Towards a differential definition of atopy: Anisakis simplex and the relationship between parasites and arthropods in respiratory allergy

Protective as well as enhancing effects of parasite infections on allergic disease have been postulated. Previous studies on this relationship focused frequently on skin test reactivity against aeroallergens, being house dust mites (HDM) the main agents responsible for a positive atopy outcome.
We aimed to analyse the possible relationship between human parasite infection induced Anisakis simplex urticaria and respiratory allergy.
A total of 86 patients with gastro-allergic Anisakiasis and 203 patients with chronic urticaria sensitized against A. simplex were studied for sensitization against aeroallergens and evaluated for rhinoconjunctivitis or bronchial asthma (RCBA). We compared the results with a control group of 250 consecutive patients referred for evaluation of allergic RCBA and atopy prevalence data of our region.
Whereas no effect of A. simplex related disease on the overall allergic respiratory disease could be detected, a highly significant higher prevalence of RCBA associated HDM sensitization, but diminished allergy against other common aeroallergens (pollen, mould or dander) was observed in these groups.
The relationship between A. simplex parasitism-associated acute or chronic urticaria on one side and allergic respiratory disease on the other side depends on the definition of atopy. We propose a differential definition of atopy, with a special emphasis on arthropod related sensitization.     

钩虫感染诱导宿主免疫反应及其潜在治疗价值研究进展

钩虫病是影响人类健康的全球性公共卫生问题之一,尤其在热带及亚热带地区,人群钩虫感染较为普遍。近年来,随着寄生虫感染免疫学研究的不断深入,发现钩虫等蠕虫感染引起的宿主免疫应答作用的“双向性”日益凸显：一方面诱导宿主产生杀伤感染蠕虫的免疫应答;另一方面也会引起宿主产生一系列有利于维持寄生虫寄生的免疫学改变,即通过多种复杂机制调控宿主免疫状态,导致感染宿主过敏性及自身免疫性疾病的发病减少或症状减轻,这为此类疾病的干预提供了新的思路。本文对钩虫感染后宿主免疫应答,及其对过敏性哮喘、炎症性肠病及类风湿性关节炎等疾病的潜在治疗价值研究进展进行综述。     

钩虫感染诱导宿主免疫反应及其潜在治疗价值研究进展

钩虫病是影响人类健康的全球性公共卫生问题之一，尤其在热带及亚热带地区，人群钩虫感染较为普遍。近年来，随着寄生虫感染免疫学研究的不断深入，发现钩虫等蠕虫感染引起的宿主免疫应答作用的“双向性”日益凸显：一方面诱导宿主产生杀伤感染蠕虫的免疫应答；另一方面也会引起宿主产生一系列有利于维持寄生虫寄生的免疫学改变，即通过多种复杂机制调控宿主免疫状态，导致感染宿主过敏性及自身免疫性疾病的发病减少或症状减轻，这为此类疾病的干预提供了新的思路。本文对钩虫感染后宿主免疫应答，及其对过敏性哮喘、炎症性肠病及类风湿性关节炎等疾病的潜在治疗价值研究进展进行综述。     

Parasites and allergy: Observations from Brazil

Brazil is a middle‐income country undergoing the epidemiological transition. Effects of changes in daily life habits and access to clean water, sanitation and urban services on a growing urban population have contributed to a double burden of both infectious and noncommunicable chronic diseases. Studies have indicated that parasite infections may modulate the human immune system and influence the development of allergic conditions such as asthma. However, there is no consensus in the published literature on the effects of parasitic infections on allergy, perhaps as a consequence of factors determining the epidemiology of these infections that vary between populations such as age of first infection, duration and chronicity of infections, parasite burden and species, and host genetic susceptibility. In this review, we discuss the observations from Brazil concerning the relationship between parasite infections and allergy.     

