scholarly journals Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation

2021 ◽  
pp. 2003393
Author(s):  
William W. Busse ◽  
Monica Kraft ◽  
Klaus F. Rabe ◽  
Yamo Deniz ◽  
Paul Rowe ◽  
...  
Keyword(s):  
Immunoglobulin E ◽  
Persistent Asthma ◽  
Response To Treatment ◽  
Immune Mediators ◽  
Type 2 Cytokines ◽  
Key Issues ◽  
Ige Mediated ◽  
Sputum Eosinophils ◽  
Type 2 Inflammation

Asthma is a complex respiratory disease that varies in severity and response to treatment. Several asthma phenotypes with unique clinical and inflammatory characteristics have been identified. Endotypes, based on distinct molecular profiles, help to further understand the heterogeneity within asthma. Type 2 inflammation, involving both the innate (type 2 innate lymphoid cell) and adaptive (T helper type 2 cells) immune systems, underpins the complex pathophysiology of chronic inflammation in asthma, as well as the presence of comorbid disease (such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and atopic dermatitis). Type 2 inflammation is characterised by upregulation of type 2 cytokines interleukin (IL)-4, IL-5, and IL-13, immunoglobulin E (IgE)-mediated release of immune mediators, and dysfunction of epithelial or epidermal barriers. Targeting these key proximal type 2 cytokines has shown efficacy in recent studies adopting a personalised approach to treatment using targeted biologics. Elevated levels of biomarkers downstream of type 2 cytokines, including fractional exhaled nitric oxide, serum IgE, and blood and sputum eosinophils, have been linked to mechanisms involved in type 2 inflammation, and have the potential to aid diagnosis, and predict and monitor response to treatment. The objective of this review is to summarise the current understanding of the biology of type 2 inflammation in asthma, examine its influence on type 2 inflammatory comorbidities, and discuss how type 2 inflammatory biomarkers can be harnessed to further personalise treatments in the age of biologic medicines.

Targeted Molecular Therapies in Allergy and Rhinology

2020 ◽  
pp. 019459982096523
Author(s):  
Cecelia C. Damask ◽  
Matthew W. Ryan ◽  
Thomas B. Casale ◽  
Mario Castro ◽  
Christine B. Franzese ◽  
...  
Keyword(s):  
Granulomatosis With Polyangiitis ◽  
Immunoglobulin E ◽  
Clinical Trial Data ◽  
Biologic Agents ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Molecular Therapies ◽  
Targeted Molecular Therapies ◽  
Eosinophilic Granulomatosis ◽  
Type 2 Inflammation

Biologic agents, monoclonal antibodies that target highly-specific molecular pathways of inflammation, are becoming integrated into care pathways for multiple disorders that are relevant in otolaryngology and allergy. These conditions share common inflammatory mechanisms of so-called Type 2 inflammation with dysregulation of immunoglobulin E production and eosinophil and mast cell degranulation leading to tissue damage. Biologic agents are now available for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, eosinophilic granulomatosis with polyangiitis (EGPA), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). This paper summarizes the diagnosis and management of these conditions and critically reviews the clinical trial data that has led to regulatory approval of biologic agents for these conditions.

scholarly journals Exacerbation Risk and Type 2 Inflammation in Placebo Patients During a Phase 2b Study of Dupilumab in Patients With Uncontrolled Persistent Asthma

2018 ◽  
Vol 141 (2) ◽  
pp. AB112
Author(s):  
Mario Castro ◽  
Brian N. Swanson ◽  
Shyamalie Jayawardena ◽  
Jennifer D. Hamilton ◽  
Nikhil Amin ◽  
...  
Keyword(s):  
Persistent Asthma ◽  
Exacerbation Risk ◽  
Type 2 Inflammation

IgG4 Expression in Patients with Eosinophilic Otitis Media

ORL ◽  
2021 ◽  
pp. 1-5
Author(s):  
Masahiro Takahashi ◽  
Aiko Oka ◽  
Shin Kariya ◽  
Yuka Gion ◽  
Yasuharu Sato ◽  
...  
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Profound Hearing Loss ◽  
Middle Ear Mucosa ◽  
Type 2 Cytokines ◽  
Cochlear Implant Surgery ◽  
Middle Ear Disease ◽  
Type 2 Inflammation ◽  
Ear Effusion

