The role of innate immunity in asthma development and protection: Lessons from the environment

Asthma, a complex, chronic disease characterized by airway inflammation, hyperresponsiveness and remodelling, affects over 300 million people worldwide. While the disease is typically associated with exaggerated allergen‐induced type 2 immune responses, these responses are strongly influenced by environmental exposures that stimulate innate immune pathways capable of promoting or protecting from asthma. The dual role played by innate immunity in asthma pathogenesis offers multiple opportunities for both research and clinical interventions and is the subject of this review.     

Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome

It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.     

Endotoxin exposure in allergy and asthma: reconciling a paradox

Well-established evidence links endotoxin exposure, especially in the workplace, to airways disease. Endotoxin can increase disease severity by acting as a natural adjuvant to augment asthma and atopic inflammation. Recent studies suggest that it can even act on its own, causing a distinct endotoxic form of asthma. Other studies, however, contradict the paradigm that endotoxin's influence is solely a negative one. Epidemiologic associations of environmental endotoxin exposure with allergy and asthma prevention are consistent with hygiene hypothesis associations of other microbial exposures or infections with a lower incidence of atopic disease. Currently, microbe-derived products are being developed as potential therapies for allergy and asthma. Thus it is an ideal time to consider endotoxin as a prototype of a natural intervention with microbial components. Nature's ongoing experiment with endotoxin can provide clues for the development of effective and safe microbe-based products for disease treatment and prevention. This article will discuss (1) conventional paradigms in which endotoxin-induced immune modulation by T(H)1-type induction leads to mitigation of T(H)2-type immune development, allergen sensitization, and atopic inflammation; (2) newer concepts of T(H)1-type immune responses that may provide additional asthma-protective effects by preventing airways remodeling; (3) home and environmental features that significantly contribute to endotoxin exposure; (4) different aspects of asthma mediated by endotoxin exposure; and (5) how to understand endotoxin's paradoxical nature of serving as both friend and foe.     

Genetics of airway hyperresponsiveness.

Asthma is a disease characterized by intermittent airway obstruction, inflammatory cell infiltrates, increased mucus production, lung epithelial remodeling, and airway hyperreactivity. The genetics of asthma, as investigated in animal models, is poorly understood. Because no animal model of asthma mimics all of the pathologic and physiological features of asthma, genetic studies have focused on several phenotypes, including intrinsic or native airway hyperreactivity. It is generally accepted that both genetic and environmental factors determine the phenotypic expression of this complex disease. The genetics of airway hyperresponsiveness, as investigated in the mouse, are presented in this review. The inbred mouse currently represents the most valuable genetic resource for understanding the factors that control this complex phenotype.     

Asthma in children

Asthma is the most common chronic disease in childhood characterized by chronic bronchial inflammation of variable intensity accompanied by spontaneous or drug reversible airflow obstruction. The onset of asthma, clinical presentation and response to therapy are influenced by numerous genetic and environmental factors. Asthma in childhood is characterized by its heterogeneity in terms of possible etiology, degree of inflammation and airway obstruction, lung function as well as the natural course of disease that may persist and continue to adulthood. Protective factors linked to early life experiences have also been delineated which may impact the development of asthma. Pathophysiological mechanisms of allergic reaction as an excessive inflammation driven by T-helper-2 (Th2) immunity, offer poor understanding of the heterogeneity of clinical disease. A recently introduced approach defines asthma as a syndrome that comprises of several subtypes or endotypes based on entirely novel pathways to disease. Timely diagnosis and adequate treatment are necessary to prevent irreversible airway remodeling and consequent decrease in pulmonary function.     

