Association of TLR4 (896A/G and 1196C/T) Gene Polymorphisms with Asthma Risk: A Meta-Analysis

Li, Shaojun; Xie, Xinming; Song, Yang; Jiang, Hongtao; Wu, Xiaojuan; Su, Xiaofan; Yang, Lan; Li, Manxiang

doi:10.12659/msm.895380

Cited by 8 publications

(3 citation statements)

References 42 publications

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“…A recent meta-analysis performed by Li et al revealed a significant association between TLR4 1196C/T polymorphism and asthma patients, but not with the 896A/G polymorphism. 62 Similar results have also been reported by Yao et al 63 and Sinha et al 64 in North Indians. Zhang et al further genotyped individuals with asthma for TLR4 variants to make comparison with asthma severity and T cell subpopulations and found that variant rs1927907 may be related to asthma severity and the degree of TLR4 expression on the surface of Tregs.…”

Section: Cellular Mediators Of Inflammation In Asthma Airway Epitheliumsupporting

confidence: 85%

Advances and Evolving Concepts in Allergic Asthma

Tung

Landers

et al. 2018

Semin Respir Crit Care Med

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Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E-secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting factors such as fibrinogen. Recent clinical trials have demonstrated that targeting inflammatory pathways orchestrated through IL-4, IL-5, IL-13, and the prostaglandin receptor CRTH2 is potentially highly effective in adult asthma.

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Section: Cellular Mediators Of Inflammation In Asthma Airway Epitheliumsupporting

confidence: 85%

Advances and Evolving Concepts in Allergic Asthma

Tung

Landers

et al. 2018

Semin Respir Crit Care Med

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“…MPL is a component of the adjuvant Pollinex Quattro, which has undergone randomised clinical trials in allergic rhinitis in man. However, there is not a clear indication as to the role of TLR4 in asthma nor atopic diseases, with meta-analyses having identified that TLR4 polymorphisms may be either preventative ( 79 ) or represent risk factors ( 53 ) for development of asthma while TLR4 protein levels are enhanced in the nasal mucosa of patients with allergic rhinitis ( 55 ). Whilst MPL has been used clinically as an adjuvant, lipopolysaccharide (LPS) has been used in the majority of in vitro and animal mechanistic studies.…”

Section: Extracellular Tlrsmentioning

confidence: 99%

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

et al. 2020

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Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human in vitro experiments and in vivo in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.

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“…In support of these findings, interruption of the clotting system by administering anticoagulants such as heparin has previously been shown to be beneficial in asthma [47,48]. Additionally, TLR4 impacts the expression of asthma in complex ways, such that multiple TLR4 ligands have been shown to enhance disease expression in mice [25,39,49] and TLR4 polymorphisms confer either enhanced [50] or reduced [51] asthma susceptibility. Th2 and Th17 cell activation, through antigen presentation by dendritic cells, but usually without inducing disease.…”

Section: Proteolytic Induction Of Type 2 Immunitymentioning

confidence: 84%

Airway Mycosis and the Regulation of Type 2 Immunity

Knight

Anvari

et al. 2020

JoF

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Filamentous fungi of the Aspergillus genus and others have long been linked to the induction of type 2 immunity that underlies IgE-mediated hypersensitivity responses. This unique immune response is characterized by the production of the allergy-associated T helper cell type 2 (Th2) and Th17 cytokines interleukin 4 (IL-4), IL-13, and IL-17 that drive IgE, eosinophilia, airway hyperresponsiveness and other manifestations of asthma. Proteinases secreted by filamentous fungi promote type 2 immunity, but the mechanism by which this occurs has long remained obscure. Through detailed biochemical analysis of household dust, microbiological dissection of human airway secretions, and extensive modeling in mice, our laboratory has assembled a detailed mechanistic description of how type 2 immunity evolves after exposure to fungi. In this review we summarize three key discoveries: (1) fungal proteinases drive the type 2 immune response; (2) the relationship between fungi, proteinases, and type 2 immunity is explained by airway mycosis, a form of non-invasive fungal infection of the airway lumen; and (3) the innate component of proteinase-driven type 2 immunity is mediated by cleavage of the clotting protein fibrinogen. Despite these advances, additional work is required to understand how Th2 and Th17 responses evolve and the role that non-filamentous fungi potentially play in allergic diseases.

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Association of TLR4 (896A/G and 1196C/T) Gene Polymorphisms with Asthma Risk: A Meta-Analysis

Cited by 8 publications

References 42 publications

Advances and Evolving Concepts in Allergic Asthma

Advances and Evolving Concepts in Allergic Asthma

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

Airway Mycosis and the Regulation of Type 2 Immunity

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