Summary of the Keystone Symposium "Origins of allergic disease: Microbial, epithelial and immune interactions," March 24-27, Tahoe City, California.

The aims of the Keystone Symposium conference, "Origins of allergic disease: Microbial, epithelial and immune interactions" were to present and discuss potential microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders, as well as immune mechanisms that might suggest novel disease prevention or intervention strategies. Cross-talk and sharing of ideas among participating experts in basic science and clinical aspects of allergic diseases provided substantial insight into the concept of allergic disorders as a systems disease. The overriding message distilled from the discussions was that damage to epithelial surfaces lies at the origin of the various manifestations of allergic disease. The epithelium of the lungs, gut, and skin, which operates as a critical sensor of environmental stimuli, is besieged by an onslaught of contemporary environmental forces including an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. Collectively, this onslaught leads to alterations of lung, skin, or gut epithelial surfaces, driving a type 2 immune response that underlies most, if not all, of the atopic diseases. Possible remedies for treatment and prevention of allergic diseases were discussed, including a precision medicine approach using biologics, oral desensitization, targeted gut microbiome alterations, and behavior alteration.

DeKruyff RH ，Zhang W ，Nadeau KC ，Leung DYM ，Wills-Karp M ... -  《-》

The origins of allergy from a systems approach.

The origins of allergic diseases have traditionally been explained by immunoglobulin E-mediated immune responses to account for asthma, atopic dermatitis, atopic rhinitis, and food allergy. Research insights into disease origins support a broader array of factors that predispose, initiate, or exacerbate altered immunity in allergic diseases, such as (1) inherent epithelial barrier dysfunction; (2) loss of immune tolerance; (3) disturbances in the gut; and (4) organ-specific microbiomes, diet, and age. Here, we discuss these influences that together form a better understanding of allergy as a systems disease. We summarize recent advances in epithelial dysfunction, environmental influences, inflammation, infection, alterations in the specific microbiome, and inherent genetic predisposition. We performed a literature search targeting primary and review articles. We explored microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders and evaluated immune mechanisms suggesting novel disease prevention or intervention strategies. Damage to epithelial surfaces lies at the origin of various manifestations of allergic disease. As a sensor of environmental stimuli, the epithelium of the lungs, gut, and skin is affected by an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. This collectively leads to alterations of lung, skin, or gut epithelial surfaces, driving a type 2 immune response that underlies atopic diseases. Treatment and prevention of allergic diseases include biologics, oral desensitization, targeted gut microbiome alterations, and changes in behavior. Understanding the spectrum of allergy as a systems disease will allow us to better define the mechanisms of allergic disorders and improve their treatment.

Krempski JW ，Dant C ，Nadeau KC 《-》

Outside-in hypothesis revisited: The role of microbial, epithelial, and immune interactions.

Our understanding of the origin of allergic diseases has increased in recent years, highlighting the importance of microbial dysbiosis and epithelial barrier dysfunction in affected tissues. Exploring the microbial-epithelial-immune crosstalk underlying the mechanisms of allergic diseases will allow the development of novel prevention and treatment strategies for allergic diseases. This review summarizes the recent advances in microbial, epithelial, and immune interactions in atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma. We performed a literature search, identifying relevant recent primary articles and review articles. Dynamic crosstalk between the environmental factors and microbial, epithelial, and immune cells in the development of atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma underlies the pathogenesis of these diseases. There is substantial evidence in the literature suggesting that environmental factors directly affect barrier function of the epithelium. In addition, T-helper 2 (TH2) cells, type 2 innate lymphoid cells, and their cytokine interleukin 13 (IL-13) damage skin and lung barriers. The effects of environmental factors may at least in part be mediated by epigenetic mechanisms. Histone deacetylase activation by type 2 immune response has a major effect on leaky barriers and blocking of histone deacetylase activity corrects the defective barrier in human air-liquid interface cultures and mouse models of allergic asthma with rhinitis. We also present and discuss a novel device to detect and monitor skin barrier dysfunction, which provides an opportunity to rapidly and robustly assess disease severity. A complex interplay between environmental factors, epithelium, and the immune system is involved in the development of systemic allergic diseases.

Sugita K ，Soyka MB ，Wawrzyniak P ，Rinaldi AO ，Mitamura Y ，Akdis M ，Akdis CA ... -  《-》

Recent developments and highlights in mechanisms of allergic diseases: Microbiome.

All body surfaces are exposed to a wide variety of microbes, which significantly influence immune reactivity within the host. This review provides an update on some of the critical novel findings that have been published on the influence of the microbiome on atopic dermatitis, food allergy and asthma. Microbial dysbiosis has consistently been observed in the skin, gut and lungs of patients with atopic dermatitis, food allergy and asthma, respectively, and the role of specific microbes in allergic disorders is being intensively investigated. However, many of these discoveries have yet to be translated into routine clinical practice.

Lunjani N ，Satitsuksanoa P ，Lukasik Z ，Sokolowska M ，Eiwegger T ，O'Mahony L ... -  《-》

Outstanding animal studies in allergy II. From atopic barrier and microbiome to allergen-specific immunotherapy.

Jensen-Jarolim E ，Pali-Schöll I ，Roth-Walter F 《-》