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1.
Allergol Int ; 71(3): 310-317, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35662539

RESUMO

In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host-pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.

2.
Front Allergy ; 3: 889221, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35769567

RESUMO

Background: Type 2 inflammation underlies the chronicity of disease in subgroups of patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and atopic dermatitis (AD), that often co-exist. Although several studies have investigated the unmet needs of asthma, AD and CRSwNP as such, little is known about the similarities and differences in experiences and perspectives of the current management of patients with comorbid Type 2 inflammatory diseases. Aims: To improve insight into the common and organ-specific needs of patients with Type 2 inflammation and comorbidities, allowing the formulation of recommendations to better address these needs in the future. Methodology: This qualitative study was conducted between July 2021 and December 2021 using semi-structured face-to-face or telephone interviews with patients suffering from year-long severe chronic Type 2 inflammation and at least one co-morbid inflammatory condition. Seven participating academic centers in Europe interviewed asthma (Copenhagen and Leuven), CRSwNP (London, Amsterdam and Crete) and/or AD (Oldenburg and Zurich) patients on patient characteristics, disease severity, shortcomings of current care pathways and suggestions for improvement of care. Transcripts were analyzed using an inductive thematic analysis approach. Results: Eighty-one patients with severe Type 2 inflammation and comorbidities were interviewed. Similar needs were recognized by patients with Type 2 inflammation, with both a lack of coordination in care and a lack of a real cure reported as being most frustrating. However, several needs are specific to asthma, CRSwNP and AD. Suggestions for improvement of care were generic across diseases, such as the implementation of a multidisciplinary approach, the improved facilitation of access to better treatments, the increase of general awareness on disease burden, and better educational programs for healthcare providers and patients. Of note, patients with CRSwNP also stated the need for alternatives to sinus surgery, whereas patients with asthma requested better medical care to prevent exacerbations and patients with AD would warmly welcome the reimbursement of emollients. Conclusion: Patients with asthma, CRSwNP and AD have shared unmet needs that need to be addressed by physicians, the academic community and health policy makers. This survey provides unique recommendations made by patients for the implementation of better care.

3.
Front Immunol ; 13: 837097, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634346

RESUMO

Recently, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) was identified as a negative immune checkpoint regulator (NCR) that is mainly expressed in hematopoietic cells. Preclinical studies have shown that VISTA blockade results in impeded tumor growth and improved survival. Nevertheless, little is known about the physiological role of VISTA expression in macrophages. This study focused on the differential expression of VISTA in human monocytes and macrophages in order to elucidate a putative role of VISTA regulation upon macrophage polarization and activation. We observed that human peripheral monocytes constitutively release soluble VISTA, which was regulated via matrix metalloproteinases. However, monocyte stimulation with cytokines that induce macrophage differentiation, such as granulocyte-macrophage colony-stimulating (GM-CSF) and macrophage colony-stimulating factor (M-CSF), substantially reduced soluble VISTA release. VISTA release was further affected by various pro- and anti-inflammatory stimuli that led to macrophage polarization, where activated M1 macrophages generally released more VISTA than M2 macrophages. Additionally, we observed that stimulation of activated macrophages with the toll-like receptor 4 ligand lipopolysaccharide (LPS) led to a further decrease of soluble VISTA release. Moreover, we found that soluble VISTA impairs T cell cytotoxic activity but did not induce their programmed death. Our results suggest that VISTA is constantly produced and released in the peripheral blood where it may contribute to peripheral tolerance.


Assuntos
Proteínas de Checkpoint Imunológico , Ativação Linfocitária , Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Humanos , Macrófagos
4.
J Dermatol Sci ; 106(3): 132-140, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35537882

RESUMO

BACKGROUND: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. OBJECTIVE: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. METHODS: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (ADMut) (n = 15), along with matched wild-type (ADWt) patients and healthy controls. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. RESULTS: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of ADWt demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional ADWt or ADMut skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. CONCLUSIONS: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont.


