Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Allergy ; 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35255168

RESUMO

BACKGROUND: Atopic dermatitis (AD) and psoriasis represent two of the most common inflammatory skin diseases in developed countries. A hallmark of both diseases is T-cell infiltration into the skin. However, it is still not clarified to what extent these infiltrating T cells are antigen-specific skin-homing T cells or unspecific heterogeneous bystander cells. METHODS: To elucidate this, T cells from lesional skin and from blood of 9 AD and 10 psoriasis patients were compared by receptor (TCR) sequencing. Therefore, peripheral blood mononuclear cells (PBMC) were cell-sorted according to expression of the cutaneous leukocyte antigen (CLA) into skin-homing (CLA+ ) and non-skin-homing (CLA- ) subfractions. Aeroallergen-specific T-cell lines were grown from AD patients' PBMC in parallel. RESULTS: Intra-individual comparison of TCRB CDR3 regions revealed that clonally expanded T cells in skin lesions of both AD and psoriasis patients corresponded to skin-homing circulating T cells. However, in psoriasis patients, these T-cell clones were also detectable to a larger extent among CLA- circulating T cells. Up to 28% of infiltrating cells in AD skin were identified as allergen-specific by overlapping TCR sequences. CONCLUSIONS: Our data show that in line with the systemic nature of psoriasis, T-cell clones that infiltrate psoriatic skin lesions do not exclusively possess skin-homing ability and are therefore most probably specific to antigens that are not exclusively expressed or located in the skin. T cells driving AD skin inflammation appear to home nearly exclusively to the skin and are, to a certain extent, specific to aeroallergens.

2.
Allergy ; 77(4): 1245-1253, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34601735

RESUMO

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide and Staphylococcus aureus colonization and secondary infections occur in the majority of AD patients. Allergic sensitizations against microbial antigens have been discussed as possible trigger factors of AD. Recently, we reported IgE sensitization against fibronectin-binding protein 1 (FBP1), an essential virulence component in S. aureus, in a subgroup of patients suffering from AD. To expand these findings by investigating delayed-type immune reactions, the objective of this study was to detect and phenotypically characterize FBP1-specific T cells as possible trigger factors in AD. METHODS: Immunodominant T-cell epitopes were mapped by proliferation testing of patient-derived FBP1-specific T-cell lines after stimulation with single 15mer peptides, which were derived from different functional domains of the FBP1 sequence. Major histocompatibility complex class II tetramers carrying immunodominant epitopes successfully stained T helper cells in 8 out of 8 HLA-matched, IgE-sensitized AD patients. RESULTS: Cytokine profiling of multimer-sorted cells revealed that predominantly the type 2 cytokines IL-13 and IL-4 were secreted by these cells. In contrast, IL-17, the marker cytokine for response to extracellular pathogens, was scarcely detectable. CONCLUSIONS: We demonstrate that FBP1 contains immunodominant peptides that induce a specific pro-inflammatory T helper cell response with increased Th2 levels that can drive an allergic inflammation in sensitized AD patients.


Assuntos
Dermatite Atópica , Infecções Estafilocócicas , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Fibronectinas/metabolismo , Humanos , Imunoglobulina E , Pele , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus
3.
J Clin Invest ; 132(3)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34847081

RESUMO

Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteinases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-ß1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.


Assuntos
Citocinas/deficiência , Derme/metabolismo , Fibroblastos/metabolismo , Homeostase , Queratinócitos/metabolismo , Ubiquitinas/deficiência , Linhagem Celular Transformada , Citocinas/metabolismo , Humanos , Ubiquitinas/metabolismo
4.
Allergol Select ; 5: 287-292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532637

RESUMO

The increased permeability of the skin barrier towards environmental factors such as allergens is considered a key factor in the pathogenesis of atopic dermatitis (AD). Strengthening the skin barrier through basic skin therapy represents the basis of any therapy for AD. It is well known that genetic factors as well as the skin inflammation itself contribute to the weakening of the barrier; here, recent studies have led to a deeper understanding of the complex structures of the epidermis. The possibility of counteracting the disease preventively by the use of basic skin therapy from birth on has been studied intensively in recent years. This article summarizes recent findings on the effects of basic skin therapy as a primary and secondary preventive measure.

