Importantly, if they activate autophagy in eosinophils, this counterregulates eosinophil cytolysis....the authors not only demonstrate in a very elegant fashion a new pathway for eosinophil ...cytolysis, they were also able to link cytolysis with counterregulating autophagy and open new pathways for at least experimental intervention.Interestingly, autophagy, rather than endoplasmic reticulum stress, contributed to IL-13-induced eotaxin-3 peptide secretion also from human airway epithelial cells.6-8 A link between the epithelial-mesenchymal transition unit and autophagy has been shown in other models of allergic asthma.9,10 A further link between autophagy and asthma has been established for human rhinovirus, respiratory syncytial virus, coronavirus, adenovirus, and influenza A virus through the role of autophagy in the defense against respiratory tract viruses, which represent a major exacerbation factor for asthma.Table I Key discoveries on the journey to the autophagosome 1955 Lysosomes de Duve 1966 Function of lysosome (“autophagy”) de Duve 1968 Autophagosome Arstila, Trump 1979 Proteasome Harshko, Chiecanova, Rose 1980 Ubiquitin Wilkinson, Urban, Haas 1992 Autophagosome as machinery of autophagy Ohsumi 1993 The first autophagy gene, ATG1 Ohsumi 1 M. Tsukada, Y. Ohsumi, Saccharomyces cerevisiae, FEBS Lett, Vol. 333, 1993, 169-174 2 K. Takeshige, M. Baba, S. Tsuboi, T. Noda, Y. Ohsumi, Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction, J Cell Biol, Vol. 119, 1992, 301-311 3 N. Mizushima, T. Noda, T. Yoshimori, Y. Tanaka, T. Ishii, M.D. George, A protein conjugation system essential for autophagy, Nature, Vol. 395, 1998, 395-398 4 Y. Ichimura, T. Kirisako, T. Takao, Y. Satomi, Y. Shimonishi, N. Ishihara, A ubiquitin-like system mediates protein lipidation, Nature, Vol. 408, 2000, 488-492 5 S. Radonjic-Hoesli, X. Wang, E. de Graauw, C. Stoeckle, B. Styp-Rekowska, R. Hlushchuk, Eosinophil cytolysis requires the RIPK3-MLKL signaling pathway and is counter-regulated by autophagy, J Allergy Clin Immunol, Vol. 140, 2017, 1632-1642 6 G.Y. Ban, D.L. Pham, T.H. Trinh, S.I. Lee, D.H. Suh, E.M. Yang, Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target, Clin Exp Allergy, Vol. 46, 2016, 48-59 7 J.D. Dickinson, Y. Alevy, N.P. Malvin, K.K. Patel, S.P. Gunsten, M.J. Holtzman, IL13 activates autophagy to regulate secretion in airway epithelial cells, Autophagy, Vol. 12, 2016, 397-409 8 A.A. Zeki, S. Ott, K. Sandhu, S. Ghavami, N.J. Kenyon, The complex roles of endoplasmic reticulum stress and autophagy in modulating Eotaxin-3 production and secretion from human airway epithelial cells, Am J Respir Crit Care Med, Vol. 189, 2014, A5683 9 Z. Cao, P. Pan, H. Tan, Q. Tan, Z. Wang, X. Su, Anti-nerve growth factor antibody reduces airway hyperresponsiveness in a mouse model of asthma by down-regulating the level of autophagy in lungs, Zhonghua Jie He He Hu Xi Za Zhi, Vol. 37, 2014, 507-511 10 I.-H.
Update on epigenetics in allergic disease Harb, Hani, MSc; Renz, Harald, MD
Journal of allergy and clinical immunology,
01/2015, Letnik:
135, Številka:
1
Journal Article
Recenzirano
Chronic inflammatory diseases, including allergies and asthma, are the result of complex gene-environment interactions. One of the most challenging questions in this regard relates to the biochemical ...mechanism of how exogenous environmental trigger factors modulate and modify gene expression, subsequently leading to the development of chronic inflammatory conditions. Epigenetics comprises the umbrella of biochemical reactions and mechanisms, such as DNA methylation and chromatin modifications on histones and other structures. Recently, several lifestyle and environmental factors have been investigated in terms of such biochemical interactions with the gene expression–regulating machinery: allergens; microbes and microbial compounds; dietary factors, including vitamin B12, folic acid, and fish oil; obesity; and stress. This article aims to update recent developments in this context with an emphasis on allergy and asthma research.
Antisense molecules: A new class of drugs Potaczek, Daniel P., MD, PhD; Garn, Holger, PhD; Unger, Sebastian D ...
Journal of allergy and clinical immunology,
05/2016, Letnik:
137, Številka:
5
Journal Article
Recenzirano
Odprti dostop
An improved understanding of disease pathogenesis leads to identification of novel therapeutic targets. From a pharmacologic point of view, these can be addressed by small chemical compounds, ...so-called biologicals (eg, mAbs and recombinant proteins), or by a rather new class of molecule based on the antisense concept. Recently, a new wave of clinical studies exploring antisense strategies is evolving. In addition to cancer, they include predominantly trials on infectious and noninfectious diseases, such as chronic inflammatory and metabolic conditions. This article, based on a systematic PubMed literature search, highlights recent developments in this emerging field.