Assuntos
Dermatite Atópica , /metabolismo , Dermatite Atópica/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Mutação , Pele/metabolismo , Staphylococcus aureus
6.
Front Med (Lausanne) ; 8: 639097, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33644104

RESUMO

Pruritus represents one of the most common symptoms in dermatology and general medicine. Chronic pruritus severely impairs the quality of life of affected patients. During the last two decades a number of modulators and mediator of pruritus have been identified. Recently, Interleukin (IL)-31 and its receptor complex attracted significant interest, as clinical phase two studies demonstrated therapeutic efficacy of the neutralizing IL-31 receptor A (IL-31RA) antibody nemolizumab in patients suffering from atopic dermatitis or prurigo nodularis. IL-31 has also been shown to play relevant roles in allergic contact dermatitis, urticaria, mastocytosis, allergic rhinitis and asthma. Here, we summarize the current knowledge of the novel cytokine IL-31 and its receptor regarding cellular origin, regulation, signaling pathways and their involvement in biological processes such as pruritus, neuronal growth, inflammation, barrier dysfunction and tissue remodeling.

7.
Front Med (Lausanne) ; 8: 627985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681256

RESUMO

Pruritus is a common, but very challenging symptom with a wide diversity of underlying causes like dermatological, systemic, neurological and psychiatric diseases. In dermatology, pruritus is the most frequent symptom both in its acute and chronic form (over 6 weeks in duration). Treatment of chronic pruritus often remains challenging. Affected patients who suffer from moderate to severe pruritus have a significantly reduced quality of life. The underlying physiology of pruritus is very complex, involving a diverse network of components in the skin including resident cells such as keratinocytes and sensory neurons as well as transiently infiltrating cells such as certain immune cells. Previous research has established that there is a significant crosstalk among the stratum corneum, nerve fibers and various immune cells, such as keratinocytes, T cells, basophils, eosinophils and mast cells. In this regard, interactions between receptors on cutaneous and spinal neurons or on different immune cells play an important role in the processing of signals which are important for the transmission of pruritus. In this review, we discuss the role of various receptors involved in pruritus and inflammation, such as TRPV1 and TRPA1, IL-31RA and OSMR, TSLPR, PAR-2, NK1R, H1R and H4R, MRGPRs as well as TrkA, with a focus on interaction between nerve fibers and different immune cells. Emerging evidence shows that neuro-immune interactions play a pivotal role in mediating pruritus-associated inflammatory skin diseases such as atopic dermatitis, psoriasis or chronic spontaneous urticaria. Targeting these bidirectional neuro-immune interactions and the involved pruritus-specific receptors is likely to contribute to novel insights into the underlying pathogenesis and targeted treatment options of pruritus.

8.
Scand J Immunol ; 93(6): e13032, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33624312

RESUMO

Over the last century, eosinophils have been regarded ambiguously either as 'friends' or 'foes'. Recent developments have greatly enhanced our understanding of the role and function of eosinophils in health and disease. Pathogenic eosinophilic inflammation can lead to severe diseases in various organs, such as the gastrointestinal tract, airways, heart and skin. In a 2-day focus workshop of the German Society for Allergology and Clinical Immunology (DGAKI), the state of the art was discussed and practical recommendations for diagnosis and treatment of eosinophilic diseases, with a particular focus on new biologics, such as anti-interleukin 5 and anti-interleukin 5R, were derived.


Assuntos
Suscetibilidade a Doenças , Eosinófilos/fisiologia , Animais , Biomarcadores , Comunicação Celular/genética , Comunicação Celular/imunologia , Citocinas/metabolismo , Gerenciamento Clínico , Eosinofilia/diagnóstico , Eosinofilia/etiologia , Eosinofilia/metabolismo , Homeostase/genética , Homeostase/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Mastócitos/imunologia , Mastócitos/metabolismo , Especificidade de Órgãos
9.
Allergol Select ; 5: 72-76, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33521511

RESUMO

Severe allergic reactions to vaccines are very rare. Single severe reactions have occurred worldwide after vaccination with the new mRNA-based COVID-19 vaccines. PEG2000 is discussed as a possible trigger. We provide guidance on risk assessment regarding COVID-19 vaccination in patients with allergic diseases and suggest a standardized, resource-oriented diagnostic and therapeutic procedure. Reports of severe allergic reactions in the context of COVID-19 vaccination can be made via www.anaphylaxie.net using an online questionnaire.

