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2.
Toxicol Lett ; 317: 68-81, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31580885

RESUMO

Skin sensitization, frequently leading to allergic contact dermatitis (ACD), is authenticated to be a significant endpoint in the field of drug discovery and cosmetics. The initiation of ACD, also known as the skin sensitization mechanism, has been documented as an adverse outcome pathway (AOP), which can be studied experimentally and computationally. In this study, we collected 154 haptens and applied systems toxicology methods to develop a reaction-substructure-compound- target-pathway network system. For the collected haptens, their key substructures were identified and associated with their protein binding reactions. The targets of haptens, including the known targets collected from four databases and the potential targets predicted via our balanced substructure-drug-target network-based inference (bSDTNBI) method, were matched to skin proteins to obtain skin targets. The dermatitis-related pathways were enriched and were subject to literature verification. The network system we developed can be applied to predict the reactions, targets and pathways of new haptens, which contributed to evaluating chemical safety and optimizing chemical structures. The study of skin sensitization mechanism is helpful for understanding the skin immunity and resisting ACD.


Assuntos
Dermatite Alérgica de Contato/etiologia , Haptenos/toxicidade , Pele/efeitos dos fármacos , Biologia de Sistemas , Toxicologia/métodos , Animais , Dermatite Alérgica de Contato/imunologia , Dermatite Alérgica de Contato/metabolismo , Haptenos/química , Humanos , Estrutura Molecular , Ligação Proteica , Mapas de Interação de Proteínas , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Relação Estrutura-Atividade
3.
Nat Commun ; 10(1): 4432, 2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570755

RESUMO

The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.


Assuntos
Imunoglobulina G/imunologia , Pênfigo/imunologia , Pênfigo/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pele/imunologia , Animais , Autoanticorpos/metabolismo , Doenças Autoimunes/metabolismo , Cavéolas , Modelos Animais de Doenças , Dinaminas/metabolismo , Orelha/patologia , Endocitose , Células Endoteliais/metabolismo , Feminino , Imunoglobulina G/sangue , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Pênfigo/patologia , Pele/patologia , Vesículas Transportadoras/metabolismo
4.
Nat Commun ; 10(1): 4401, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562311

RESUMO

Tissue-resident memory CD8+ T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors. However, whether Trm cells cross-talk with dendritic cells (DCs) to support anti-tumor immunity remains unclear. Here we show that antigen-specific activation of skin Trm cells leads to maturation and migration to draining lymph nodes of cross-presenting dermal DCs. Tumor rejection mediated by Trm cells triggers the spread of cytotoxic CD8+ T cell responses against tumor-derived neo- and self-antigens via dermal DCs. These responses suppress the growth of intradermal tumors and disseminated melanoma lacking the Trm cell-targeted epitope. Moreover, analysis of RNA sequencing data from human melanoma tumors reveals that enrichment of a Trm cell gene signature associates with DC activation and improved survival. This work unveils the ability of Trm cells to amplify the breath of cytotoxic CD8+ T cell responses through DCs, thereby strengthening anti-tumor immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Memória Imunológica/imunologia , Melanoma/imunologia , Pele/imunologia , Animais , Antígenos/imunologia , Movimento Celular/imunologia , Apresentação Cruzada/imunologia , Humanos , Linfonodos/imunologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pele/citologia , Linfócitos T Citotóxicos/imunologia
5.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 595-600, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537243

RESUMO

Objective To observe the effect of esculentoside A (EsA) on Th17 cell-related factors in psoriasis-like mouse model. Methods A total of 48 female BALB/c mice were randomly divided into blank control group, model group, Tuiyin decoction group [66.60 g/(kg.d)], low-, middle- and high-dose groups of EsA [5, 10, 20 mg/(kg.d), respectively], 8 mice in each group. Psoriasis mouse model was induced by imiquimod. Pathological changes of skin lesions in mice were assessed by psoriasis area and severity index (PASI) and HE staining. ELISA was used to detect the changes of interleukin-17 (IL-17), IL-22, IL-6 and tumor necrosis factor-α (TNF-α). Results Compared with the model group, the skin lesions, pathological changes and PASI scores were improved after the treatments with either Tuiyin decoction or EsA, among which the PASI score of Tuiyin decoction group and high-dose group of EsA decreased significantly. The expression of Th17 cell-related factors of the model group was obviously higher than that of the blank control group. Each treated group had obviously lower expression than the model group, and the expression of IL-6 of high-dose group of EsA was close to the blank control group. Conclusion EsA may improve the skin lesions of the psoriasis-like mice by down-regulating the expression of Th17 cell-related cytokines.


