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Genetics and Asthma
Published in Jonathan A. Bernstein, Mark L. Levy, Clinical Asthma, 2014
Rebecca E. Slager, Xingnan Li, Deborah A. Meyers, Eugene R. Bleecker
Recent genome-wide association study (GWAS) approaches have identified several genes or loci that are associated with asthma susceptibility,1–4 including the ORM1-like 3/gasdermin-like (ORMDL3/GSDML) region of chromosome 17q21, interleukin 33 (IL-33) and its receptor interleukin 1 receptor-like 1 isoform 1 (IL-1RL1), thymic stromal lymphopoietin (TSLP), the major histocompatibility (MHC) region on 6p21, and interleukin 13 (IL-13). Some of these genes have previously been linked to asthma or other related allergic phenotypes in earlier candidate gene or positional cloning studies, suggesting that shared inflammatory pathways may be affected. For example, the MHC region was one of the first asthma susceptibility loci identified5 and it appears to play a major role in asthma and allergen sensitization.3 Regulatory T cell signaling genes, such as the SMAD family member 3 (SMAD3), encoding a transcriptional modulator related to transforming growth factor β, may also play a critical role in the development of asthma. A number of these susceptibility genes have been replicated in some but not all populations, suggesting that there may be heterogeneity in the genetic risk in populations of different ethnic backgrounds. The results from major GWAS and meta-analyses of asthma reviewed in this chapter are summarized in Table 3.1.
Dermatologic Disorders Causing Vulvar Disease
Published in William J. Ledger, Steven S. Witkin, Vulvovaginal Infections, 2017
William J. Ledger, Steven S. Witkin
Aphthous ulcers are a predominant feature of Behçet’s disease, a systematic recurrent immuno-inflammatory vasculitis, mainly affecting young adults. It is characterized by recurrent genital and oral ulcerations, uveitis, and neurological, vascular, pulmonary, and articular manifestations in some individuals.11 The appearance of genital aphthous ulcers is very common. The disease is rare in the Americas and Europe and is most common in Turkey, the Middle East, and the Far East. This geographic distribution strongly suggests a genetic component, and carriage of HLA-B51 has been associated with development of Behçet’s disease.12 The prevailing hypothesis is that when an individual with a genetic susceptibility to develop Behçet’s disease is exposed to a viral or bacterial infection, an autoimmune response is triggered that results in the appearance of clinical symptoms. Interestingly, the concentration of a minor subset of T lymphocytes, gamma delta T cells, is increased in the circulation of individuals with either recurrent aphthous ulcers or Behçet’s disease. Gamma delta T cells recognize, proliferate, and produce pro-inflammatory mediators in response to hsp60, lending further support to the suggestion that hsp60 might be a target antigen for development of autoimmunity leading to aphthous ulcerations. Very recent investigations have also noted the involvement of natural killer cells13 and the pro-inflammatory cytokine, interleukin-33,14 as contributing to Behçet’s disease symptomatology. Since pregnancy favors the predominance of a humoral immune response and inhibition of cell-medicated immunity, it was of interest to determine the effect of pregnancy on Behçet’s disease manifestations. No consistent response was observed. Symptoms improved in some women, became worse in others, and remained the same in a third group of patients.15
Interleukin (IL)-33 immunobiology in asthma and airway inflammatory diseases
Published in Journal of Asthma, 2022
Interleukin-33 (IL-33) is an alarmin that senses damage/activation of epithelial or endothelial cells and responds immediately by its release into the cytoplasm and extracellular fluids from the nucleus (1). It was first identified in endothelial cells as a nuclear protein called NF-HEV (nuclear factor from high endothelial venules) (1), and in 2005, it was reidentified as a member of the IL-1 family that binds to its orphan receptor ST2 (2). Upon binding to ST2 as an extracellular cytokine, IL-33 stimulates type 2 innate lymphoid cells (ILC2), mast cells, basophils, and T-helper type 2 (Th2) cells to secrete high levels of IL-5, IL-9, and IL-13 (3,4). These Th2 cytokines are involved in the pathogenesis of multiple disease processes including allergy and asthma. Additionally, IL-33 expression has been implicated in environmental-induced nonallergic airway inflammation such as agricultural organic dust exposure (5). Emerging roles for IL-33 include repair, inflammation, homeostasis, and fibrosis. However, the precise mechanisms of IL-33 activation are not well understood and the downstream signaling pathways are complex. Understanding immunobiology of IL-33 is necessary to comprehend the clinical relevance and potential of this versatile cytokine. This review seeks to connect the relevance of IL-33 biology in allergic and nonallergic asthma and chronic inflammatory airway diseases to current and potential clinical interventions.
