Toll-like receptor ligands: hygiene, atopy and therapeutic implications

PURPOSE OF REVIEW: Allergic and certain other inflammatory diseases have become more common in industrialized countries over the past few decades. One potential explanation for such trends is that with a decreased incidence of microbial exposures, as a result of modern public health practices, an important source of immune stimulation has been lost, with a consequent increase in inflammatory responses and their associated diseases. This review will focus on our current understanding of how microbial exposures impact on host immunity and the pathogenesis of allergic diseases. RECENT FINDINGS: In the past decade, it has become clear that a number of molecular interactions between immunocytes and microbial compounds are mediated by Toll-like receptors on host cells. Moreover, recent investigations have suggested that ligands for different Toll-like receptors have the potential both to inhibit and promote the development of allergic hypersensitivities and diseases. SUMMARY: On the basis of studies discussed herein, we speculate that physiological exposures to Toll-like receptor ligands have important yet complex effects on immune homeostasis and host susceptibility towards atopic diseases. Moreover, we anticipate that a fuller understanding of how physiological Toll-like receptor ligand exposures impact on immune development will lead to novel therapeutic interventions for the prevention and treatment of atopic diseases.     

Bacterial and fungal agents in house dust and wheeze in children: the PARSIFAL study

BACKGROUND: Growing up on a farm and an anthroposophic lifestyle are associated with a lower prevalence of allergic diseases in childhood. This might be related to increased inhalatory exposure to microbial agents. OBJECTIVE: To assess the association between microbial agents in house dust and atopic wheeze in farm children, Steiner school children and reference children. METHODS: Levels of bacterial endotoxin, fungal beta(1,3)-glucans and fungal extracellular polysaccharides (EPS) in mattress and living room floor dust were measured in a population of 270 atopic (=Phadiatop-positive) children with self-reported wheezing, including 168 current atopic wheezers, and 441 non-atopic, non-symptomatic controls. These children were selected from a cross-sectional study in five European countries. RESULTS: In the study population as a whole, average levels of mattress dust endotoxin, EPS and glucans were slightly (1.1-1.2-fold; P<0.10) higher in control children than in atopic wheezers. Atopic wheeze was related to mattress levels of endotoxin, EPS and glucans in farm and farm-reference children. However, when adjusting for group (farm vs. farm-reference children), the associations became non-significant whereas the group effect remained. No associations between atopic wheeze and microbial agents were observed in Steiner and Steiner-reference children. For current atopic wheeze, the farm effect became non-significant after adjustment for microbial agent levels. CONCLUSION: Not only bacterial endotoxin but also mould components might offer some protection against atopic wheeze in children. However, the protective effect of being raised on a farm was largely unexplained by the mattress microbial agent levels measured in this study.     

Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial

BACKGROUND: The increase in allergic diseases is attributed to a relative lack of microbial stimulation of the infantile gut immune system. Probiotics, live health-promoting microbes, might offer such stimulation. OBJECTIVE: We studied the effect of a mixture of 4 probiotic bacterial strains along with prebiotic galacto-oligosaccharides in preventing allergic diseases. METHODS: We randomized 1223 pregnant women carrying high-risk children to use a probiotic preparation or a placebo for 2 to 4 weeks before delivery. Their infants received the same probiotics plus galacto-oligosaccharides (n = 461) or a placebo (n = 464) for 6 months. At 2 years, we evaluated the cumulative incidence of allergic diseases (food allergy, eczema, asthma, and allergic rhinitis) and IgE sensitization (positive skin prick test response or serum antigen-specific IgE level >0.7 kU/L). Fecal bacteria were analyzed during treatment and at age 2 years. RESULTS: Probiotic treatment compared with placebo showed no effect on the cumulative incidence of allergic diseases but tended to reduce IgE-associated (atopic) diseases (odds ratio [OR], 0.71; 95% CI, 0.50-1.00; P = .052). Probiotic treatment reduced eczema (OR, 0.74; 95% CI, 0.55-0.98; P = .035) and atopic eczema (OR, 0.66; 95% CI, 0.46-0.95; P = .025). Lactobacilli and bifidobacteria more frequently (P < .001) colonized the guts of supplemented infants. CONCLUSION: Probiotic treatment showed no effect on the incidence of all allergic diseases by age 2 years but significantly prevented eczema and especially atopic eczema. The results suggest an inverse association between atopic diseases and colonization of the gut by probiotics. CLINICAL IMPLICATIONS: The prevention of atopic eczema in high-risk infants is possible by modulating the infant's gut microbiota with probiotics and prebiotics.     