Assuntos
Dermatite/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Psoríase/tratamento farmacológico , Saponinas/farmacologia , Células Th17/imunologia , Animais , Citocinas/imunologia , Dermatite/imunologia , Feminino , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleanólico/farmacologia , Psoríase/induzido quimicamente , Distribuição Aleatória , Pele/imunologia , Pele/patologia
6.
Nat Commun ; 10(1): 3569, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395875

RESUMO

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αßTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αßTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αßTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.


Assuntos
Carbamazepina/efeitos adversos , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Síndrome de Stevens-Johnson/imunologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Antígeno HLA-B15/genética , Antígeno HLA-B15/imunologia , Humanos , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/patologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/transplante
7.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454926

RESUMO

Interleukin (IL)-23 is considered an effective therapeutic target for the treatment of psoriasis because of the crucial role of the IL-23/IL-17 axis in the pathogenesis of psoriasis, and it has recently been reported to be involved in ILC3 cell differentiation. In this study, we report that eukaryotically expressed rhIL23R-CHR/Fc, as an endogenous extracellular receptor analogue, could be a natural antagonist in an imiquimod (IMQ)-induced psoriasis-like mouse model, including the antagonizing effect of suppressed inflammation in the skin lesion, decreased production of pro-inflammatory cells, and reduced the expression of pro-inflammatory factors. The rhIL23R-CHR/Fc fusion protein inhibits both innate immune and adaptive immune-mediated inflammatory responses. These findings shed light on rhIL23R-CHR/Fc as a promising candidate therapy for the treatment of psoriasis.


Assuntos
Imunidade Inata/efeitos dos fármacos , Psoríase/etiologia , Psoríase/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Domínios e Motivos de Interação entre Proteínas , Psoríase/tratamento farmacológico , Psoríase/patologia , Receptores de Interleucina/química , Receptores de Interleucina/genética , Proteínas Recombinantes de Fusão/genética , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Th17/citologia
8.
Immunology ; 158(3): 171-193, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424569

RESUMO

Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft-versus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (Vm ) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R+ T cells than healthy human skin. In line with that, 25-fold more D1R+ T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam (Corlopam) - a D1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-α, interferon-γ, interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1ß and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required.


Assuntos
Fenoldopam/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Psoríase/imunologia , Receptores Dopaminérgicos/imunologia , Pele/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos CD28/imunologia , Citocinas/imunologia , Feminino , Humanos , Lectinas Tipo C/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Pele/patologia , Linfócitos T/patologia
9.
Cell Prolif ; 52(6): e12677, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31441145

RESUMO

The skin is a highly complex organ, responsible for sensation, protection against the environment (pollutants, foreign proteins, infection) and thereby linked to the immune and sensory systems in the neuro-immuno-cutaneous (NIC) system. Cutaneous innervation is a key part of the peripheral nervous system; therefore, the skin should be considered a sensory organ and an important part of the central nervous system, an 'active interface' and the first connection of the body to the outside world. Peripheral nerves are a complex class of neurons within these systems, subsets of functions are conducted, including mechanoreception, nociception and thermoception. Epidermal and dermal cells produce signalling factors (such as cytokines or growth factors), neurites influence skin cells (such as via neuropeptides), and peripheral nerves have a role in both early and late stages of the inflammatory response. One way this is achieved, specifically in the cutaneous system, is through neuropeptide release and signalling, especially via substance P (SP), neuropeptide Y (NPY) and nerve growth factor (NGF). Cutaneous, neuronal and immune cells play a central role in many conditions, including psoriasis, atopic dermatitis, vitiligo, UV-induced immunosuppression, herpes and lymphomas. Therefore, it is critical to understand the connections and interplay between the peripheral nervous system and the skin and immune systems, the NIC system. Relevant in vitro tissue models based on human skin equivalents can be used to gain insight and to address impact across research and clinical needs.


