artigo em Inglês | MEDLINE | ID: mdl-32179158

RESUMO

BACKGROUND: Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. OBJECTIVE: The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. METHODS: We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. RESULTS: In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine-producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg-cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. CONCLUSIONS: During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.

2.
Exp Dermatol ; 29(1): 102-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31566815

RESUMO

Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88-/- ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1-/- ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1ß (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1ß neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response.

3.
Nat Protoc ; 14(9): 2707-2747, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451784

RESUMO

Nitrogen-vacancy (NV) quantum defects in diamond are sensitive detectors of magnetic fields. Owing to their atomic size and optical readout capability, they have been used for magnetic resonance spectroscopy of nanoscale samples on diamond surfaces. Here, we present a protocol for fabricating NV diamond chips and for constructing and operating a simple, low-cost 'quantum diamond spectrometer' for performing NMR and electron spin resonance (ESR) spectroscopy in nanoscale volumes. The instrument is based on a commercially available diamond chip, into which an NV ensemble is ion-implanted at a depth of ~10 nm below the diamond surface. The spectrometer operates at low magnetic fields (~300 G) and requires standard optical and microwave (MW) components for NV spin preparation, manipulation, and readout. We demonstrate the utility of this device for nanoscale proton and fluorine NMR spectroscopy, as well as for the detection of transition metals via relaxometry. We estimate that the full protocol requires 2-3 months to implement, depending on the availability of equipment, diamond substrates, and user experience.


Assuntos
Diamante/química , Espectroscopia de Ressonância de Spin Eletrônica/instrumentação , Espectroscopia de Ressonância Magnética/instrumentação , Nanotecnologia/instrumentação , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Espectroscopia de Ressonância Magnética/métodos , Nanopartículas/química , Processamento de Sinais Assistido por Computador
5.
Immunohorizons ; 3(7): 306-316, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31356160

RESUMO

Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.


Assuntos
Autoanticorpos/biossíntese , Autoimunidade/imunologia , Técnicas de Inativação de Genes , Interleucina-2/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo
7.
Proc Natl Acad Sci U S A ; 116(18): 8966-8974, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30962381

RESUMO

Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.


Assuntos
Arachis/imunologia , Imunoglobulina E/imunologia , Hipersensibilidade a Amendoim/imunologia , Alérgenos/imunologia , Basófilos/imunologia , Degranulação Celular , Epitopos/química , Epitopos/imunologia , Galectina 3/farmacologia , Humanos , Hipersensibilidade , Mastócitos/imunologia , Nanopartículas/uso terapêutico
8.
Arch Dermatol Res ; 310(3): 197-207, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29368135

RESUMO

The Stat6VT mouse model of atopic dermatitis (AD) is induced by T-cell-specific expression of a constitutively active form of the protein signal transducer and activator of transcription 6 (STAT6). Although AD-like lesions are known to develop in Stat6VT mice, this study was designed to determine if these mice develop acute and chronic phases of disease similar to humans. To address this, AD-like lesions from Stat6VT mice were harvested at two different timepoints relative to their onset. Lesions harvested within 1 week after development were defined as acute lesions, and those present for 1 month or more were defined as chronic lesions. Acute and chronic AD-like lesions from Stat6VT mice exhibited histologic findings and cytokine expression patterns similar to acute and chronic AD lesions in humans. Further analysis revealed increased levels of interleukin (IL)-33 transcripts in AD-like lesions compared to Stat6VT nonlesional and wild-type skin controls. Immunofluorescence also revealed increased numbers of IL-33+ keratinocytes in Stat6VT lesional skin and localized IL-33+ keratinocytes to a keratin 5+ subset. Furthermore, AD-like disease was more severe in IL-33-deficient Stat6VT mice compared to IL-33-sufficient Stat6VT mice. These studies suggest that Stat6VT mice can serve as a model of acute and chronic AD and that IL-33 may attenuate inflammation in this system.