Clinical approaches towards asthma and chronic obstructive pulmonary disease based on the heterogeneity of disease pathogenesis

Asthma and chronic obstructive pulmonary disease (COPD) are each heterogeneous disease classifications that include several clinical and pathophysiological phenotypes. This heterogeneity complicates characterization of each disease and, in some cases, hinders the selection of appropriate treatment. Therefore, in recent years, emphasis has been placed on improving our understanding of the various phenotypes of asthma and of COPD and identifying biomarkers for each phenotype. Likewise, the concept of the endotype has been gaining acceptance; an endotype is a disease subtype that is defined by unique or distinctive functional or pathophysiological mechanisms. Endotypes of asthma or COPD may be primarily characterized by increased susceptibility to type 2 inflammation, increased susceptibility to viral infections, bacterial colonization or impaired lung development. The ‘Dutch hypothesis’ is as follows: gene variants underlying particular endotypes interact with detrimental environmental stimuli (e.g. smoking, viral infection and air pollution) and contribute to the ultimate development of asthma, COPD or both. Novel approaches that involve multidimensional assessment should facilitate identification and management of the components that generate this heterogeneity. Ultimately, patients with chronic inflammatory lung diseases may be treated based on these endotypes as determined by the respective biomarkers that correspond to individual endotypes instead of on disease labels such as asthma, COPD or even asthma–COPD overlap syndrome (ACOS).     

Prevention of asthma: where are we in the 21st century?

Asthma is the most common chronic disease of childhood and, in the latter part of the 20th century, reached epidemic proportions. Asthma is generally believed to result from gene-environment interactions. There is consensus that a ‘window of opportunity’ exists during pregnancy and early in life when environmental factors may influence its development. We review multiple environmental, biologic and sociologic factors that may be important in the development of asthma. Meta-analyses of studies have demonstrated that multifaceted interventions are required in order to develop asthma prevention. Multifaceted allergen reduction studies have shown clinical benefits. Asthma represents a dysfunctional interaction with our genes and the environment to which they are exposed, especially in fetal and early infant life. The increasing prevalence of asthma also may be an indication of increased population risk for the development of other chronic non-communicable autoimmune diseases. This review will focus on the factors which may be important in the primary prevention of asthma. Better understanding of the complex gene–environment interactions involved in the development of asthma will provide insight into personalized interventions for asthma prevention.     

Mechanisms of severe asthma

The mechanisms behind the development of severe asthma are poorly understood. However, these patients disproportionately consume healthcare resources related to asthma. Severe asthma may develop over time, or may develop shortly after onset of the disease. The genetic and environmental elements that may be most important in the development of severe disease are poorly understood. Physiologically, these patients often have air trapping and airway collapsibility. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, an apparently different pathology, structural changes likely to be remodelling related, and predominant distal disease. Treatment remains problematic and likely will remain so until a better understanding of this disease develops.     

The curious 2000-year case of asthma

Millions worldwide have asthma, with the numbers succumbing increasing sharply in the past two decades. After 2000 years of scientific study, who succumbs to asthma when is as puzzling as who regains health when and how. The discipline of psychosomatic medicine and science investigates and treats diseases like asthma that typically confound general medicine. Still psychosomatic medicine, like general medicine, only manages but does not remedy asthma, which can currently only be in remission but not cured. This historical review reveals the progress and missteps that have been made in the study and treatment of asthma by comparing the general medicine approach with the major research findings on asthma published over 60 years in Psychosomatic Medicine. Research has identified antecedent, collateral, and subsequent factors to scientifically describe and control this disease in terms of diagnosis, management, and treatment. Paradoxically and regrettably, the prognosis for those with asthma is worse than ever. Curious also that a noninfectious disease should spread so rapidly and mostly for specific groups identified by variables like age, gender, ethnicity, and socioeconomic status. Furthermore, partial, not full, family concordance indicates merely genetic influence, not determination. General medicine now focuses on enumerating the range of environmental and situational triggers, or stimuli, producing asthma and describing the pathophysiology of bronchial inflammation. With a more comprehensive multifactorial approach, psychosomatic medicine seems well suited to investigate further the physiological, psychological, social, and environmental factors implicated in this medical conundrum. A future challenge for psychosomatic medicine is to stem the tide of rising prevalence and cure the disease of asthma.     