Update on skin allergy

Skin diseases with an allergic background such as atopic dermatitis, allergic contact dermatitis, and urticaria are very common. Moreover, diseases arising from a dysfunction of immune cells and/or their products often manifest with skin symptoms. This review aims to summarize recently published articles in order to highlight novel research findings, clinical trial results, and current guidelines on disease management. In recent years, an immense progress has been made in understanding the link between skin barrier dysfunction and allergic sensitization initiating the atopic march. In consequence, new strategies for treatment and prevention have been developed. Novel pathogenic insights, for example, into urticaria, angioedema, mastocytosis, led to the development of new therapeutic approaches and their implementation in daily patient care. By understanding distinct pathomechanisms, for example, the role of IL‐1, novel entities such as autoinflammatory diseases have been described. Considerable effort has been made to improve and harmonize patient management as documented in several guidelines and position papers.     

The role of the intestinal microbiota in the development of atopic disorders

The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed.     

Microbiome and its impact on gastrointestinal atopy

The prevalence of allergic conditions has continuously increased in the last few decades in Westernized countries. A dysbiotic gut microbiome may play an important role in the development of allergic diseases. Genetic, environmental, and dietary factors may alter the commensal microbiota leading to inflammatory dysregulation of homeostasis. Murine and human studies have begun to elucidate the role of the microbiota in the pathogenesis of atopic diseases including asthma, atopic dermatitis, and food allergies. However, the role of the microbiome in most eosinophilic gastrointestinal diseases (EGIDs) is not yet known. This review provides an overview of what is currently known about the development of tolerance from both molecular and clinical standpoints. We also look at the gut‐specific microbiome and its role in atopic conditions with the hope of applying this knowledge to the understanding, prevention, and treatment of EGIDs, particularly EoE.     

γδ T cells and inflammatory skin diseases

Approximately 25% of the population suffers from skin diseases. The most common forms of skin diseases are the inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis. These diseases are described as T cell–mediated diseases induced by either allergens or autoantigens. Classically, the focus has been on the role of αβ T cells, but it is becoming increasingly clear that γδ T cells play a central role in inflammatory skin diseases. In particular, an important role of IL-17A–producing γδ T cells in these inflammatory skin diseases has been shown in various disease models in mice. Interestingly, various epidermal proteins, which appear to be linked to inflammatory conditions in the skin by yet undescribed mechanisms, are expressed by specific subsets of thymic epithelial cells and mutations in these proteins seem to affect γδ T cell development. The focus of this review is how mutations in epidermal proteins affect γδ T cell development and how γδ T cells, and in particular of IL-17A–producing γδ T cells, contribute to inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis.     

Are infections protecting from atopy?

The 'Hygiene Hypothesis' proposes that overcrowding and unhygienic contacts early in life may protect from atopic diseases by facilitating exposure to microbes. Longitudinal studies have recently shown that among subjects exposed early in life to other children at home, or at day care, the risk of wheezing steadily declined with age to levels significantly lower than controls. Evidences supporting a protective role of respiratory infections or BCG immunization on the development of allergic asthma are still insufficient. By contrast, the observation of a lower prevalence of atopic sensitization among children raised on a farm has been consistently reproduced. Several new studies have recently investigated the role of changes of human microbial flora, declining exposure to foodborne and orofecal infections, to helminths and to environmental sources of endotoxin as putative contributors to the rise of allergy and asthma cases among populations living with a western lifestyle.     

Can oral pathogens influence allergic disease?

The hygiene hypothesis contends that fewer opportunities for infections and microbial exposures have resulted in more widespread asthma and atopic disease. Consistent with that hypothesis, decreases in infectious oral diseases over the past half century have coincided with increases in the prevalence of asthma and other allergic diseases. This observation has led some researchers to speculate that exposures to oral bacteria, including pathogens associated with periodontal diseases, such as gingivitis and periodontitis, might play a protective role in the development of asthma and allergy. Colonization of the oral cavity with bacteria, including some species of periodontal pathogens, begins shortly after birth, and the detection of serum antibodies to oral pathogens in early childhood provides evidence of an early immune response to these bacteria. Current knowledge of the immune response to oral bacteria and the immunologic pathogenesis of periodontal diseases suggests biologically plausible mechanisms by which oral pathogens could influence the risk of allergic disease. However, studies investigating the association between oral pathogen exposures and allergic disease are few in number and limited by cross-sectional or case-control design, exclusion of young children, and use of surrogate measures of oral bacterial colonization. Additional studies, particularly well-designed case-control studies among very young children and prospective birth cohort?studies, are needed.     