Objective: Eosinophilic otitis media (EOM) is an intractable middle ear disease recognized by an eosinophil enriched middle ear effusion and mucosa. Although precise pathogenesis of EOM remains unclear, it is characterized by type 2 inflammation. Since IgG4 is an IgG subclass induced by type 2 cytokines such as IL-4 and IL-13, we sought to characterize and compare local IgG4 expression in patients with and without EOM. Methods: Twelve patients with bilateral profound hearing loss, 9 of which underwent a cochlear implant surgery, were enrolled in this study (6 with EOM and 6 without EOM). The surgical specimens were harvested during surgery and were subjected to IgG4 immunostaining. Result: The middle ear mucosa showed the presence of a large number of IgG4-positive cells in patients with EOM, which was significantly higher than that in patients without EOM. Conclusion: Local IgG4 expression was observed in patients with EOM in comparison to those without EOM, suggesting that IgG4 contributes to EOM pathogenesis.

scholarly journals A retrospective cohort study to evaluate the relationship of airway hyperresponsiveness to type 2 biomarkers in persistent asthma

2021 ◽  
Vol 5 (1) ◽  
pp. 008-013
Author(s):  
Chan Rory ◽  
Kuo Chris RuiWen ◽  
Lipworth Brian
Keyword(s):  
Airway Hyperresponsiveness ◽  
Immunoglobulin E ◽  
Persistent Asthma ◽  
Specific Ige ◽  
Elevated Type ◽  
Challenge Testing ◽  
Specific Immunoglobulin E ◽  
Blood Eosinophils ◽  
Relationship Of

irway hyperresponsiveness (AHR) is a hallmark of persistent asthma measured using direct or indirect airway bronchial challenge testing. The purpose of this study is to investigate the putative relationships between type 2 inflammatory biomarkers, airway geometry (FEV1 and FEF25-75) and specific IgE (RAST or skin prick) to AHR. We performed a retrospective analysis of our database (n = 131) of patients with asthma. Of these subjects, 75 had a histamine challenge and 56 had a mannitol challenge. Fractional exhaled nitric oxide (FeNO) and specific immunoglobulin E (IgE) but not blood eosinophils were significantly higher in patients with AHR to either histamine or mannitol. FEV1 % and FEF25 - 75 % were significantly lower in patients with AHR. Elevated Type 2 biomarkers including FeNO and specific IgE but not blood eosinophils were associated with AHR. Highlights: FeNO and specific IgE but not blood eosinophils are raised in patients with airway hyperresponsiveness.

scholarly journals ACO (Asthma–COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review

Diagnostics ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 859
Author(s):  
Naoya Fujino ◽  
Hisatoshi Sugiura
Keyword(s):  
Immunoglobulin E ◽  
Rapid Decline ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Diagnostic Biomarkers ◽  
Diagnosis Criteria ◽  
Molecular Pathophysiology ◽  
Over 40 Years ◽  
Type 2 Inflammation

Asthma and chronic obstructive pulmonary disease (COPD) are now recognized to be able to co-exist as asthma–COPD overlap (ACO). It is clinically relevant to evaluate whether patients with COPD concurrently have components of asthma in primary care. This is because: (i) ACO is a relatively common condition among asthma (over 40 years of age) or COPD irrespective of its diagnosis criteria; (ii) patients with ACO can have higher frequency of exacerbation and more rapid decline in lung function than those with asthma or COPD; and (iii) asthmatic features such as eosinophilic airway inflammation are promising indicators for prediction of inhaled corticosteroid-responsiveness in COPD. The aim of this review to evaluate diagnostic markers for ACO. We searched PubMed for articles related to ACO published until 2020. Articles associated with diagnostic biomarkers were included. We identified a total of 25 studies, some of which have revealed that a combination of biomarkers such as fractional exhaled nitric oxide and serum immunoglobulin E is useful to discern type 2 inflammation in the airways of COPD. Here, we review the current understanding of the clinical characteristics, biomarkers and molecular pathophysiology of ACO in the context of how ACO can be differentiated from COPD.

scholarly journals Developing food allergy: a potential immunologic pathway linking skin barrier to gut

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2660 ◽  
Author(s):  
Yui-Hsi Wang
Keyword(s):  
Food Allergy ◽  
Mast Cells ◽  
Immunoglobulin E ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Allergic Reactions ◽  
Mucosal Mast Cells ◽  
Life Threatening ◽  
Ige Mediated