Association of atopy, asthma, allergic rhinoconjunctivitis, atopic dermatitis and intestinal helminth infections in Cuban children

Objective To examine the relationship of past and current intestinal helminth infections with asthma, allergic rhinoconjunctivitis, atopic dermatitis and atopy. Methods Cross‐sectional study of 1320 children aged 4–14 years from two Cuban municipalities. Helminth infections were determined by stool examination and parental questionnaire. Asthma, rhinoconjunctivitis and atopic dermatitis were diagnosed by International Study of Asthma and Allergies in Childhood questionnaire, asthma additionally by spirometry, atopy by skin prick testing. Results Questionnaire‐based frequencies were 21% for asthma, 14% for allergic rhinoconjunctivitis and 8% for atopic dermatitis. According to spirometry, 4% had asthma; 20% had a positive skin prick test. A history of infection for Enterobius vermicularis was associated with increased risk of atopic dermatitis (OR 1.88, P = 0.001) and allergic rhinoconjunctivitis (OR 1.34, P = 0.046), and hookworm with increased risk of allergic rhinoconjunctivitis (OR 2.77, P = 0.021). A positive stool examination for Ascaris lumbricoides infection was negatively associated with atopic dermatitis (OR 0.22, P = 0.007). Asthma and atopy were unrelated to helminth infections. Conclusion Current A. lumbricoides infection protects against atopic dermatitis in Cuban children, while past infection with E. vermicularis and hookworm are risk factors for allergic rhinoconjunctivitis and/or atopic dermatitis. Apparently, interactions differ depending on the type of helminth and atopic disease and on the time of helminth infestation.     

Worms: Pernicious parasites or allies against allergies?

Type 2 immune responses are most commonly associated with allergy and helminth parasite infections. Since the discovery of Th1 and Th2 immune responses more than 30 years ago, models of both allergic disease and helminth infections have been useful in characterizing the development, effector mechanisms and pathological consequences of type 2 immune responses. The observation that some helminth infections negatively correlate with allergic and inflammatory disease led to a large field of research into parasite immunomodulation. However, it is worth noting that helminth parasites are not always benign infections, and that helminth immunomodulation can have stimulatory as well as suppressive effects on allergic responses. In this review, we will discuss how parasitic infections change host responses, the consequences for bystander immunity and how this interaction influences clinical symptoms of allergy.     

Helminth infections: Protection from atopic disorders

Westernized countries are suffering from an epidemic rise in immunologic disorders, such as childhood allergy. A popular explanation is that the increased prevalence in allergy is due to a diminished or altered exposure to gut-dwelling microbes, resulting in a disordered immunoregulation. Various population studies have provided a strong case for the involvement of helminth infections in this respect. Detailed analysis of helminth-induced immune responses showed that helminths not only prime for polarized Th2 responses but also potently induce T-cell hyporesponsiveness. Recently, it has been demonstrated that helminths induce suppressed host immune responses by the priming for regulatory T cells. It is proposed that this regulatory T cell-inducing activity accounts for the protection observed in the development of allergic disorders. It would be interesting to define and characterize particular helminth molecules that have profound immunomodulatory capacities as a target for therapeutic application in the treatment or prophylaxis of allergic manifestations.     

Prevalence of asthma and atopy in sarcoidosis

Background and objective: We hypothesized that the prevalence of allergic disorders, characterized by the release of type 2 cytokines (IL‐4, IL‐5, IL‐10), would be lower in sarcoidosis in which there is a dominant type 1 immune response (IL‐2, interferon‐gamma). The objective was to measure the prevalence of atopy and self‐reported asthma in patients with sarcoidosis. Methods: Sarcoidosis patients (n = 136, 72 M, age range 22–75), recruited in the outpatient setting, completed a modified European Community Respiratory Health Survey. 123 of these patients provided blood for allergy testing. Results: For the cohort as a whole the self‐reported prevalence of asthma ever (21.5%) and asthma attack in the last 12 months (7.5%), was high as was wheezing (42.1%), breathlessness with wheeze (22.3%) and use of an asthma medication (13.1%). The prevalence of atopy was 34%. These data are not different from the previously reported prevalence of asthma and atopy in New Zealand. Conclusions: The same prevalence of asthma symptoms and atopy as in the normal population suggests that the immune system is not skewed away from mounting T helper type 2 immune responses in sarcoidosis.     

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)‐induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen‐challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum‐induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica.     

Immunomodulation and allergy.