Assuntos
Dermatite Atópica/patologia , Interleucina-33/metabolismo , Queratina-15/metabolismo , Queratinócitos/metabolismo , Fator de Transcrição STAT6/metabolismo , Animais , Modelos Animais de Doenças , Inflamação/patologia , Interleucina-33/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/patologia , Células Th1/imunologia , Células Th2/imunologia
9.
Immunology ; 152(3): 451-461, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28653395

RESUMO

Poly-ADP ribose polymerase-14 (PARP14 or ARTD8) was initially identified as a transcriptional co-activator for signal transducer and activator of transcription 6 (Stat6), where the presence of interleukin-4 (IL-4) and activated Stat6 induces the enzymatic activity of PARP14 that promotes T helper type 2 differentiation and allergic airway disease. To further our understanding of PARP14 in allergic disease, we studied the function of PARP14 in allergic inflammation of skin using mice that express constitutively active Stat6 in T cells (Stat6VT) and develop spontaneous inflammation of the skin. We mated Stat6VT mice to Parp14-/- mice and observed that approximately 75% of the Stat6VT × Parp14-/- mice develop severe atopic dermatitis (AD)-like lesions, compared with about 50% of Stat6VT mice, and have increased morbidity compared with Stat6VT mice. Despite this, gene expression in the skin and the cellular infiltrates was only modestly altered by the absence of PARP14. In contrast, we saw significant changes in systemic T-cell cytokine production. Moreover, adoptive transfer experiments demonstrated that decreases in IL-4 production reflected a cell intrinsic role for PARP14 in Th2 cytokine control. Hence, our data suggest that although PARP14 has similar effects on T-cell cytokine production in several allergic disease models, the outcome of those effects is distinct, depending on the target organ of disease.


Assuntos
Dermatite Atópica/prevenção & controle , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Transcrição STAT6/metabolismo , Pele/enzimologia , Transferência Adotiva , Animais , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/enzimologia , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosforilação , Poli(ADP-Ribose) Polimerases/deficiência , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/imunologia , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Índice de Gravidade de Doença , Transdução de Sinais , Pele/imunologia , Pele/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/transplante , Tirosina
10.
Dermatol Online J ; 23(2)2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329488

RESUMO

Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Capecitabina/efeitos adversos , Erupção por Droga/etiologia , Erupções Liquenoides/induzido quimicamente , Erupção por Droga/diagnóstico , Erupção por Droga/patologia , Feminino , Antebraço , Humanos , Erupções Liquenoides/diagnóstico , Erupções Liquenoides/patologia , Pessoa de Meia-Idade
11.
J Allergy Clin Immunol ; 139(1): 142-151.e5, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27554818

RESUMO

BACKGROUND: Atopic dermatitis (AD) is characterized by intense pruritis and is a common childhood inflammatory disease. Many factors are known to affect AD development, including the pleiotropic cytokine IL-4. Yet little is known regarding the direct effects of IL-4 on keratinocyte function. OBJECTIVE AND METHODS: In this report RNA sequencing and functional assays were used to define the effect of the allergic environment on primary keratinocyte function and wound repair in mice. RESULTS: Acute or chronic stimulation by IL-4 modified expression of more than 1000 genes expressed in human keratinocytes that are involved in a broad spectrum of nonoverlapping functions. Among the IL-4-induced changes, repression of fibronectin critically impaired the human keratinocyte wound response. Moreover, in mouse models of spontaneous and induced AD-like lesions, there was delayed re-epithelialization. Importantly, topical treatment with fibronectin restored the epidermal repair response. CONCLUSION: Keratinocyte gene expression is critically shaped by IL-4, altering cell fate decisions, which are likely important for the clinical manifestations and pathology of allergic skin disease.


Assuntos
Fibronectinas/imunologia , Interleucina-4/imunologia , Queratinócitos/imunologia , Cicatrização/imunologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição STAT6/genética , Pele/imunologia , Transcriptoma/efeitos dos fármacos , Cicatrização/genética
12.
Proc Natl Acad Sci U S A ; 113(49): 14133-14138, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27911765

RESUMO

Magnetic fields from neuronal action potentials (APs) pass largely unperturbed through biological tissue, allowing magnetic measurements of AP dynamics to be performed extracellularly or even outside intact organisms. To date, however, magnetic techniques for sensing neuronal activity have either operated at the macroscale with coarse spatial and/or temporal resolution-e.g., magnetic resonance imaging methods and magnetoencephalography-or been restricted to biophysics studies of excised neurons probed with cryogenic or bulky detectors that do not provide single-neuron spatial resolution and are not scalable to functional networks or intact organisms. Here, we show that AP magnetic sensing can be realized with both single-neuron sensitivity and intact organism applicability using optically probed nitrogen-vacancy (NV) quantum defects in diamond, operated under ambient conditions and with the NV diamond sensor in close proximity (∼10 µm) to the biological sample. We demonstrate this method for excised single neurons from marine worm and squid, and then exterior to intact, optically opaque marine worms for extended periods and with no observed adverse effect on the animal. NV diamond magnetometry is noninvasive and label-free and does not cause photodamage. The method provides precise measurement of AP waveforms from individual neurons, as well as magnetic field correlates of the AP conduction velocity, and directly determines the AP propagation direction through the inherent sensitivity of NVs to the associated AP magnetic field vector.