Immunoglobulin E (IgE)-mediated food allergy is an adverse reaction to foods and is driven by uncontrolled type-2 immune responses. Current knowledge cannot explain why only some individuals among those with food allergy are prone to develop life-threatening anaphylaxis. It is increasingly evident that the immunologic mechanisms involved in developing IgE-mediated food allergy are far more complex than allergic sensitization. Clinical observations suggest that patients who develop severe allergic reactions to food are often sensitized through the skin in early infancy. Environmental insults trigger epidermal thymic stromal lymphopoietin and interleukin-33 (IL-33) production, which endows dendritic cells with the ability to induce CD4+TH2 cell-mediated allergic inflammation. Intestinal IL-25 propagates the allergic immune response by enhancing collaborative interactions between resident type-2 innate lymphoid cells and CD4+TH2 cells expanded by ingested antigens in the gastrointestinal tract. IL-4 signaling provided by CD4+TH2 cells induces emigrated mast cell progenitors to become multi-functional IL-9-producing mucosal mast cells, which then expand greatly after repeated food ingestions. Inflammatory cytokine IL-33 promotes the function and maturation of IL-9-producing mucosal mast cells, which amplify intestinal mastocytosis, resulting in increased clinical reactivity to ingested food allergens. These findings provide the plausible view that the combinatorial signals from atopic status, dietary allergen ingestions, and inflammatory cues may govern the perpetuation of allergic reactions from the skin to the gut and promote susceptibility to life-threatening anaphylaxis. Future in-depth studies of the molecular and cellular factors composing these stepwise pathways may facilitate the discovery of biomarkers and therapeutic targets for diagnosing, preventing, and treating food allergy.

Relationship between longitudinal changes in type‐2 inflammation, immunoglobulin E sensitization, and clinical outcomes in young asthmatics

2021 ◽  
Vol 11 (7) ◽  
Author(s):  
Nikolaos Tsolakis ◽  
Tiago Jacinto ◽  
Christer Janson ◽  
Magnus Borres ◽  
Andrei Malinovschi ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Immunoglobulin E ◽  
Longitudinal Changes ◽  
Type 2 Inflammation

scholarly journals Pruritus as a Distinctive Feature of Type 2 Inflammation

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 303
Author(s):  
Simone Garcovich ◽  
Martina Maurelli ◽  
Paolo Gisondi ◽  
Ketty Peris ◽  
Gil Yosipovitch ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Skin Diseases ◽  
Skin Surface ◽  
Lymphoid Cells ◽  
Common Symptom ◽  
Prurigo Nodularis ◽  
Chronic Itch ◽  
Type 2 Cytokines ◽  
Type 2 Inflammation

Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients’ quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.

scholarly journals Histamine-Releasing Factor, a New Therapeutic Target in Allergic Diseases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1515 ◽  
Author(s):  
Yu Kawakami ◽  
Kazumi Kasakura ◽  
Toshiaki Kawakami
Keyword(s):  
Recombinant Proteins ◽  
Complex Disease ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Ige Mediated ◽  
Human Basophils ◽  
Type 2 Inflammation

Histamine-releasing activities on human basophils have been studied as potential allergy-causing agents for four decades. An IgE-dependent histamine-releasing factor (HRF) was recently shown to interact with a subset of immunoglobulins. Peptides or recombinant proteins that block the interactions between HRF and IgE have emerged as promising anti-allergic therapeutics, as administration of them prevented or ameliorated type 2 inflammation in animal models of allergic diseases such as asthma and food allergy. Basic and clinical studies support the notion that HRF amplifies IgE-mediated activation of mast cells and basophils. We discuss how secreted HRF promotes allergic inflammation in vitro and in vivo complex disease settings.

scholarly journals Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines

2018 ◽  
Vol 215 (3) ◽  
pp. 841-858 ◽  
Author(s):  
Jason Miska ◽  
Jen Bon Lui ◽  
Kevin H. Toomer ◽  
Priyadharshini Devarajan ◽  
Xiaodong Cai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Immunity ◽  
De Novo ◽  
Antitumor Activities ◽  
Type 2 Cytokines ◽  
Immune Therapies ◽  
Type 2 Inflammation

Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the TH1 or TH17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor α broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.

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