Segregation analysis of asthma: recessive major gene component for asthma in relation to history of atopic diseases

Although asthma has a significant heritable component, the mode of inheritance remains controversial because of the complexity of the disease and the influence of environmental factors. Segregation analysis for asthma are performed with and without a history of atopic diseases (dermatitis and rhinitis) after adjusting for environmental factors. To investigate whether asthma may be inherited through a major gene with two alleles, the REGD program of the Statistical Analysis for Genetic Epidemiology (SAGE) package was conducted in 1,990 individuals from 227 families with at least one asthmatic child in a cross-sectional study of respiratory diseases in Southern Taiwan. Other covariates adjusted for included age, sex, current smoking, and environmental tobacco smoking. The hypothesis of Mendelian model and no parent-offspring transmission was rejected. However, when the variables of atopic disease and environmental factors were included in the model as covariates, the models for a two-allele gene with a recessive or codominant inheritance could not be rejected, and Akaike's Information Criterion was smaller (1,377. 13) for the recessive model than all of the other models tested, assuming a major gene with a population frequency of 0.56 +/- 0.04. However, Mendelian model without family effect was rejected. In conclusion, a history of asthma in parents is a strong risk factor for asthma in offspring. Under the assumptions of the applied segregation, at least one major gene exists that could be a gene involved also in allergy. However, the data suggest that a single locus gene explains a portion of asthma that is related to the history of atopic diseases. In addition, a polygenic/multifactorial (genetic and environmental factors) influence with a recessive component inheritance may be involved in the pathogenesis of asthma.     

Epithelial function and dysfunction in asthma

Asthma was previously defined as an allergic Th2‐mediated inflammatory immune disorder. Recently, this paradigm has been challenged because not all pathological changes observed in the asthmatic airways are adequately explained simply as a result of Th2‐mediated processes. Contemporary thought holds that asthma is a complex immune disorder involving innate as well as adaptive immune responses, with the clinical heterogeneity of asthma perhaps a result of the different relative contribution of these two systems to the disease. Epidemiological studies show that exposure to certain environmental substances is strongly associated with the risk of developing asthma. The airway epithelium is first barrier to interact with, and respond to, environmental agents (pollution, viral infection, allergens), suggesting that it is a key player in the pathology of asthma. Epithelial cells play a key role in the regulation of tissue homeostasis by the modulation of numerous molecules, from antioxidants and lipid mediators to growth factors, cytokines, and chemokines. Additionally, the epithelium is also able to suppress mechanisms involved in, for example, inflammation in order to maintain homeostasis. An intrinsic alteration or defect in these regulation mechanisms compromises the epithelial barrier, and therefore, the barrier may be more prone to environmental substances and thus more likely to exhibit an asthmatic phenotype. In support of this, polymorphisms in a number of genes that are expressed in the bronchial epithelium have been linked to asthma susceptibility, while environmental factors may affect epigenetic mechanisms that can alter epithelial function and response to environmental insults. A detailed understanding of the regulatory role of the airway epithelium is required to develop new therapeutic strategies for asthma that not only address the symptoms but also the underlining pathogenic mechanism(s) and prevent airway remodelling.     

Genetics of asthma.

Asthma is a complex disease with a phenotype that has been clinically difficult to define. Associated phenotypes including bronchial hyperresponsiveness and atopy have provided useful objective alternatives in genetic and epidemiologic studies. Although asthma genes have not yet been identified, much progress has been made toward this goal. Genetic studies indicate that multiple genes are involved in the pathogenesis of this disease, and chromosomal regions likely to harbor asthma susceptibility genes have been replicated in several studies. Environmental factors, including smoking, diet, and viral respiratory infections, have also been implicated in the etiology of asthma. Directly linking these exposures as causes of asthma, however, has also proved difficult. Furthermore, interaction between susceptibility genes and environmental factors is probable and is a challenge currently being pursued by investigators worldwide. Understanding the fundamental gene-environmental interactions in the development of asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention.     

Mechanisms of Asthma and Implications for Its Prevention and Treatment: A Personal Journey

My research career has focused on the causes of asthma and its treatment. After establishing the key role that mast cells play in the inflammatory response in asthma, attention was turned towards understanding disease chronicity and variability across the lifecourse. Through a combination of studies on airway biopsies and primary cell cultures we have established that asthma is primarily an epithelial disease driven by increased environmental susceptibility to injury and an altered repair response as depicted by sustained activation of the epithelial mesenchymal trophic unit (EMTU) that is invoked in foetal branching morphogenesis. Varied activation of the EMTU connects the origins of asthma to its progression over time with involvement of epithelial susceptibility through impaired barrier and innate immune functions and altered mesenchymal susceptibility as exemplified by polymorphisms of the metalloprotease gene, ADAM33. Taken together these observations have led to a fundamental re-evaluation of asthma pathogenesis. Rather than placing allergic inflammation as the prime abnormality, it is proposed that the airway epithelium lies at the center of asthma pathogenesis, and that in conjunction with the underlying mesenchyme, it is the principle orchestrator of both the induction of asthma and its evolution over the lifecourse. This concept has provided ''the basis for a new preventative and therapeutic approach focused more on increasing the airways resistance to environmental insults rather than suppressing downstream inflammation once it is established.     