Assuntos
Inflamação/imunologia , Neuropeptídeos/imunologia , Pele/metabolismo , Engenharia Tecidual , Animais , Epiderme/metabolismo , Humanos , Imunossupressão/métodos , Pele/imunologia
10.
Nat Commun ; 10(1): 3897, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467285

RESUMO

Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans. Here we analyze the phenotype, temporal dynamics, regulation and trafficking of NK cells in a patient cohort with acute dengue virus infection. NK cells are robustly activated and proliferate during the first week after symptom debut. Increased IL-18 levels in plasma and in induced skin blisters of DENV-infected patients, as well as concomitant signaling downstream of the IL-18R, suggests an IL-18-dependent mechanism in driving the proliferative NK cell response. Responding NK cells have a less mature phenotype and a distinct chemokine-receptor imprint indicative of skin-homing. A corresponding NK cell subset can be localized to skin early during acute infection. These data provide evidence of an IL-18-driven NK cell proliferation and priming for skin-homing during an acute viral infection in humans.


Assuntos
Dengue/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Pele/imunologia , Animais , Antígenos CD , Antígenos de Diferenciação de Linfócitos T , Antígeno CD56/genética , Proliferação de Células , Vírus da Dengue , Humanos , Interleucina-18/metabolismo , Lectinas Tipo C , Camundongos , Fenótipo , Receptores CCR5 , Receptores CXCR3 , Receptores de Interleucina-18/metabolismo , Transdução de Sinais
11.
Artif Cells Nanomed Biotechnol ; 47(1): 3540-3547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31437010

RESUMO

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of Dermatophagoides Farinae (D. farinae Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual D. farinae Drops groups (high-dose, medium-dose and low-dose), respectively. Statistical analysis was performed in three groups: Full Analysis Set, Per Protocol Set and Safety Set. 48 cases have withdrawn from the study before the end of study. As primary outcomes, significant decreases in scoring atopic dermatitis and total medication score were showed in medium-dose and high-dose D. farinae Drops groups. In the sixth visit, the skin lesion area showed a statistically significant difference between high-dose/medium-dose D. farinae Drops group and placebo group (p < .05). Most adverse events are slight, and no life-threatening adverse drug reaction happened. Our research demonstrates the beneficial effect of SLIT with high or medium dose D. farinae Drops on AD, and the treatment was well tolerated.


Assuntos
Dermatite Atópica/imunologia , Dermatite Atópica/terapia , Ácaros/imunologia , Imunoterapia Sublingual/métodos , Adulto , Animais , Dermatite Atópica/patologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Placebos , Pele/imunologia , Pele/patologia
12.
Toxicol Lett ; 314: 172-180, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31404593

RESUMO

Vesicants cause a multitude of cutaneous reactions like erythema, blisters and ulcerations. After exposure to sulfur mustard (SM) and related compounds, patients present dermal symptoms typically known for chemicals categorized as skin sensitizer (e.g. hypersensitivity and flare-up phenomena). However, although some case reports led to the assumption that SM and other alkylating compounds represent sensitizers, a comprehensive investigation of SM-triggered immunological responses has not been conducted so far. Based on a well-structured system of in chemico and in vitro test methods, the Organization for Economic Co-operation and Development (OECD) established procedures to categorize agents on their skin sensitizing abilities. In this study, the skin sensitizing potential of SM and three related alkylating agents (AAs) was assessed following the OECD test guidelines. Besides SM, investigated AAs were chlorambucil (CHL), nitrogen mustard (HN3) and 2-chloroethyl ethyl sulfide (CEES). The methods are described in detail in the EURL ECVAM DataBase service on ALternative Methods to animal experimentation (DB-ALM). In accordance to OECD recommendations, skin sensitization is a pathophysiological process starting with a molecular initiating step and ending with the in vivo outcome of an allergic contact dermatitis. This concept is called adverse outcome pathway (AOP). An AOP links an adverse outcome to various key events which can be assayed by established in chemico and in vitro test methods. Positive outcome in two out of three key events indicates that the chemical can be categorized as a skin sensitizer. In this study, key event 1 "haptenation" (covalent modification of epidermal proteins), key event 2 "activation of epidermal keratinocytes" and key event 3 "activation of dendritic cells" were investigated. Covalent modification of epidermal proteins measured by using the DPRA-assay provided distinct positive results for all tested substances. Same outcome was seen in the KeratinoSens assay, investigating the activation of epidermal keratinocytes. The h-CLAT assay performed to determine the activation of dendritic cells provided positive results for SM and CEES but not for CHL and HN3. Altogether, following OECD requirements, our results suggest the classification of all investigated substances as skin sensitizers. Finally, a tentative AOP for SM-induced skin sensitization is suggested.