The role of vitamin D in the immunopathogenesis of allergic skin diseases

Vitamin D plays key roles in innate and adaptive immunity through the stimulation of Toll-like receptors, increasing pro-inflammatory cytokine production, and possibly enhancing T helper type 2 responses. These mechanisms may explain the growing body of evidence connecting vitamin D to allergic diseases, including asthma, food allergies, and allergic rhinitis. The data relating vitamin D to allergic skin diseases are equivocal with studies linking both high and low vitamin D levels to an increased risk of developing atopic dermatitis. In this paper, we describe the role of vitamin D in the immunopathogenesis of atopic dermatitis and other allergic skin diseases.     

The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines

Atopic dermatitis often precedes the development of other atopic diseases. The atopic march describes this temporal relationship in the natural history of atopic diseases. Although the pathophysiological mechanisms that underlie this relationship are poorly understood, epidemiological and genetic data have suggested that the skin might be an important route of sensitization to allergens. Animal models have begun to elucidate how skin barrier defects can lead to systemic allergen sensitization. Emerging data now suggest that epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 may drive the progression from atopic dermatitis to asthma and food allergy. This review focuses on current concepts of the role of skin barrier defects and epithelial cell-derived cytokines in the initiation and maintenance of allergic inflammation and the atopic march.     

Current insights into the role of human β‐defensins in atopic dermatitis

Anti‐microbial peptides or host defence peptides are small molecules that display both anti‐microbial activities and complex immunomodulatory functions to protect against various diseases. Among these peptides, the human β‐defensins (hBDs) are localized primarily in epithelial surfaces, including those of the skin, where they contribute to protective barriers. In atopic dermatitis skin lesions, altered skin barrier and immune dysregulation are believed to be responsible for reduced hBD synthesis. Impaired hBD expression in the skin is reportedly the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis. Although hBDs have considerable beneficial effects as anti‐microbial agents and immunomodulators and may ameliorate atopic dermatitis clinically, recent evidence has also suggested the negative effects of hBDs in atopic dermatitis development. In the current review, we provide an overview of the regulation of hBDs and their role in the pathogenesis of atopic dermatitis. The efforts to utilize these molecules in clinical applications are also described.     

Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma,atopic dermatitis and chronic obstructive pulmonary disease

Background  

For allergic disorders, the increasing prevalence over the past decade has been attributed in part to the lack of microbial burden in developed countries ('hygiene hypothesis'). Variation in genes encoding toll-like receptors (TLRs) as the receptor system for the first innate immune response to microbial stimuli has been implicated in various inflammatory diseases. We evaluated here the role of a coding variation, Ser249Pro, in the TLR6 gene in the pathogenesis of asthma, atopic dermatitis (AD) and chronic obstructive pulmonary disease (COPD).     

Reduced levels of soluble CD14 in atopic children

BACKGROUND: A reduced microbial stimulation has been reported as a reason for the increasing prevalence of atopic diseases in industrialized countries. Antigen-presenting cells (APC), responding to microbial signals by pattern recognition receptors such as CD14, have an important role in the development of the Th1/Th2 balance. OBJECTIVE: We hypothesized that atopic children have a lower expression of CD14 on monocytes and lower soluble CD14 levels (sCD14). METHODS: Seventy-six children were followed prospectively from birth and signs of atopic disease were evaluated. The expression of CD14 on monocytes was analysed with flow cytometry at 0, 3, 6, 12 and 18 months. Circulating levels of sCD14 were analysed by ELISA and total IgE was analysed by fluoroenzymo immunoassay at these ages, and in a subgroup, followed up at 7 years. RESULTS: Levels of sCD14 were reduced at 7 years both in children with a current or a cumulative history of atopy compared to non-atopic children with P=0.002 and 0.001, respectively. Sensitized children with atopic symptoms had lower sCD14 at 3 and 18 months and at 7 years of age than non-atopic non-sensitized children with P=0.023, 0.039 and 0.008, respectively. CONCLUSION: The lower levels of sCD14 observed in atopic children may be a consequence of an atopic family heredity and/or atopic disease, but it may also reflect a reduced capacity to respond to microbial signals.     

Are atopic individuals genetically predisposed to produce a specific protease profile in antigen processing?

Genetic factors play a major role in the development of allergic diseases such as asthma and atopic dermatitis. Since allergic response involves immune processes such as antigen-processing and -presentation, it is conceivable that the genes involved in the regulation of these processes may be crucial in determining an individual's susceptibility to allergic diseases. In this paper, it is proposed that proteases, used in antigen-processing, are involved in the genetic predisposition to allergic diseases.     

IL-17 and IL-22 in atopic allergic disease

A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis. Whereas sparse data point to a protective role of the increasing amounts of Th22 cells that are found in chronic stages of both allergies, the data on Th17 cells paint different pictures for the contribution of Th17 cells during subsequent stages of these two forms of allergy.     