5.
J Invest Dermatol ; 141(8): 1879-1881, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34303467

RESUMO

The application of biologics in clinical practice allows immunological observations under real-life conditions. In a new article in the Journal of Investigative Dermatology, Bakker et al. (2021) use deep immune cell phenotyping to demonstrate how dupilumab acts in a targeted fashion on skin-homing T cells, the driver cells of atopic dermatitis.


Assuntos
Interleucina-13 , Interleucina-4 , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Humanos
6.
J Cyst Fibros ; 20(1): 149-153, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540173

RESUMO

Blood of the three clinically most concordant and most discordant p.Phe508del homozygous monozygous twin pairs of the European Cystic Fibrosis Twin and Sibling Study was examined in two postzygotic attributes that generate diversity between monozygous twins, i.e. the repertoire of the CDR3 region of the T-cell receptor ß chains and the DNA methylation at 450,000 genomic CpG sites. Methylation patterns in peripheral blood of twins changed at selected cell-type-independent positions and the immune cells of the twins showed individual profiles of the T cell receptor repertoire reflecting the plasticity of the immune system of genetically identical humans with cystic fibrosis to cope with the environment.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Doenças em Gêmeos/genética , Gêmeos Monozigóticos/genética , Adolescente , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino
7.
Curr Opin Allergy Clin Immunol ; 20(4): 374-380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32590506

RESUMO

PURPOSE OF REVIEW: The route of allergen sensing via the skin appears to influence the immune system towards mounting a type 2 response, especially in genetically predisposed individuals. Allergens recognized this way may derive from microbial, animal, food, or other plant sources and trigger atopic dermatitis. Allergens can be grouped into families depending on their structure and function, harboring significant structural and sequence similarities. Cross-reactivity between allergens is believed to arise as a consequence, and to underlie the development of further atopic diseases. RECENT FINDINGS: Especially for the plant allergens of the families of PR10-related proteins and profilins, immune cross-reactions have been described. Actual studies support that food and pollen allergens can aggravate skin lesions in patients suffering from atopic dermatitis. Further on, allergens derived from air-borne or skin-borne fungi belong to common allergen families and bear cross-reactivity potential. Cross-reactivity to human homologous proteins, so-called autoallergens, is discussed to contribute to the chronification of atopic dermatitis. SUMMARY: Due to high evolutionary conservation, allergic reactions can be triggered by highly homologous members of allergen families on the humoral as well as on the cellular level.


Assuntos
Alérgenos/imunologia , Dermatite Atópica/imunologia , Hipersensibilidade Alimentar/imunologia , Pele/imunologia , Alérgenos/efeitos adversos , Antígenos de Fungos/imunologia , Antígenos de Plantas/efeitos adversos , Antígenos de Plantas/imunologia , Aspergillus/imunologia , Doença Crônica , Reações Cruzadas , Dermatite Atópica/complicações , Dermatite Atópica/genética , Dermatite Atópica/microbiologia , Hipersensibilidade Alimentar/genética , Proteínas Fúngicas/imunologia , Predisposição Genética para Doença , Humanos , Imunoglobulina E/imunologia , Malassezia/imunologia , Proteínas de Vegetais Comestíveis/efeitos adversos , Proteínas de Vegetais Comestíveis/imunologia , Pólen/efeitos adversos , Pólen/imunologia , Profilinas/efeitos adversos , Profilinas/imunologia , Fatores de Risco , Pele/microbiologia , Pele/patologia
8.
Front Immunol ; 10: 2128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552053