Assuntos
Substâncias para a Guerra Química/toxicidade , Irritantes/toxicidade , Gás de Mostarda/toxicidade , Testes de Irritação da Pele/normas , Pele/efeitos dos fármacos , Biomarcadores/metabolismo , Substâncias para a Guerra Química/classificação , Clorambucila/classificação , Clorambucila/toxicidade , Guias como Assunto , Humanos , Irritantes/classificação , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Mecloretamina/classificação , Mecloretamina/toxicidade , Gás de Mostarda/análogos & derivados , Gás de Mostarda/classificação , Medição de Risco , Pele/imunologia , Pele/metabolismo
13.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31331954

RESUMO

Group A Streptococcus (GAS) commonly causes pharyngitis and skin infections. Little is known why streptococcal pharyngitis usually does not lead to pneumonia and why the skin is a favorite niche for GAS. To partially address these questions, the effectiveness of neutrophils in clearing wild-type (wt) M1T1 GAS strain MGAS2221 from the lung and from the skin was examined in murine models of intratracheal pneumonia and subcutaneous infection. Ninety-nine point seven percent of the MGAS2221 inoculum was cleared from the lungs of C57BL/6J mice at 24 h after inoculation, while there was no MGAS2221 clearance from skin infection sites. The bronchial termini had robust neutrophil infiltration, and depletion of neutrophils abolished MGAS2221 clearance from the lung. Phagocyte NADPH oxidase but not myeloperoxidase was required for MGAS2221 clearance. Thus, wt M1T1 GAS can be cleared by neutrophils using an NADPH oxidase-dependent mechanism in the lung. MGAS2221 induced robust neutrophil infiltration at the edge of skin infection sites and throughout infection sites at 24 h and 48 h after inoculation, respectively. Neutrophils within MGAS2221 infection sites had no nuclear staining. Skin infection sites of streptolysin S-deficient MGAS2221 ΔsagA were full of neutrophils with nuclear staining, whereas MGAS2221 ΔsagA infection was not cleared. Gp91phox knockout (KO) and control mice had similar GAS numbers at skin infection sites and similar abilities to select SpeB activity-negative (SpeBA-) variants. These results indicate that phagocyte NADPH oxidase-mediated GAS killing is compromised in the skin. Our findings support a model for GAS skin tropism in which GAS generates an anoxic niche to evade phagocyte NADPH oxidase-mediated clearance.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Pulmão/enzimologia , NADPH Oxidases/imunologia , Neutrófilos/enzimologia , Infecções Estreptocócicas/enzimologia , Streptococcus pyogenes/patogenicidade , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Feminino , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/genética , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Especificidade de Órgãos , Fagócitos/enzimologia , Fagócitos/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/imunologia , Estreptolisinas/deficiência , Estreptolisinas/genética , Estreptolisinas/imunologia
14.
Am J Dermatopathol ; 41(8): 606-610, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31335417

RESUMO

RAS-associated autoimmune leukoproliferative disease (RALD) is a recently described noninfectious and nonmalignant clinical syndrome characterized by autoimmune disorders, massive splenomegaly, modest lymphadenopathy, and monocytosis. On the molecular level, RALD is defined by somatic mutations of either NRAS or KRAS gene in a subset of hematopoietic cells. To date, there is a dearth of well-documented histopathologic description of cutaneous involvement by RALD in the literature. In the current case report, a 43-year-old female patient with a history of RALD presented with clinical pictures of sepsis and an erythematous rash in the left lower extremity. Histologic examination revealed a dense perivascular and interstitial infiltrate of immature myeloid cells admixed with scattered neutrophils involving the dermis and subcutaneous adipose tissue, imparting a panniculitis-like histologic pictures. There was a strong angiocentric propensity of the immature hematopoietic cells as well as extensive extravasation of red blood cells, even in the subcutaneous adipose tissue. Immunohistochemically, the immature hematopoietic cells were positive for CD43, CD4, and CD68, but negative for CD34, CD117, and myeloperoxidase. Overall, the histologic and cytologic findings were highly reminiscent of histiocytoid Sweet syndrome. Review of the English literature revealed cutaneous involvements by RALD only in patients with KRAS mutation compared with none of its NRAS counterparts. However, larger clinicopathologic studies on cutaneous involvement by RALD are warranted. The term "RALD cutis" with its histologic and molecular features is suggested to serve as a potential groundwork for future studies of this rare phenomenon.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Dermatopatias/diagnóstico , Pele/patologia , Síndrome de Sweet/diagnóstico , Adulto , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Fenótipo , Valor Preditivo dos Testes , Pele/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia , Síndrome de Sweet/imunologia , Síndrome de Sweet/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31300128