A major function of the immune system is to protect the body from infection and the diseases caused by infectious agents. The immune system also provides protection against cancer cells, for once they arise, cancers can essentially behave as "foreign" cells capable of causing pathology. In contrast, allergy is a manifestation of the immune response to certain environmental cells or molecules that are usually neither a threat for infection nor cancer. Allergic reactions are generally an annoynance, even life-threatening. I will focus on type I allergy, characterized in part by induction of IgE antibody responses to allergens. It should be noted that not all IgE responses cause allergic symptoms. There is even evidence that IgE responses to tropical helminthic parasites offer a degree of immunity to reinfection. I have three objectives: (1) review T cell differentiation leading to the Th1/Th2 paradigm; (2) evaluate the increased prevalence of atopy, including asthma, as a consequence of a Th2-dominated immune system; (3) relate the high prevalence of asthma in inner city United States black children to the relatively recent migration of their ancestors from tropical regions of Africa, where genetically biased Th2-dependent IgE responses may be important in protection against high burdens of parasitic worms.     

The role of dendritic cells in immune regulation and allergic airway inflammation

Abstract: Dendritic cells (DC) are potent antigen presenting cells that display an extraordinary capacity to present antigen to naïve T‐cells and initiate primary immune responses. In the context of the lung and upper airway it is clear that DC play a key role in the regulation of adaptive immune responses to inhaled antigen. DC are particularly sensitive to signals derived from microbes, allergens and the airway tissue microenvironment. By the nature of the signals they provide at the time of antigen presentation, DC can polarize naïve T‐cells into either T‐helper type 1 (Th1) or Th2 effector cells, and are increasingly recognized as having a central role in the establishment of T‐cell memory and peripheral immune tolerance. DC form a network within the upper airway and lung, and are rapidly recruited from the circulation in response to a variety of proinflammatory stimuli. Studies using animal models have highlighted the role of DC in both the initiation and maintenance of allergic airway inflammation. In early childhood, human DC are functionally immature, and this is thought to contribute to the development of allergic sensitization in those children who are genetically at risk for the development of atopy. Increased numbers of airway mucosal DC are found in both allergic rhinitis and asthma, while studies of blood‐derived DC have emphasized important differences between the function of DC from atopic and normal individuals. This article reviews recent information on the involvement of DC in allergic airway disease, and the mechanisms by which DC could be exploited as targets for therapy in asthma and allergic rhinitis.     

Ascaris lumbricoids Infection as a Risk Factor for Asthma and Atopy in Rural Bangladeshi Children

Controversy persists as to whether helminth infections cause or protect against asthma and atopy. The aim of this study was to investigate the effects of helminth infection on asthma and atopy among Bangladeshi children. A total of 912 children aged 4.5 years (mean = 54.4, range = 53.5–60.8 months) participated in a cross-sectional study nested into a randomized controlled trial in Bangladesh. Ever-asthma, ever-wheezing and current wheezing were identified using the International Study of Asthma and Allergies in Childhood questionnaire. Current helminth infection was defined by the presence of helminth eggs in stools, measured by routine microscopic examination. Repeated Ascaris infection was defined by the presence of anti-Ascaris IgE ≥ 0.70 UA/ml in serum measured by the CAP-FEIA method. Atopy was defined by specific IgE to house dust mite (anti-DP IgE) ≥ 0.70 UA/ml measured by the CAP-FEIA method and/or positive skin prick test (≥ 5 mm). Anti-Ascaris IgE was significantly associated with ever asthma (odds ratio (OR) = 1.86, 95% CI: 1.14–3.04, highest vs. lowest quartile; P for trend 0.016). Anti-Ascaris IgE was also significantly associated with positive anti-DP IgE (OR = 9.89, 95% CI: 6.52–15.00, highest vs. lowest; P for trend < 0.001) and positive skin prick test (OR = 1.69, 95% CI: 1.01–2.81, highest vs. lowest, P for trend 0.076). These findings suggest that repeated Ascaris infection is a risk factor for asthma and atopy in rural Bangladeshi children. Further analysis is required to examine the mechanism of developing asthma and atopy in relation to helminth infection.     

Exosome‐transported microRNAs of helminth origin: new tools for allergic and autoimmune diseases therapy?