12.
Front Immunol ; 11: 580557, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329552

RESUMO

Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy. AML cells are capable of impairing the anti-cancer activities of cytotoxic lymphoid cells. This includes the inactivation of natural killer (NK) cells and killing of T lymphocytes. Here we report for the first time that V-domain Ig-containing suppressor of T cell activation (VISTA), a protein expressed by T cells, recognizes galectin-9 secreted by AML cells as a ligand. Importantly, we found that soluble VISTA released by AML cells enhances the effect of galectin-9, most likely by forming multiprotein complexes on the surface of T cells and possibly creating a molecular barrier. These events cause changes in the plasma membrane potential of T cells leading to activation of granzyme B inside cytotoxic T cells, resulting in apoptosis.


Assuntos
Antígenos B7/metabolismo , Galectinas/metabolismo , Linfócitos T Citotóxicos/imunologia , Antígenos de Neoplasias , Apoptose , Citotoxicidade Imunológica , Granzimas/metabolismo , Humanos , Ligantes , Potenciais da Membrana , Ligação Proteica , Multimerização Proteica , Células THP-1 , Evasão Tumoral
14.
J Dtsch Dermatol Ges ; 18(6): 660, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32519495
15.
Anticancer Res ; 40(5): 2947-2953, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366447

RESUMO

BACKGROUND/AIM: miRNA expression patterns vary within primary rectal cancers and play a pivotal role in carcinogenesis. It is unknown, however, if these regulatory changes also play a role in local recurrent rectal cancers. In this study, the expression of various angiogenetic small non-coding ribonucleic acids, namely miRNA-21, miRNA-215, miRNA-221, and miRNA-222 were analysed in cancerous and healthy rectal tissues. PATIENTS AND METHODS: miRNA expression was analyzed via quantitative polymerase chain reaction (qPCR). Samples were obtained from 20 patients who were treated for local recurrent rectal cancer at the Department for general and visceral surgery, Klinikum Oldenburg, Germany. RESULTS: No significant differences in the expression of miRNA-221, miRNA-222 and miRNA-215 were observed between cancerous and healthy rectal tissues. However, a significant differential expression was detected for miRNA-21. CONCLUSION: miRNA-21 is differentially expressed in recurrent rectal cancer tissue and healthy tissues. However, miRNA-215, miRNA-221 and miRNA-222 are not significantly differentially expressed.


Assuntos
MicroRNAs/metabolismo , Neoplasias Retais/genética , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias Retais/patologia
16.
Clin Exp Allergy ; 50(5): 577-584, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31925827

RESUMO

BACKGROUND: Pruritus is a major symptom of atopic dermatitis (AD) and is transmitted by a subpopulation of non-myelinated C-type free nerve endings in the epidermis and upper dermis. Stimulation of these nerve terminals is affected by histamine, neurotrophins and physical factors. Eosinophils of patients with AD are a source of neurotrophins, including brain-derived neurotrophic factor (BDNF), levels of which correlate with disease severity. OBJECTIVE: The purpose of this study was to determine the anatomical localization of eosinophils in the skin of patients with AD with regard to peripheral nerves and to investigate whether eosinophils induce sprouting and neurite outgrowth in murine sensory neurons. METHODS: Cryosections of skin derived from AD and control (NA) patients were subjected to immunofluorescence analysis with markers for eosinophils, BDNF and neuronal cells. Stimulated eosinophil supernatants were used for the treatment of cultured peripheral mouse dorsal root ganglia (DRG) neurons followed by morphometric analysis. RESULTS: Dermal axon density and the proximity of eosinophils to nerve fibres were significantly higher in AD patients vs NA. Both neuronal projections and eosinophils expressed BDNF. Furthermore, activated eosinophil supernatants induced BDNF-dependent mouse DRG neuron branching. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that BDNF-positive eosinophils are also localized in close proximity with nerve fibres in AD, suggesting a functional relationship between BDNF-expressing eosinophils and neuronal projections. These observations suggest that eosinophils may have considerable impact on pruritus by supporting sensory nerve branching.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/imunologia , Dermatite Atópica , Derme , Eosinófilos , Epiderme , Células Receptoras Sensoriais , Adolescente , Adulto , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Derme/imunologia , Derme/inervação , Derme/patologia , Eosinófilos/imunologia , Eosinófilos/patologia , Epiderme/imunologia , Epiderme/inervação , Epiderme/patologia , Feminino , Humanos , Masculino , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/patologia
17.
Clin Cosmet Investig Dermatol ; 12: 707-719, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632119

RESUMO

Lupus erythematosus tumidus (LET) is an uncommon and photosensitive inflammatory skin disorder which is characterised by erythematous urticarial plaques. In the last 20 years, extensive research on clinical and histological aspects of the disease have led to a better characterization of this nosological entity and to differentiate it from other similar or related diseases. Today, LET is considered as a separate subtype of cutaneous lupus erythematosus (CLE) with a benign, intermittent clinical course (intermittent CLE, ICLE) and only rarely associated with systemic lupus erythematosus (SLE).