Background Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly ...from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown. Objectives We sought to assess the asthma-protective effect of unprocessed cow's milk consumption in a birth cohort and to determine whether the differences in the fatty acid (FA) composition of unprocessed farm milk and industrially processed milk contributed to this effect. Methods The Protection Against Allergy—Study in Rural Environments (PASTURE) study followed 1133 children living in rural areas in 5 European countries from birth to age 6 years. In 934 children milk consumption was assessed by using yearly questionnaires, and samples of the “usually” consumed milk and serum samples of the children were collected at age 4 years. Doctor-diagnosed asthma was parent reported at age 6 years. In a nested case-control study of 35 asthmatic and 49 nonasthmatic children, 42 FAs were quantified in milk samples. Results The risk of asthma at 6 years of age was reduced by previous consumption of unprocessed farm milk compared with shop milk (adjusted odds ratio for consumption at 4 years, 0.26; 95% CI, 0.10-0.67). Part of the effect was explained by the higher fat content of farm milk, particularly the higher levels of ω-3 polyunsaturated FAs (adjusted odds ratio, 0.29; 95% CI, 0.11-0.81). Conclusion Continuous farm milk consumption in childhood protects against asthma at school age partially by means of higher intake of ω-3 polyunsaturated FAs, which are precursors of anti-inflammatory mediators.
Laboratory tests play an increasing role in risk assessment, diagnostics, and disease monitoring. Great advances have been achieved lately, particularly in the field of clinical immunology and ...allergy. These include neonatal screening of immunodeficiencies and asthma biomarkers and investigation into the role of recombinant allergens in in vitro testing. The latter area has implications for the diagnostics of food allergy, pollen-induced allergies, asthma, and insect allergies.
Background Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental ...condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. Objective This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Methods Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH 1- and TH 2-relevant genes of CD4+ T cells. Results Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-γ dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-γ expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH 2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH 2 regulatory region conserved noncoding sequence 1 (CNS1). Conclusion These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection.
Background Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. Objectives To investigate associations ...between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. Methods Supernatants from phorbol 12-myristate 13-acetate/ionomycin–stimulated CB mononuclear cells were assessed for the production of IFN-γ, TNF-α, IL-5, IL-10, and IL-12. Results Significantly higher levels of IFN-γ and TNF-α in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-γ and TNF-α in umbilical blood. Conclusion Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.
Recent advances indicate that asthma is a heterogeneous disease, with both innate and adaptive immune responses contributing to the pathogenesis of various asthma phenotypes.1,2 TH2-driven asthma ...represents a large subgroup characterized by a dominance of TH2 cytokines, production of IgE antibodies, mast cell activation, and the presence of airway and blood eosinophilia. Deoxyribozymes (DNAzymes) are synthetic single-stranded DNA antisense molecules that contain highly specific binding domains for the target mRNA (GATA3 mRNA in the case of the human GATA3 DNAzyme hgd40) attached to an intrinsic catalytic domain that executes target mRNA cleavage.3-6 Clinical efficacy of SB010 (drug formulation of hgd40 for inhaled application) inhalation was recently shown in a clinical allergen-provocation trial performed in patients with mild asthma exhibiting TH2-driven disease. Study protocol (see Fig E1 in this article's Online Repository at www.jacionline.org), primary outcome, and detailed information on procedures, inclusion and exclusion criteria, safety, biomarker assessment, and statistical analysis were reported elsewhere.7 The trial was registered with ClinicalTrials.gov (NCT01743768). Characteristic Blood eosinophils >= 3% Blood eosinophils >= 4% Blood eosinophils >= 5% Placebo n = 15 SB010 n = 18 Placebo n = 12 SB010 n = 12 Placebo n = 9 SB010 n = 8 Age (y) 36.4 ± 12.3 33.8 ± 9.8 35.0 ± 12.3 33.3 ± 11.0 33.4 ± 12.0 32.4 ± 12.8 Body mass index (kg/m2) 25.41 ± 3.17 26.39 ± 3.44 24.77 ± 3.21 26.68 ± 3.85 23.49 ± 2.52 25.29 ± 2.67 Baseline-FEV1 (% of predicted) 88.3 ± 12.0 92.9 ± 12.1 90.2...
Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was ...the aim of the International von-Behring-Röntgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies.
To provide an overview of studied cellular and noncellular blood-derived asthma biomarkers.
PubMed literature review.
Articles discussing cellular and noncellular bloodborne asthma biomarkers.
...Discussed asthma biomarkers include peripheral blood cell counts of T cells, fibrocytes, or granulocytes, as well as levels of cytokines, periostin, IgE, and lipid mediators with or without stimulation. Moreover, this article summarizes the association of various blood biomarkers with the type of airway inflammation, presence of atopy, and dominance of specific T-cell subsets and associated pathways in asthma. Furthermore, biomarkers are here listed according to their proposed clinical use, such as diagnosis, disease phenotyping, classification of severity, assessment of disease control, and monitoring of and predicting treatment response.
Further research on asthma biomarkers may improve asthma endotyping and ultimately lead to personalized treatment.
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