Unsuitability of bakery work for a person with atopy: a study of 234 bakery workers.

A disease of the atopic group was established in 25% of bakery employees investigated: 9% had asthma, 25% allergic rhinitis and 5% atopic eczema. The definite role of flour dust as an allergen maintaining asthma was established in 14 of 21 bakery employees with asthma. The onset of asthma in bakery work occurred after an average of 4.2 years of exposure to flour dust. The study revealed that 71% of the bakers suffering from an atopic disease had close relations with a history of atopic disease, whereas the corresponding percentage for the healthy group was 17. The results indicated that no person with current atopic disease or earlier signs of one should be given employment in the bakery branch. A relative bar to employment appears to be also the occurrence of these forms of diseases in the applicant's close relations.     

A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children

BACKGROUND: Bacterial signals play an important role in the maturation of the immune system. Polymorphisms in genes coding for receptors to bacterial components can alter the immune responsiveness of the host to microbial agents and may indicate the development of aberrant immune responses that are associated with immune-mediated diseases such as atopic diseases. OBJECTIVE: The study's objective was to investigate the relationship between TLR4 and CD14 gene polymorphisms, the LPS responsiveness of PBMCs, and the presence of asthma and allergic rhinoconjunctivitis in children. METHODS: The TLR4 (Asp299Gly) and CD14/-159 polymorphisms were determined in 115 Swedish children aged 8 and 14 years. LPS-induced IL-12(p70), IL-10, and IFN-gamma responses of PBMCs from 69 of the children were analyzed by means of ELISA. The levels of soluble CD14 in serum samples were analyzed by means of ELISA, and the total IgE levels were analyzed by means of UniCAP Total IgE (Pharmacia Diagnostics, Uppsala, Sweden). RESULTS: Decreased LPS-induced IL-12(p70) and IL-10 responses were associated with the TLR4 (Asp299Gly) polymorphism and independently with asthma, especially atopic asthma. The TLR4 (Asp299Gly) polymorphism was associated with a 4-fold higher prevalence of asthma in school-aged children (adjusted odds ratio 4.5, 95% CI 1.1-17.4) but not to allergic rhinoconjunctivitis. CONCLUSION: A TLR4 polymorphism modifies innate immune responses in children and may be an important determinant for the development of asthma. This may influence the outcome of intervention studies that use microbial stimuli as immune modulators.     

The prevalence of allergic diseases in primary school children in Edirne, Turkey

Background Allergic diseases present a major health burden for children as shown by the rising morbidity and increased mortality from asthma. Information on the prevalences of allergic disorders and contributing factors as well will help to establish feasible measures to change this trend, and more efficient assignment of the limited health resources. Objective To assess the prevalences of asthma and other allergic diseases and the contribution of various risk factors in primary school children in Edirne, Turkey. Methods Children aged 7 to 12 in primary schools in the municipality and 24 villages of Edirne were surveyed via a questionnaire completed by the parents. The cumulative (lifetime) and current (last 12 months) prevalences of allergic diseases and the presence of passive smoking, atopic family history, animal contact and breast-feeding in infancy were determined. Results A total of 5412 children (70.1% from the metropolitan and 29.9% from the rural area) were enrolled. The cumulative and current prevalences of all allergic diseases were 24.6% and 9.9% respectively. The cumulative (lifetime) prevalences of bronchial asthma, wheezing, allergic rhinitis and atopic dermatitis were 16.4%, 18.9%, 12.3% and 2.2%, and the current (last 12 months) prevalences were 5.6%, 5.8%, 4.5% and 0.9% respectively. Three-fourths of the children were exposed to tobacco smoke at home. Atopic heredity appeared the most prominent risk factor for any allergic disorder. Neither age, breast-feeding nor place of habitation affected the occurrence of allergic disorders. Animal contact was a significant risk factor for asthma and wheezing (adjusted odd ratios (OR) and 95% confidence intervals (CI) for current prevalences are 1.38 (CI= 1.04–1.83) and 1.35 (CI= 1.02–1.78) respectively), exposure to indoor tobacco smoke for wheezing (OR =1.52, CI= 1.10–2.09), and male gender for asthma (OR = 1.50, CI= 1.16–1.93). Current prevalences for all allergic diseases were significantly lower than those previously reported in Ankara, Turkey. Conclusions Allergic diseases are a major health burden for primary school children in Edirne, Turkey. Although atopic heredity appears to be the foremost important risk factor, reduction of exposure to indoor tobacco smoke and animal contact, especially for those with atopic family history, are important preventive measures. The impact of environmental exposures on distinguishing prevalences of allergic diseases in Ankara and Edirne should be further investigated.