Chronic diseases associated with inflammation show fast annual increase in their incidence. This has been associated with excessive hygiene habits that limit contacts between the immune system and helminth parasites. Helminthic infections induce regulation and expansion of regulatory T cells (Treg) leading to atypical Th2 type immune responses, with downregulation of the inflammatory component usually associated with these type of responses. Many cells, including those of the immune system, produce extracellular vesicles called exosomes which mediate either immune stimulation (DCs) or immune modulation (T cells). The transfer of miRNAs contained in T‐cell exosomes has been shown to contribute to downregulate the production of inflammatory mediators. It has been recently described the delivery to the host–parasite interface of exosomes containing miRNAs by helminths and its internalization by host cells. In this sense, helminth microRNAs transported in exosomes and internalized by immune host cells exert an important role in the expansion of Treg cells, resulting in the control of inflammation. We here provide relevant information obtained in the field of exosomes, cell–cell communication and miRNAs, showing the high potential of helminth miRNAs delivered in exosomes to host cells as new therapeutic tools against diseases associated with exacerbated inflammatory responses.     

Roles of IL-18 in basophils and mast cells.

Basophils and mast cells are effecter cells in allergen/IgE-mediated immune responses. They induce type 1 immediate immune response in airway or other organ, resulting in bronchial asthma and other allergic diseases. However, they also play a critical role in host defense against infection with helminthes. Upon linkage of FcepsilonRI with a complex of allergen and IgE, basophils and mast cells release a large amount of Th2 cytokines and chemical mediators. Therefore these responses are "acquired allergic responses" and induce allergic diseases, such as bronchial asthma. However, basophils and mast cells derived from cultured bone marrow cells with IL-3 for 10 days express IL-18Ralpha chain and produce Th2 cytokines in response to the stimulation with IL-3 and IL-18 without FcepsilonRI cross-linkage. Furthermore, they produce Th2 cytokines upon stimulation with several TLR ligands, such as LPS. This finding may suggest the presence of allergen/IgE-independent allergic responses, which we would like to designate as "innate allergic response". However, in vivo treatment with IL-18 and IL-2 protects against gastrointestinal nematode infection by activating intestinal mucosal mast cells in STAT6-independent manner, suggesting the importance of innate allergic response against helminth infection. Here we discuss the functional role of IL-18-induced "innate allergic response" in disease and host defense.     

Intestinal worms and human allergy

The immunoepidemiological interactions between intestinal worm (or geohelminth) infections and allergy are of great interest to parasitologists, immunologists, and allergists because of the close similarities between the human immune response to geohelminth parasites and environmental allergens. Allergic diseases appear to be most rare in populations living in the rural tropics with high rates of infection with geohelminth parasites, and this has led to suggestions that the relationship between geohelminth infections and allergy may be causal. Allergic sensitization and disease results from a complex interaction between environmental exposures and genetic background, and the numerous epidemiological studies that have investigated the relationship between allergy and geohelminth infections have provided conflicting findings. The strongest epidemiological evidence for a causal association is provided by intervention studies that demonstrate evidence for an effect of anthelmintic treatment on atopy or asthma risk. There is evidence also for an inverse relationship between geohelminth infection and either atopy or asthma symptoms from cross-sectional studies that have been conducted in areas of high infection prevalence. Chronic geohelminth infections could affect allergy risk by modulation of the immune response to environmental allergens, and an area of great research activity at present is the investigation of the role of regulatory T cells in modulating host inflammatory responses. However, a causal association between geohelminth infections and allergy remains to be proven, and prospective and intervention studies are required that investigate the development of allergy in early life at a time when humans are first exposed to geohelminth parasites and their antigens.     

Eosinophilia during intestinal infection

Eosinophilia is a common finding in tropical developing countries, and is mainly caused by chronic helminth infections, predominantly of the gut. Although only a minority of infections is symptomatic, development during childhood can be impaired, and in some patients serious complications and sequelae may occur. Eosinophilia in helminth infection is typically associated with a strong Th2 immune response, and eosinophils can effectively kill or damage larvae and adult worms in vitro. However, in vivo, eosinophils are only partly effective in the control of helminth infection, and recent research has shown that eosinophils are involved in a range of immunomodulatory effects, such as increased production of the down-modulatory cytokines interleukin 10 and tumour growth factor beta, as well as stimulation of regulatory T cells and alternatively activated macrophages. Increasing evidence suggests that immunomodulation favours parasite survival and reduces immune pathology. On the other hand, immunomodulation induced by helminth infections may contribute to protection from allergic and autoimmune responses, as proposed by the 'hygiene hypothesis' to explain the increase in allergic diseases in the industrialised world. The predictive value of eosinophilia for the presence of helminth infections is limited and depends on the epidemiological background and the extent of the eosinophilia. It increases considerably in populations with a high prevalence of parasitic infections, as in developing tropical countries or in travellers to those areas.     