13.
Eur J Immunol ; 46(11): 2609-2613, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27510401

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt-/- ) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt-/- mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.


Assuntos
Dermatite Atópica/imunologia , Pele/imunologia , Pele/patologia , Células Th2/imunologia , Animais , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Permeabilidade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT6/genética , Pele/fisiopatologia
14.
Sci Transl Med ; 7(308): 308ra160, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26446957

RESUMO

Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing membrane-bound ST2 (mST2) [T helper 2 (TH2) cells and ST2(+)FoxP3(+) regulatory T cells]. We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-γ, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17-producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid-derived suppressor cells, and decreasing the frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of green fluorescent protein (GFP)-positive MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD and that the ST2/IL-33 pathway could be investigated in other T cell-mediated immune disorders with loss of tolerance.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/uso terapêutico , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Doença Enxerto-Hospedeiro/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
15.
BMC Res Notes ; 7: 942, 2014 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-25532711

RESUMO

BACKGROUND: The welfare of pet rabbits is an area of growing interest in Europe and the UK. This study analyses questionnaire results from a diverse population of 1254 rabbit owners from three different geographical areas in England with the aim of providing an accurate representation of how pet rabbits are currently housed and cared for and key aspects of their health and welfare. RESULTS: Rabbits were kept in a variety of different housing types, the most common being a traditional hutch/cage (59%). Although the majority had additional exercise areas, access was often unpredictable, or ill-timed, which may compromise welfare. Only 41.9% of owners kept their rabbit with conspecifics, limiting their ability to engage in social behaviour. Of those rabbits housed with a companion, although many were reported to be amicable and to engage in positive interactions, over a quarter were reported to fight at least occasionally (25.3%), whilst 22.7% guarded resources and 27.1% avoided one another. Whilst low levels of some of these behaviours may be a normal part of social interaction, the relatively high levels reported here suggest that not all cohabiting pairs of rabbits are compatible, which is potentially a significant welfare issue.Although the vast majority of owners fed hay for over 10% this was less than daily. Pelleted foods were very popular (71.4% at least daily) compared to commercial muesli mixes (32.6%). As in previous studies, dental problems were commonly reported (12.2% of rabbits); however, so were eye problems (12.9%), digestive problems (11.5%) and parasites (11.3%). A large proportion of rabbits (58%) were thought to be fearful of loud noises, and 61% were not reported as calm when handled by their owner, which may be a significant concern for this species. CONCLUSION: This study has confirmed and expanded on previous findings: many pet rabbits were found to be in good health, had compatible companions and were provided with enriched living areas. However, it also found numerous welfare issues that affect large numbers of pet rabbits. We suggest further studies are required exploring the accuracy of owner reports (which possibly under-report many problems) and prioritising the issues raised here.


Assuntos
Criação de Animais Domésticos/estatística & dados numéricos , Bem-Estar do Animal/estatística & dados numéricos , Animais de Estimação , Inquéritos e Questionários , Adulto , Criação de Animais Domésticos/normas , Bem-Estar do Animal/normas , Animais , Vínculo Homem-Animal de Estimação , Inglaterra , Feminino , Geografia , Abrigo para Animais/normas , Abrigo para Animais/estatística & dados numéricos , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Propriedade , Coelhos
16.
Invest Ophthalmol Vis Sci ; 55(6): 3803-8, 2014 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-24845637

