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Molecular Research on Mucosal Immunity
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Molecular Research on Mucosal Immunity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 48136

Special Issue Editors

Prof. Dr. Clive Robinson

E-Mail Website
Guest Editor
Institute for Infection and Immunity, Novel Therapeutics and Vaccinology Centre, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK
Interests: molecular basis of allergenicity; Innate immune signalling; drug design and development; asthma; atopic dermatitis; allergic rhinitis
Prof. Dr. Geoffrey Stewart

E-Mail Website
Guest Editor
School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia
Interests: allergen structure and function; innate immunity; house dust mite biology; NlpC/P60 peptidoglycan endopeptidases

Special Issue Information

Dear Colleagues,

We invite you to submit reviews, commentaries or research papers for this Special Issue “Molecular Research on Mucosal Immunity”, which will focus on recent advances and future priorities in this field. We welcome articles with a cellular or molecular mechanistic focus, those with clinical orientation, or those offering cross-functional perspectives that will inspire others to engage with this research community.

Innate and adaptive mechanisms protect mucosal surfaces (e.g., the skin, gastrointestinal tract, genitourinary tract and respiratory tract) against potential pathogens and also guard against inappropriate responses to innocuous proteins, such as food components and allergens. However, abnormal operation of these processes causes disease. The past 40 years have seen an explosion in our understanding of cellular and molecular events following the cross-linkage of allergen-specific IgE on mast cells and basophils. In contrast, less attention has been given to understanding events which lie upstream, such as the nature of allergenicity and the initiation of allergic sensitisation. Recent progress on these questions, and how they are affected by other mucosal responses such as antiviral defence, make it timely to review the field and next steps. Therefore, this Special Issue will focus on recent advances in understanding the relationship between innate immune responses and the development of allergic disease. It will examine recent progress in understanding the molecular basis of allergenicity and how allergens initiate and/or exacerbate disease mechanisms at mucosal surfaces through elaborate innate signalling events which are now being revealed as central to mucosal responses to a miscellany of unrelated pathogenetic agents.

Prof. Dr. Clive  Robinson
Prof. Dr. Geoffrey Stewart
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • asthma
  • atopic dermatitis
  • allergic rhinitis
  • food allergy
  • antigen presentation
  • allergen structure and function
  • innate lymphoid cells
  • pattern recognition receptors and their ligands
  • allergen-virus interactions
  • inflammatory mediators
  • intercellular junctions
  • microbiome
  • inflammasome

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Published Papers (7 papers)

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Research

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34 pages, 3416 KiB  
Article
Allergen Delivery Inhibitors: Characterisation of Potent and Selective Inhibitors of Der p 1 and Their Attenuation of Airway Responses to House Dust Mite Allergens
by Jihui Zhang, Jie Chen, Jie Zuo, Gary K. Newton, Mark R. Stewart, Trevor R. Perrior, David R. Garrod and Clive Robinson
Int. J. Mol. Sci. 2018, 19(10), 3166; https://doi.org/10.3390/ijms19103166 - 15 Oct 2018
Cited by 12 | Viewed by 4931
Abstract
Group 1 allergens of house dust mites (HDM) are globally significant triggers of allergic disease. They are considered as initiator allergens because their protease activity enables the development of allergy to a spectrum of unrelated allergens from various sources. This initiator-perpetuator function identifies [...] Read more.
Group 1 allergens of house dust mites (HDM) are globally significant triggers of allergic disease. They are considered as initiator allergens because their protease activity enables the development of allergy to a spectrum of unrelated allergens from various sources. This initiator-perpetuator function identifies Group 1 HDM allergens as attractive drug design targets for the first small-molecule approach directed towards a non-human, root cause trigger of allergic disease. The purpose of this study was to: (i) identify exemplar inhibitors of these allergens using Der p 1 as a design template, and (ii) characterise the pharmacological profiles of these compounds using in vitro and in vivo models relevant to allergy. Potent inhibitors representing four different chemotypes and differentiated by mechanism of action were investigated. These compounds prevented the ab initio development of allergy to the full spectrum of HDM allergens and in established allergy they inhibited the recruitment of inflammatory cells and blunted acute allergic bronchoconstriction following aerosol challenge with the full HDM allergen repertoire. Collectively, the data obtained in these experiments demonstrate that the selective pharmacological targeting of Der p 1 achieves an attractive range of benefits against exposure to all HDM allergens, consistent with the initiator-perpetuator function of this allergen. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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Review