RESUMO

The use of dogs as animal model for human atopic dermatitis (AD) is well known. Striking similarities in the pathogenesis of AD have been demonstrated. Similar alteration of host defense peptides (HDP) have been identified in both species. However, the ultrastructural/molecular alterations associated with HDPs secretion in AD have not been elucidated. We were able to use a multidisciplinary approach to investigate the secretion of HDP in canine skin. The contemporary use of indirect immunofluorescence, ELISA and scanning immune-electron microscopy gave fundamental insights in the pathomechanism of HDP alteration in AD. An increased intracellular expression and a reduced secretion of HDPs is present in atopic skin. An increased presence of HDPs was seen on the surface of atopic skin. These results suggested a defective secretion and an increased adhesion of HDPs to atopic corneocytes might be the reason of the reduced killing activity of HDPs in AD.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Dermatite Atópica/veterinária , Doenças do Cão/fisiopatologia , Pele/imunologia , Pele/patologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Bactérias/imunologia , Dermatite Atópica/imunologia , Dermatite Atópica/fisiopatologia , Doenças do Cão/imunologia , Cães , Técnica Indireta de Fluorescência para Anticorpo , Microscopia Eletrônica de Varredura , Pele/ultraestrutura
16.
Immunology ; 158(1): 47-59, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315156

RESUMO

During probing and blood feeding, haematophagous mosquitoes inoculate a mixture of salivary molecules into their vertebrate hosts' skin. In addition to the anti-haemostatic and immunomodulatory activities, mosquito saliva also triggers acute inflammatory reactions, especially in sensitized hosts. Here, we characterize the oedema and the cellular infiltrate following Aedes aegypti mosquito bites in the skin of sensitized and non-sensitized BALB/c mice by flow cytometry. Ae. aegypti bites induced an increased oedema in the ears of both non-sensitized and salivary gland extract- (SGE-)sensitized mice, peaking at 6 hr and 24 hr after exposure, respectively. The quantification of the total cell number in the ears revealed that the cellular recruitment was more robust in SGE-sensitized mice than in non-sensitized mice, and the histological evaluation confirmed these findings. The immunophenotyping performed by flow cytometry revealed that mosquito bites were able to produce complex changes in cell populations present in the ears of non-sensitized and SGE-sensitized mice. When compared with steady-state ears, the leucocyte populations significantly recruited to the skin after mosquito bites in non-sensitized and sensitized mice were eosinophils, neutrophils, monocytes, inflammatory monocytes, mast cells, B-cells and CD4+ T-cells, each one with its specific kinetics. The changes in the absolute number of cells suggested two cell recruitment profiles: (i) a saliva-dependent migration; and (ii) a migration dependent on the immune status of the host. These findings suggest that mosquito bites influence the skin microenvironment by inducing differential cell migration, which is dependent on the degree of host sensitization to salivary molecules.


Assuntos
Aedes/imunologia , Quimiotaxia de Leucócito , Edema/imunologia , Mordeduras e Picadas de Insetos/imunologia , Leucócitos/imunologia , Mastócitos/imunologia , Saliva/imunologia , Pele/imunologia , Animais , Microambiente Celular , Modelos Animais de Doenças , Feminino , Cinética , Masculino , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos
17.
Microbiol Immunol ; 63(9): 379-391, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310013

RESUMO

The immune system with large number of molecules protects the host against a plethora of continuously evolving microbes. Major histocompatibility complex (MHC) molecules serve as cardinal elements of the adaptive immune system responsible for the activation of the adaptive immunity in the host. The present study reports MHCI molecule in freshwater carp, Catla catla, and its differential expression in immunologically relevant tissues post-infection with Gram-negative and Gram-positive bacteria. The MHCI sequence of C. catla had 502 bp nucleotides encoding putative 146 amino acids. The phylogenetic analysis exhibited its evolutionary conservation within the Cyprinidae family and formed a different clade with the higher vertebrates. Simultaneously, CXCR3 and CXCR4 chemokines were cloned and characterized for their expression in infected tissues. Analysis of immunologically relevant tissues of the infected fish exhibited an increase of MHCI gene expression and the down-regulation of CXCR3 and CXCR4 chemokines, indicating a tricky interaction between the innate and adaptive immune system. It was found that intestine, skin and spleen played a crucial role in the contribution of the defense activity which instigated the self-immunity. These immune activities can provide useful information to understand the interaction of self and non-self- immune system in freshwater fish, Catla catla.