The GLP-1 receptor in airway inflammation in asthma: a promising novel target?
Published in Expert Review of Clinical Immunology, 2021
Ashley Y. Wu, R. Stokes Peebles
It is estimated that over 25 million people in the US (330 million globally) currently suffer from asthma [11]. Classically, asthma is considered a predominantly allergic disease, mediated by type 2 inflammatory immune cells such as CD4+ T-helper type 2 (Th2) cells, mast cells, eosinophils, basophils, and group 2 innate lymphoid cells (ILC2s). In this chronic lung disease, airway hyperresponsiveness leads to bronchospasm, mucus production, and reversible obstruction, though over time, airway remodeling can result in airway smooth muscle hypertrophy, mucus metaplasia, and collagen deposition. As part of the innate immune response to certain environmental antigens, interleukin-33 (IL-33) is secreted predominantly by airway epithelial cells and macrophages. IL-33 potentiates a type 2 allergic inflammatory response, activating immune cells including ILC2s, Th2 cells, mast cells, and basophils [12,13]. These cells then, in turn, secrete numerous cytokines including IL-4, IL-5, IL-9, and IL-13, which stimulate structural cells in the lung such as goblet cells and smooth muscle cells to cause airway remodeling. Furthermore, these type 2 cytokines can act back on leukocytes such as CD4+ T-cells, eosinophils, basophils, mast cells, and B-cells to further amplify allergic responses. Of note, IL-4 and IL-13 can induce B-cells to isotype switch to produce IgE [14].
Sesamin attenuates intestinal injury in sepsis via the HMGB1/TLR4/IL-33 signalling pathway
Published in Pharmaceutical Biology, 2020
Zhi-Ling Li, Min Gao, Ming-Shi Yang, Xue-Fei Xiao, Jing-Jing Liu, Bing-Chang Yang
Interleukin-33 (IL-33) (Ozcan et al. 2004) is expressed in the intestinal epithelium, lung and pulmonary endothelium (Moussion et al. 2008). It has been reported that TLR-4 activity is dependent IL-33 signalling in allergic inflammation in mice (Tjota et al. 2013) as well as in acute systemic injury (Chang et al. 2016). As a member of the IL-1 family, IL-33 binds to its corresponding receptor suppression of tumorigenicity 2 (ST2), which is expressed on the surface of mast cells or T helper 2 (Th2) cells, leading to the activation of the p38 MAPK/NF-κB pathway and ultimately enhancing the production of Th2-associated cytokines (Schmitz et al. 2005). It is interesting that IL-33 has been reported to reduce inflammatory cell infiltration in the mouse mucosa and indirectly induce tolerogenic CD103+ dendritic cells (DCs). High mobility group box 1 (HMGB1) released by macrophages has been demonstrated to be an important mediator of organ damage in severe sepsis and is expressed at a high level in experimental animal models, causing lethal damage, according to early studies (Wang et al. 1999; Yang et al. 2004). By binding to the TLR4 surface receptor, HMGB1 exerts its effect on inflammation. Evidence has also shown that HMGB1 is involved in TLR4-dependent increases in IL-33 expression (Chang et al. 2017), thus, indicating the potential regulatory role of the HMGB1/TLR4/IL-33 axis in the pathophysiology of sepsis.