Atopy and helminths

In this article, the authors review current and latest evidence linking helminth infections and the development of atopy. Although there is intense ongoing investigation and debate on this issue, the review of experimental, clinical and epidemiological data apparently shows that helminth infections can have beneficial aspects in regard to the pathogenesis of atopy and allergic diseases. Despite the fact that simplistic views are not recommended, it seems that polyclonal IgE production and mainly the stimulation of host immunoregulatory networks leading to synthesis of anti-inflammatory cytokines (IL-10, TGF-beta and others) can provide new insights into how mechanisms that helminths have developed throughout their evolution and that are useful for parasite evasion and persistence, could also be used in humans in order to provide new approaches in atopy prevention.     

Parasites and allergy: Observations from Africa

Population studies from the African continent have observed a marked increase in the prevalence of allergy‐related diseases over the past few decades, but the cause of this rise is not fully understood. The most investigated potential risk factor has been the relationship between exposure to helminths and allergy‐related outcomes. Immunologically, parallels exist between responses to helminths and to allergens as both are associated with elevated levels of immunoglobulin E, increased numbers of T helper 2 cells and other immune cells. However, epidemiological studies from the African continent have found inconsistent results. In this review, observations from population studies carried out in Africa over the last decade that focus on the relationship between helminth infections and allergy‐related outcomes are examined. How these findings advance our understanding of the complex interactions between helminths and allergies at the population level is also explored as well as some of the underlying immune mechanisms involved. This knowledge is important for better diagnosis, treatment and prevention of allergy‐related diseases and has wider global significance.     

Chronic Helminth Infections Protect Against Allergic Diseases by Active Regulatory Processes

Developed countries are suffering from an epidemic rise in immunologic disorders, such as allergy-related diseases and certain autoimmunities. Several studies have demonstrated a negative association between helminth infections and inflammatory diseases (eg, allergy), providing a strong case for the involvement of helminth infections in this respect. However, some studies point in the opposite direction. The discrepancy may be explained by differences in frequency, dose, time, and type of helminth. In this review, new studies are discussed that may support the concept that chronic helminth infections in particular—but not acute infections—are associated with the expression of regulatory networks necessary for downmodulating allergic immune responses to harmless antigens. Furthermore, different components of regulatory networks are highlighted, such as the role of regulatory T and B cells, modulation of dendritic cells, early innate signals from structural cells (eg, epithelial cells), and their individual contributions to protection against allergic diseases. It is of great interest to define and characterize specific helminth molecules that have profound immunomodulatory capacities as targets for therapeutic application in the treatment or prophylaxis of allergic manifestations.     

A co‐infection with two gastrointestinal nematodes alters host immune responses and only partially parasite dynamics

Given their global distribution and abilities to persist in the host, helminths can play a crucial role in affecting risk of infections by increasing individual variation in infection. Helminth co‐infections are of particular interest because by altering host immune responses, they can modify host susceptibility and thus intensity and transmission of other parasites/pathogens. The dynamics of co‐infection were examined using two helminths of the European rabbit. Individuals were simultaneously challenged with a primary dose of both parasites, and changes in intensity were examined in relation to local and systemic immune responses. Both helminths persisted in co‐infected rabbits; however, contrasting dynamics and immune responses were observed. Graphidium strigosum intensity was high throughout the co‐infection, while Trichostrongylus retortaeformis intensity decreased but was not completely cleared. A Th2 response was observed against G. strigosum, while a mixed Th1/Th2 profile was found to T. retortaeformis. A comparison with our previous work on single infections showed that G. strigosum intensity was higher in co‐infected than single infected hosts, while T. retortaeformis showed no significant changes. Differences were also observed in the cytokine profiles, blood cell concentrations and antibody trends. Overall, host variability during helminth co‐infections can be generated by significant differences in immune responses and/or parasite dynamics.