RESUMO

Atopic dermatitis (AD), one of the most frequent inflammatory skin diseases worldwide, is believed to result from a disturbed skin barrier as well as aberrant immune reactions against per se harmless allergens. Starting mostly during childhood with a chronic, remitting relapsing course, the disease can persist into adulthood in about one fifth of patients. Immune reactions to self-proteins have been observed in AD patients already in the beginning of the Twentieth century, when human cellular extracts were shown to provoke skin lesions. However, the term "autoimmunity" has never been claimed, since AD is first and foremost an atopic disease. In contrast, this IgE-hallmarked autoreactivity was termed "autoallergy" and is ongoing discussed regarding its impact on the disease. Since severely affected patients tend to develop IgE-hypersensitivity reactions to numerous environmental allergens, the impact of immune responses to self-proteins is difficult to determine. On the other hand: any autoreactivity, irrespective of the magnitude, implicates the potential of driving the chronification of the disease while shaping the immune response. This review article revisits the observations made on autoallergy from an actual point of view and tries to approach the question whether these still point to a contribution to the disease.


Assuntos
Alérgenos/imunologia , Autoanticorpos/imunologia , Autoimunidade , Dermatite Atópica/imunologia , Imunoglobulina E/imunologia , Pele/imunologia , Dermatite Atópica/patologia , Humanos , Pele/patologia
9.
Curr Opin Allergy Clin Immunol ; 19(4): 319-327, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31157635

RESUMO

PURPOSE OF REVIEW: This review summarizes the mode of action of IL-4 and IL-13 in skin allergy, upcoming therapeutics and depicts key outcomes of the latest clinical trials. RECENT FINDINGS: Atopic dermatitis is considered to be one of the most common inflammatory skin disease in industrialized countries. Accompanied by strong pruritus, atopic dermatitis has a significant impact on quality of life in severely affected individuals. Aside from unspecific immunosuppressant medications, therapeutics targeting the key cytokines IL-4 and IL-13 and their downstream mediators are under development or have been approved just recently with outstanding potential. SUMMARY: The recent development of several biologics and small compounds has the potential to revolutionize the treatment of atopic dermatitis, and applying this set of state-of-the-art drugs will provide a unique chance to gain insights into this skin disorder, patient subgroups, and key inflammatory mediators.


Assuntos
Dermatite Atópica/imunologia , Hipersensibilidade/imunologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pele/patologia , Animais , Terapia Biológica , Dermatite Atópica/terapia , Humanos , Hipersensibilidade/terapia , Inflamação , Qualidade de Vida
12.
Expert Rev Clin Immunol ; 12(7): 787-96, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26967382

RESUMO

In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In recent years, vast efforts have been made to investigate the relevance and details of the immune response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL-4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but may lead to heterogeneous cytokine production involving IFN-γ and IL-17 in an allergen-dependent manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch symptoms, which still represent a challenge in daily practice, promising data have been published on the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP.


Assuntos
Imunidade Adaptativa , Dermatite Atópica/terapia , Imunoterapia/métodos , Pele/imunologia , Infecções Estafilocócicas/terapia , Staphylococcus aureus/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Dermatite Atópica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Receptores Histamínicos/metabolismo , Pele/microbiologia , Infecções Estafilocócicas/imunologia
13.
J Immunol ; 196(8): 3245-52, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26962231

RESUMO

Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8(+) T cells specific for the autoallergen Hom s 2, the α-chain of the nascent polypeptide-associated complex (α-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8(+) T cells. CD8(+) T cell immunodominant epitopes of α-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of α-NAC-specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-γ, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated α-NAC-specific CD8(+) T cells in patients with AD compared with nonatopic donors. The observed phenotype of α-NAC-specific CD8(+) T cells indicates a role in the pathogenesis of AD.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Dermatite Atópica/imunologia , Memória Imunológica/imunologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Chaperonas Moleculares/imunologia , Adulto , Epitopos de Linfócito T/imunologia , Citometria de Fluxo , Antígeno HLA-A2/imunologia , Humanos , Imunoglobulina E/imunologia , Ligação Proteica/fisiologia
16.
Int J Mol Sci ; 15(8): 13932-7, 2014 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-25116689

RESUMO

Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLß, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human cell lines. Monitoring these cell lines during the cell cycle using live cell imaging combined with confocal microscopy, we detected accumulation of MLH3 at the centrosomes. Fluorescence recovery after photobleaching (FRAP) revealed high mobility and fast exchange rates at the centrosomes as it has been reported for other DNA repair proteins. MLH3 may have a role in combination with other repair proteins in the control of centrosome numbers.