Determinants of asthma and its clinical course.

OBJECTIVE: To examine factors that influence the natural history of asthma, such as genetics, atopy, air pollution and environmental tobacco smoke, gastroesophageal reflux, and infection, to promote early identification and treatment of patients at risk for persistent asthma. DATA SOURCES: Journal articles published in English involving human subjects with asthma. STUDY SELECTION: Studies were selected for their relevance to the discussion of asthma and the factors that contribute to its persistence. Epidemiologic studies were favored in assessing the natural history of asthma from childhood to adulthood. RESULTS: Major factors that can influence the severity and persistence of asthma are genetics, atopy, pollution, environmental tobacco smoke, gastroesophageal reflux, and respiratory infections. Epidemiologic studies reveal that factors strongly linked to the persistence of childhood asthma into adult life are early age of disease onset with more severe symptoms, atopy, and level of allergen exposure. CONCLUSIONS: Although there is still much research to be done, epidemiologic studies have repeatedly proven that the natural history of asthma is in some ways predictable. Early identification of patients at risk for persistent asthma, combined with early institution of pharmacologic and nonpharmacologic intervention strategies, may lead to better outcomes.     

Epidemiology of asthma in western Europe

Asthma deaths are uncommon, but have recently increased in some countries due to problems in the management of the disease. Morbidity rates show large variations, which can be attributed to differences in defining the disease, but also to genuine variations, with a trend towards less asthma in northern Europe. It has been suggested that allergic diseases as a whole, and asthma in particular, may exhibit an upward secular trend. Risk factors include a genetic background and environmental triggering factors. The importance of genetic factors is illustrated by family studies and by extreme prevalence rates observed in some communities. Environmental factors include rapid air pollution variations which act as a trigger for asthma attacks. However, at levels currently prevailing in western Europe, air pollutants do not induce a higher incidence of asthma. Altitude generates a gradual decrease in Dermatophagoides, thus explaining both the clinical improvement in asthmatics living in altitude and a lower prevalence of asthma in populations born and living there. Among the other aero-allergens, grass pollens plays a major role in spring, elicitating asthma attacks. Some natural allergens transformed by man (castor bean, soja) can be responsible for asthma epidemics.     

The sentinel role of the airway epithelium in asthma pathogenesis

The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation.     

Childhood bronchial asthma in northern Nigeria

A review of childhood bronchial asthma in Zaria, northern Nigeria is presented. An average of twenty-three cases a year were seen over a 4-year period. Features of the disease include low incidence, late age of onset, family history of asthma in only 16% of cases and absence of eczema, but positive skin tests, as evidence of atopy. The clinical features of the disease are similar to those described in children elsewhere. The apparent conflicting reports on the epidemiology of childhood bronchial asthma in Africa are probably due to the multifactorial nature of the disease: geographical, environmental, racial, as well as factors related to the life-style of the people.     

Asthma treatment and asthma prevention: a tale of 2 parallel pathways

Three recent clinical trials used different study designs to test the hypothesis that early introduction of inhaled corticosteroids in infants and young children at high risk for the development of asthma could change the natural course of the disease. All 3 trials reached the same conclusion: treatment requirement, symptom frequency while off treatment, and lung function did not differ between children receiving active drug or placebo, with outcomes measured 2 to 4 years after randomization. These findings challenge the concept that the inflammatory processes that cause asthma symptoms and are responsive to inhaled corticosteroids are also responsible for the chronic changes in airway structure and function that are believed to predispose to the development of persistent asthma. This conclusion is supported by studies showing that bronchial hyperresponsiveness, independent of current asthma symptoms, is associated with subsequent deficits in airway function growth during childhood. Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of "asthma."     

Epithelial cell dysfunction,a major driver of asthma development

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.