18.
Front Immunol ; 10: 1383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281316

RESUMO

Many autoimmune skin diseases, such as bullous pemphigoid (BP), psoriasis and certain types of chronic urticaria, are associated with intensive pruritus. While histamine and neuropeptides have previously been ascribed to play a role in itch that accompanies these diseases, recent evidence suggests that the pruritogenic cytokine interleukin (IL)-31 is a major driver of pruritic responses. IL-31 was originally shown to be produced by activated helper T cells, particularly Th2 cells, mast cells, macrophages and dendritic cells. However, more recent evidence demonstrated that eosinophils are a major source of this cytokine too, particularly in bullous pemphigoid. Basophils have also been shown to express the cytokine which, through autocrine action, strongly supports the production of other Th2-type cytokines from these cells. These investigations suggest that the dynamic recruitment of eosinophils and basophils in some autoimmune skin diseases could play an important role in the severity of IL-31-mediated itch. Furthermore, these studies suggest that IL-31, in addition to its pruritic actions, also has potential immunomodulatory roles in terms of supporting Th2-type immunity, which often underpins IgE-associated autoimmune diseases (such as bullous pemphigoid and urticaria) as well as allergies. While the role of IL-31 in psoriasis remains to be clarified, current evidence shows that this cytokine plays a major role in BP, chronic spontaneous urticaria and dermatomyositis. This suggests potential use of IL-31 receptor-blocking therapeutic approaches (e.g., Nemolizumab) for the treatment of IL-31-associated disorders.


Assuntos
Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Interleucinas/imunologia , Prurido/imunologia , Dermatopatias/imunologia , Animais , Humanos , Interleucinas/metabolismo , Dermatopatias/complicações
19.
Allergy ; 74(12): 2427-2436, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31228881

RESUMO

BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Biomarcadores , Urticária Crônica/imunologia , Urticária Crônica/metabolismo , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/diagnóstico , Basófilos/imunologia , Basófilos/metabolismo , Urticária Crônica/diagnóstico , Feminino , Liberação de Histamina , Humanos , Imunoglobulina G/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de IgE/metabolismo , Avaliação de Sintomas , Adulto Jovem
20.
Front Pharmacol ; 10: 333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984005

RESUMO

Calcineurin inhibitors potentially prevent pro-allergic mediator release from basophils and mast cells but are rarely used systemically due to ubiquitous expressions of target signaling proteins. However, specific targeting of allergic effector cells with these inhibitors could circumvent unwanted side effects. We recently demonstrated the biocompatibility of gold nanoparticles (AuNPs) as a platform for non-toxic delivery of signaling inhibitors due to unique physicochemical properties of these nanomaterials. Since AuNPs can be conjugated with both anti-allergic drugs and antibodies or other proteins that specifically recognize basophils and mast cells, our aims were to assess specific targeting of allergic effector cell function using AuNPs conjugated with the calcineurin inhibitor ascomycin. Purified human basophils and LAD2 human mast cells were used for investigations with AuNPs conjugated either to CD203c antibodies or containing stem cell factor (SCF), respectively, which were amine-coupled to acidic groups of reduced glutathione (GSH). GSH was also used as a spacer for immobilization of ascomycin on the gold surface. AuNPs conjugated with anti-CD203c and ascomycin strikingly blocked IgE-dependent degranulation of both purified basophils and those present in mixed leukocyte preparations, suggesting specific targeting of these cells. In contrast, LAD2 mast cell responses were not inhibited using anti-CD203c-containing nanoconjugates but were when the conjugates contained SCF. Successful targeting of allergic effector cells using gold nanoconjugates indicates that this technology may have therapeutic potential for the treatment of allergies by specifically delivering highly effective signaling inhibitors with reduced side effects.

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