Assuntos
Carpas/genética , Quimiocinas/genética , Clonagem Molecular/métodos , Cyprinidae/genética , Genes MHC Classe I/genética , Receptores CXCR3/genética , Receptores CXCR4/genética , Imunidade Adaptativa/genética , Sequência de Aminoácidos , Animais , Carpas/imunologia , Cyprinidae/imunologia , Regulação para Baixo , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Água Doce , Expressão Gênica , Filogenia , Alinhamento de Sequência , Pele/imunologia , Baço/imunologia
18.
Nutrients ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262028

RESUMO

Raw cow's milk was previously shown to suppress allergic symptoms in a murine model for food allergy. In the present study, we investigated the contribution of fat content and heat-sensitive milk components to this allergy-protective effect. In addition, we determined the potency of alkaline phosphatase (ALP), a heat-sensitive raw milk component, to affect the allergic response. C3H/HeOuJ mice were treated with raw milk, pasteurized milk, skimmed raw milk, pasteurized milk spiked with ALP, or phosphate-buffered saline for eight days prior to sensitization and challenge with ovalbumin (OVA). Effects of these milk types on the allergic response were subsequently assessed. Similar to raw milk, skimmed raw milk suppressed food allergic symptoms, demonstrated by a reduced acute allergic skin response and low levels of OVA-specific IgE and Th2-related cytokines. This protective effect was accompanied by an induction of CD103+CD11b+ dendritic cells and TGF-ß-producing regulatory T cells in the mesenteric lymph nodes. Pasteurized milk was not protective but adding ALP restored the allergy-protective effect. Not the fat content, but the heat-sensitive components are responsible for the allergy-protective effects of raw cow's milk. Adding ALP to heat-treated milk might be an interesting alternative to raw cow's milk consumption, as spiking pasteurized milk with ALP restored the protective effects.


Assuntos
Fosfatase Alcalina/imunologia , Dermatite Atópica/prevenção & controle , Manipulação de Alimentos/métodos , Hipersensibilidade Alimentar/prevenção & controle , Proteínas do Leite/imunologia , Pasteurização , Animais , Basófilos/imunologia , Basófilos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Imunoglobulinas/sangue , Lipídeos/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos Endogâmicos C3H , Ovalbumina , Desnaturação Proteica , Pele/imunologia , Pele/metabolismo , Baço/imunologia , Baço/metabolismo
19.
Nat Immunol ; 20(8): 992-1003, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263279

RESUMO

Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.


Assuntos
Interleucina-17/imunologia , Linfócitos/imunologia , Psoríase/patologia , Pele/patologia , Células Cultivadas , Humanos , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/imunologia , Interleucina-4/imunologia , Linfócitos/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Psoríase/imunologia , Receptores CCR10/metabolismo , Pele/imunologia , Fator de Crescimento Transformador beta/metabolismo
20.
Toxicol Lett ; 314: 27-36, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295538

RESUMO

Some cosmetic ingredients can act as a chemical hapten to induce an immune response; therefore, evaluating the sensitizing potential of cosmetic ingredients is essential. We previously developed a novel in chemico direct peptide reactivity assay involving a spectrophotometric evaluation (Spectro-DPRA) for animal skin sensitization tests (local lymph node assay; LLNA). Based on previous research, we expanded the test materials to confirm the effectiveness of the Spectro-DPRA method for predicting the animal skin sensitization potential, and further determined the feasibility of the method for estimating the human skin sensitization potential. Spectro-DPRA showed 83.1% or 89.1% accuracy compared to a conventional LLNA or prediction based on human data, respectively, with a combination model using both a cysteine peptide and lysine peptide cut-off. To identify the effect of the lipophilicity of a chemical on predicting the skin sensitization potential, we applied our prediction model to chemicals with a Log Pow range of -1 to 4. Overall predictability was increased, and the accuracy compared to the LLNA and human data was 91.5% and 94.9%, respectively, in the combination cut-off prediction model. In conclusion, Spectro-DPRA serves as an easy, rapid, and high-throughput in chemico screening method with high accuracy to predict the human skin sensitization potential of chemicals.


Assuntos
Alternativas aos Testes com Animais/métodos , Ensaios de Triagem em Larga Escala , Oligopeptídeos/química , Testes de Irritação da Pele/métodos , Pele/efeitos dos fármacos , Animais , Cisteína , Estudos de Viabilidade , Humanos , Ensaio Local de Linfonodo , Lisina , Estrutura Molecular , Reprodutibilidade dos Testes , Medição de Risco , Pele/imunologia , Espectrofotometria , Relação Estrutura-Atividade
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