Assuntos
Proteínas de Transporte/metabolismo , Centrossomo/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Células HEK293 , Humanos , Microscopia Confocal , Proteínas MutL
17.
J Invest Dermatol ; 134(6): 1570-1578, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24441101

RESUMO

Autoallergy is a phenomenon found in a subgroup of patients with atopic dermatitis (AD). These patients exhibit serum IgE reactivity toward autoantigens like the alpha-chain of the nascent polypeptide-associated complex (α-NAC; Hom s 2). α-NAC has been shown before to induce T-cell proliferation and secretion of IFN-γ. To elucidate the immune modulating functions α-NAC may exert, we analyzed its effects on cytokine transcription and secretion in peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells. Transcription and secretion of IFN-γ, IL-17, and IL-22 were increased in α-NAC-stimulated PBMCs. As IL-17 was significantly upregulated by α-NAC, we assessed signal transduction in PBMCs and found signal transducer and activator of transcription 3 phosphorylation in α-NAC-stimulated cells. Furthermore, we could show the importance of monocyte activation by α-NAC, as isolated T cells reacted only weakly toward the stimulation. Inhibition of IL-23 p19 led to lower amounts of IL-17 in the PBMC supernatants after α-NAC stimulation. α-NAC stimulation of PBMCs from non-allergic donors resulted in secretion of IL-10, which was greatly reduced in PBMCs from α-NAC-sensitized AD patients. Our findings provide insights into the mechanisms of autoallergy, investigating the interplay of immune cells, signaling events, and cytokines, which are known to be relevant in atopic skin inflammation.


Assuntos
Autoantígenos/imunologia , Citocinas/metabolismo , Dermatite Atópica/imunologia , Chaperonas Moleculares/metabolismo , Adulto , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Leucócitos Mononucleares/citologia , Monócitos/citologia , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Linfócitos T/citologia
18.
J Cell Biochem ; 114(10): 2405-14, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23696135

RESUMO

The human DNA mismatch repair (MMR) gene family comprises four MutL paralogues capable of forming heterodimeric MutLα (MLH1-PMS2), MutLß (MLH1-PMS1), and MutLγ (MLH1-MLH3) protein complexes. Human MutL subunits PMS2 and MLH3 contain an evolutionarily conserved amino acid motif DQHA(X)2E(X)4E identified as an endonucleolytic domain capable of incising a defective DNA strand. PMS2 of MutLα is generally accepted to be the sole executor of endonucleolytic activity, but since MLH3 was shown to be able to perform DNA repair at low levels in vitro, our aim was to investigate whether or not MLH3 is activated as a backup under MutLα-deficient conditions. Here, we report stable expression of GFP-tagged MLH3 in the isogenic cell lines 293 and 293T which are functional or defective for MLH1 expression, respectively. As expected, MLH3 formed dimeric complexes with endogenous and recombinant MLH1. MutLγ dimers were recruited to sites of DNA damage induced by UVA micro-irradiation as shown for MutLα. Surprisingly, splicing variant MLH3Δ7 lacking the endonucleolytic motif displayed congruent foci formation, implying that recruitment is not necessarily representing active DNA repair. As an alternative test for repair enzyme activity, we combined alkylation-directed DNA damage with comet formation assays. While recombinant MutLα led to full recovery of DNA damage response in MMR deficient cells, expression of MutLγ or single MLH3 failed to do so. These experiments show recruitment and persistence of MutLγ-heterodimers at UVA-induced DNA lesions. However, we demonstrate that in a MutLα-deficient background no DNA repair-specific function carried out by MutLγ can be detected in living cells.


Assuntos
Reparo de Erro de Pareamento de DNA/fisiologia , Enzimas Reparadoras do DNA/metabolismo , DNA/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular , Ensaio Cometa , DNA/metabolismo , Dano ao DNA/genética , Dano ao DNA/fisiologia , Reparo de Erro de Pareamento de DNA/genética , Enzimas Reparadoras do DNA/genética , Humanos , Imunoprecipitação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...