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17 pages, 331 KiB  
Review
Recent Advances in Allergy Research Using Humanized Mice
by Ryoji Ito, Shuichiro Maruoka, Yasuhiro Gon, Ikumi Katano, Takeshi Takahashi, Mamoru Ito, Kenji Izuhara and Satoshi Nunomura
Int. J. Mol. Sci. 2019, 20(11), 2740; https://doi.org/10.3390/ijms20112740 - 4 Jun 2019
Cited by 13 | Viewed by 4495
Abstract
The prevalence rates of allergic diseases are increasing worldwide, particularly in industrial countries. To date, many mouse models have been generated for allergy research; studies conducted using these models have suggested the importance of cross-talk between immune cells and tissue-resident non-immune cells in [...] Read more.
The prevalence rates of allergic diseases are increasing worldwide, particularly in industrial countries. To date, many mouse models have been generated for allergy research; studies conducted using these models have suggested the importance of cross-talk between immune cells and tissue-resident non-immune cells in the onset of allergic diseases. However, there are several differences between the immune systems of rodents and humans, and human studies are limited. Thus, mice reconstituted with human immune cells are a novel tool for the preclinical evaluation of the efficacy and safety of developing drugs. Genetic technologies for generating humanized mice have improved markedly in recent years. In this review, we will discuss recent progress in allergy research using humanized mice and introduce our recent humanized mouse model of airway inflammation in human immune cells. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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32 pages, 4872 KiB  
Review
Cellular and Molecular Events in the Airway Epithelium Defining the Interaction Between House Dust Mite Group 1 Allergens and Innate Defences
by Jihui Zhang, Jie Chen and Clive Robinson
Int. J. Mol. Sci. 2018, 19(11), 3549; https://doi.org/10.3390/ijms19113549 - 10 Nov 2018
Cited by 28 | Viewed by 6555
Abstract
Serodominant group 1 allergens of house dust mites (HDMs) are cysteine protease digestive enzymes. By increasing the detection of any allergen by dendritic antigen presenting cells, upregulating inflammatory signalling molecules, and activating cells crucial to the transition from innate to acquired immune responses, [...] Read more.
Serodominant group 1 allergens of house dust mites (HDMs) are cysteine protease digestive enzymes. By increasing the detection of any allergen by dendritic antigen presenting cells, upregulating inflammatory signalling molecules, and activating cells crucial to the transition from innate to acquired immune responses, the proteolytic activity of these HDM allergens also underlies their behaviour as inhalant allergens. The significance of this property is underlined by the attenuation of allergic responses to HDMs by novel inhibitors in experimental models. The group 1 HDM allergens act as prothrombinases, enabling them to operate the canonical stimulation of protease activated receptors 1 and 4. This leads to the ligation of Toll-like receptor 4, which is an indispensable component in HDM allergy development, and reactive oxidant-regulated gene expression. Intermediate steps involve epidermal growth factor receptor ligation, activation of a disintegrin and metalloproteases, and the opening of pannexons. Elements of this transduction pathway are shared with downstream signalling from biosensors which bind viral RNA, suggesting a mechanistic linkage between allergens and respiratory viruses in disease exacerbations. This review describes recent progress in the characterisation of an arterial route which links innate responses to inhaled allergens to events underpinning the progression of allergy to unrelated allergens. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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21 pages, 1703 KiB  
Review
Immunological Processes Driving IgE Sensitisation and Disease Development in Males and Females
by Jonatan Leffler, Philip A. Stumbles and Deborah H. Strickland
Int. J. Mol. Sci. 2018, 19(6), 1554; https://doi.org/10.3390/ijms19061554 - 23 May 2018
Cited by 33 | Viewed by 9268
Abstract
IgE sensitisation has increased significantly over the last decades and is a crucial factor in the development of allergic diseases. IgE antibodies are produced by B cells through the process of antigen presentation by dendritic cells, subsequent differentiation of CD4+ Th2 cells, [...] Read more.
IgE sensitisation has increased significantly over the last decades and is a crucial factor in the development of allergic diseases. IgE antibodies are produced by B cells through the process of antigen presentation by dendritic cells, subsequent differentiation of CD4+ Th2 cells, and class switching in B cells. However, many of the factors regulating these processes remain unclear. These processes affect males and females differently, resulting in a significantly higher prevalence of IgE sensitisation in males compared to females from an early age. Before the onset of puberty, this increased prevalence of IgE sensitisation is also associated with a higher prevalence of clinical symptoms in males; however, after puberty, females experience a surge in the incidence of allergic symptoms. This is particularly apparent in allergic asthma, but also in other allergic diseases such as food and contact allergies. This has been partly attributed to the pro- versus anti-allergic effects of female versus male sex hormones; however, it remains unclear how the expression of sex hormones translates IgE sensitisation into clinical symptoms. In this review, we describe the recent epidemiological findings on IgE sensitisation in male and females and discuss recent mechanistic studies casting further light on how the expression of sex hormones may influence the innate and adaptive immune system at mucosal surfaces and how sex hormones may be involved in translating IgE sensitisation into clinical manifestations. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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17 pages, 1274 KiB  