RESUMO

PURPOSE: Atopic dermatitis (AD) is a common inflammatory disease that can affect the eye, resulting in ocular pathologies, including blepharitis, keratitis, and uveitis; however, the pathogenic mechanisms underlying the ocular manifestations of AD are not well understood. METHODS: In the present study, we characterized the ocular pathologies that develop in the Stat6VT mouse model of AD. We examined the cytokine profile of the eyelid lesions, measured the behavioral response, and documented the treatment response to topical steroids. RESULTS: Our results show that Stat6VT mice spontaneously developed blepharitis, keratitis, and uveitis similar to that observed in patients with AD. Histologic findings of allergic inflammation in affected eyelids in this model include the presence of a lymphocyte-predominant infiltrate and tissue eosinophilia in the dermis. Gene expression analysis of affected eyelid tissue by quantitative PCR revealed increased amounts of mRNAs for the Th2 cytokines IL-4, IL-5, and IL-13. In addition, increased eyelid scratching was seen in Stat6VT mice with blepharitis. Topical treatment with the corticosteroid clobetasol reduced eyelid inflammation, tissue eosinophilia, and Th2 cytokine expression. CONCLUSIONS: The development of AD-like ocular pathologies in this model supports the idea that in humans, AD-associated disease of the eye may be driven by Th2-mediated inflammation and demonstrates that the Stat6VT mouse may be a useful system in which to further investigate pathogenesis of and treatment strategies for blepharitis and other ocular diseases that develop in association with AD.


Assuntos
Blefarite/genética , Dermatite Atópica/genética , Regulação da Expressão Gênica , Ceratite/genética , RNA/genética , Fator de Transcrição STAT6/genética , Animais , Blefarite/etiologia , Blefarite/metabolismo , Dermatite Atópica/complicações , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Immunoblotting , Ceratite/etiologia , Ceratite/metabolismo , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase , Fator de Transcrição STAT6/biossíntese
18.
Trends Immunol ; 35(2): 49-50, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24412411

RESUMO

Atopic dermatitis (AD) is characterized by allergic inflammation and itch. Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine implicated in AD. A paper in Cell transforms the understanding of the functional repertoire of TSLP in general and in AD in particular showing that TSLP can directly stimulate sensory neurons and provoke itch.


Assuntos
Citocinas/metabolismo , Dermatite Atópica/patologia , Transdução de Sinais , Animais , Humanos
19.
Pediatr Dermatol ; 30(5): 574-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23889122

RESUMO

Calcipotriene is a topical vitamin D3 analogue approved for the treatment of plaque and scalp psoriasis. We report the case of a 2-year-old boy whose atopic dermatitis (AD) flared in response to application of calcipotriene 0.005% cream and solution for a mistaken diagnosis of plaque and scalp psoriasis. We investigated whether the patient's eruption was secondary to an allergic contact dermatitis. In the Stat6VT mouse model of AD we tested whether calcipotriene could induce the otherwise-spontaneous AD-like phenotype. Closed patch testing was done on the patient with calcipotriene solution and cream, moisturizing cream, and 51% isopropanol. Stat6VT and wild-type (WT) mice were treated for 7 days with calcipotriene solution or vehicle (isopropanol) applied to the right and left upper back skin, respectively, after which mice were followed longitudinally for 10 weeks. Biopsy specimens from prior treatment sites were then collected for histology and RNA isolation. RNA was analyzed for interleukin (IL-4) expression using quantitative polymerase chain reaction. Patch testing was negative. Stat6VT mice, in contrast to WT mice, developed a persistent eczematous dermatitis at sites of calcipotriene application. Clinical and histologic features and high IL-4 transcript levels were consistent with the spontaneous AD-like phenotype seen in Stat6VT mice. At sites of active disease, calcipotriene can worsen a flare of AD. In Stat6VT mice, calcipotriene can induce the AD-like phenotype.


Assuntos
Calcitriol/análogos & derivados , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Fármacos Dermatológicos/efeitos adversos , Administração Tópica , Animais , Calcitriol/efeitos adversos , Calcitriol/farmacologia , Pré-Escolar , Dermatite Alérgica de Contato/patologia , Fármacos Dermatológicos/farmacologia , Modelos Animais de Doenças , Dermatoses Faciais/induzido quimicamente , Dermatoses Faciais/patologia , Humanos , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Testes do Emplastro , Fenótipo , Fator de Transcrição STAT6/genética
20.
J Immunol ; 190(5): 2447-54, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23355733

RESUMO

Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation.


Assuntos
Dermatite de Contato/metabolismo , Glicerilfosforilcolina/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Animais , Antioxidantes/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dermatite de Contato/imunologia , Dermatite de Contato/patologia , Dinitrofluorbenzeno , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Glicerilfosforilcolina/imunologia , Hidrolases/metabolismo , Imunossupressão , Peroxidação de Lipídeos/efeitos dos fármacos , Depleção Linfocítica , Camundongos , Camundongos Transgênicos , Fator de Ativação de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
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