Review
The Initiation of Th2 Immunity Towards Food Allergens
by Yosef Ellenbogen, Rodrigo Jiménez-Saiz, Paul Spill, Derek K. Chu, Susan Waserman and Manel Jordana
Int. J. Mol. Sci. 2018, 19(5), 1447; https://doi.org/10.3390/ijms19051447 - 12 May 2018
Cited by 36 | Viewed by 7807
Abstract
In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses [...] Read more.
In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Such responses are launched against harmful macroscopic parasites and noxious substances, such as venoms, but also against largely innocuous allergens. This suggests that the established understanding about sense and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters, which can activate or lower the threshold activation of the immune system, are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that forms an adaptive Th2 response. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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12 pages, 2903 KiB  
Review
Expression and Regulation of Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin Receptor Heterocomplex in the Innate–Adaptive Immunity of Pediatric Asthma
by Sheng-Chieh Lin, Fang-Yi Cheng, Jun-Jen Liu and Yi-Ling Ye
Int. J. Mol. Sci. 2018, 19(4), 1231; https://doi.org/10.3390/ijms19041231 - 18 Apr 2018
Cited by 17 | Viewed by 7029
Abstract
Asthma is a chronic inflammatory disease affecting the airway, and it is characterized by a wheezing breathing sound, variable airflow obstruction and the presence of inflammatory cells in the submucosa of the bronchi. Viral infection, pollutants and sensitivity to aeroallergens damage the epithelium [...] Read more.
Asthma is a chronic inflammatory disease affecting the airway, and it is characterized by a wheezing breathing sound, variable airflow obstruction and the presence of inflammatory cells in the submucosa of the bronchi. Viral infection, pollutants and sensitivity to aeroallergens damage the epithelium from childhood, which causes asthma. The pathogenesis of asthma includes pathways of innate stimulation by environmental microbes and irritant pathogens. Damaged epithelial cells produce thymic stromal lymphopoietin (TSLP) and stimulate myeloid dendritic cell maturation through the thymic stromal lymphopoietin receptor (TSLPR) heterocomplex. TSLP-activated myeloid dendritic cells promote naive CD4+ T cells to differentiate into T helper type 2 (Th2) phenotype CD4+ T cells. Re-exposure to allergens or environmental stimuli causes an adaptive immune response. TSLP-activated dendritic cells expressing the OX40 ligand (OX40L; CD252) trigger naive CD4+ T cells to differentiate into inflammatory Th2 effector cells secreting the cytokines interleukin-4, 5, 9, and 13 (IL-4, IL-5, IL-9 and IL-13), and the dendritic cells (DCs) promote the proliferation of allergen-specific Th2 memory cells. Allergen presentation by Th2 cells through its interaction with their receptors in the presence of major histocompatibility complex (MHC) class II on B cells and through costimulation involving CD40 and CD40L interactions results in immunoglobulin class switching from IgM to IgE. DCs and other blood cell subsets express the TSLPR heterocomplex. The regulatory mechanism of the TSLPR heterocomplex on these different cell subsets remains unclear. The TSLPR heterocomplex is composed of the IL-7Rα chain and TSLPR chain. Moreover, two isoforms of TSLP, short isoform TSLP (sfTSLP) and long isoform TSLP (lfTSLP), have roles in atopic and allergic development. Identifying and clarifying the regulation of TSLPR and IL-7Rα in pediatric asthma are still difficult, because the type of blood cell and the expression for each blood cell in different stages of atopic diseases are poorly understood. We believe that further integrated assessments of the regulation mechanism of the TSLP–TSLPR heterocomplex axis in vitro and in vivo can provide a faster and earlier diagnosis of pediatric asthma and promote the development of more effective preventive strategies at the onset of allergies. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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16 pages, 10175 KiB  
Review
Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases
by Kenji Izuhara, Yukie Yamaguchi, Shoichiro Ohta, Satoshi Nunomura, Yasuhiro Nanri, Yoshinori Azuma, Noriko Nomura, Yasuhiko Noguchi and Michiko Aihara
Int. J. Mol. Sci. 2018, 19(4), 1102; https://doi.org/10.3390/ijms19041102 - 6 Apr 2018
Cited by 43 | Viewed by 7324
Abstract
Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, [...] Read more.
Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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