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Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by transient intense skin reaction and systemic inflammation. Clinical presentation of HMB resembles other mosquito allergic responses, and it can also be difficult to clinically distinguish HMB from other severe allergic reactions. However, a distinctive pathophysiology underlies HMB. HMB belongs to a category of Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPD). Hence, HMB may progress to systemic diseases, such as hemophagocytic lymphohistiocytosis, chronic active EBV disease, and EBV-associated malignancies. A triad of elevated serum IgE, NK lymphocytosis, and detection of EBV DNA in peripheral blood is commonly observed, and identification of EBV-infected NK cells usually facilitates the diagnosis. However, the effective treatment is limited, and its precise etiology remains unknown. Local CD4+ T cell proliferation triggered by mosquito bites appears to help induce EBV reactivation and EBV-infected NK-cell proliferation. These immunological interactions may explain the transient HMB signs and symptoms and the disease progression toward malignant LPD. Further research to elucidate the mechanism of HMB is warranted for better diagnosis and treatment of HMB and other forms of EBV-associated LPD., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Epstein-Barr virus (EBV) DNA load in the blood increases in posttransplant lymphoproliferative disorders and chronic active EBV infection. In this report, we analyzed the EBV DNA load in the peripheral blood mononuclear cells (PBMCs) and plasma of patients with hydroa vacciniforme (HV) and/or hypersensitivity to mosquito bites (HMB) to understand the clinical significance of EBV DNA load. All 30 patients showed high DNA loads in the PBMCs over the cut-off level. Of 16 plasma samples, extremely high in two samples obtained from patients with hemophagocytic lymphohistiocytosis (HLH). The amount of cell-free DNA in plasma was correlated to the serum levels of lactate dehydrogenase and inversely correlated to platelet counts. These results indicate that the EBV DNA load in PBMCs can provide one of the diagnostic indicators for HV and HMB and marked elevation of cell-free EBV DNA in plasma might be related to cytolysis such as that observed in HLH., (© 2020 Wiley Periodicals, Inc.)

Human coronaviruses (HCoVs) such as HCoV-229E or OC43 are responsible for mild upper airway infections, whereas highly pathogenic HCoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, often evoke acute, heavy pneumonias. They tend to induce immune responses based on interferon and host inflammatory cytokine production and promotion of T1 immune profile. Less is known about their effect on T2-type immunity. Unlike human rhinoviruses (HRV) and Respiratory Syncytial Virus (RSV), HCoVs are not considered as a dominant risk factor of severe exacerbations of asthma, mostly T2-type chronic inflammatory disease. The relationship between coronaviruses and T2-type immunity, especially in asthma and allergy, is not well understood. This review aims to summarize currently available knowledge about the relationship of HCoVs, including novel SARS-CoV-2, with asthma and allergic inflammation., (© 2020 John Wiley & Sons Ltd.)

Background: After the Second World War, the population living in the Karelian region was strictly divided by the "iron curtain" between Finland and Russia. This resulted in different lifestyle, standard of living, and exposure to the environment. Allergic manifestations and sensitization to common allergens have been much more common on the Finnish compared to the Russian side., Objective: The remarkable allergy disparity in the Finnish and Russian Karelia calls for immunological explanations., Methods: Young people, aged 15-20 years, in the Finnish (n = 69) and Russian (n = 75) Karelia were studied. The impact of genetic variation on the phenotype was studied by a genome-wide association analysis. Differences in gene expression (transcriptome) were explored from the blood mononuclear cells (PBMC) and related to skin and nasal epithelium microbiota and sensitization., Results: The genotype differences between the Finnish and Russian populations did not explain the allergy gap. The network of gene expression and skin and nasal microbiota was richer and more diverse in the Russian subjects. When the function of 261 differentially expressed genes was explored, innate immunity pathways were suppressed among Russians compared to Finns. Differences in the gene expression paralleled the microbiota disparity. High Acinetobacter abundance in Russians correlated with suppression of innate immune response. High-total IgE was associated with enhanced anti-viral response in the Finnish but not in the Russian subjects., Conclusions and Clinical Relevance: Young populations living in the Finnish and Russian Karelia show marked differences in genome-wide gene expression and host contrasting skin and nasal epithelium microbiota. The rich gene-microbe network in Russians seems to result in a better-balanced innate immunity and associates with low allergy prevalence., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

The relationship between the severity of dengue infection and allergy is still obscure. We conducted an electronic search across 12 databases for relevant articles reporting allergic symptoms, dengue infection, and dengue classification. These studies were categorized according to dengue severity and allergy symptoms, and a meta-analysis was performed by pooling the studies in each category. Among the included 57 articles, pruritus was the most common allergic sign followed by non-specified allergy and asthma (28.6%, 13%, and 6.5%, respectively). Despite the reported significant association of dengue with pruritus and total IgE level (P < 0.05), in comparison with non-dengue cases and healthy controls, there was no association between the different severe dengue group with pruritus, skin allergy, food allergy or asthma. However, removing the largest study revealed a significant association between asthma with dengue hemorrhagic fever (DHF) rather than dengue fever (DF). In comparison with DF, DHF was associated with IgE positivity. Furthermore, specific-IgE level was higher in secondary DF rather than primary DF. There was a possible association between allergy symptoms and dengue severity progression. Further studies are needed to clarify this association.

Recent advances indicate that there is crosstalk between allergic disorders and nucleic acid sensing. Triggers that activate inflammatory mechanisms via nucleic acid sensors affect both allergic phenotypes and anti-viral responses, depending on the timing and the order of exposure. Viral respiratory infections, such as those caused by the rhinovirus, influenza, and respiratory syncytial virus, are the most frequent cause of significant asthma exacerbations through effects mediated predominantly by TLR3. However, agonists of other nucleic acid sensors, such as TLR7/8 and TLR9 agonists, may inhibit allergic inflammation and reduce clinical manifestations of disease. The allergic state can predispose the immune system to both exaggerated responses to viral infections or protection from anti-viral inflammatory responses. T H 2 cytokines appear to alter the epithelium, leading to defective viral clearance or exaggerated responses to viral infections. However, a T H 2 skewed allergic response may be protective against a T H 1-dependent inflammatory anti-viral response. This review briefly introduces the receptors involved in nucleic acid sensing, addresses mechanisms by which nucleic acid sensing and allergic responses can counteract one another, and discusses the strategies in experimental settings, both in animal and human studies, to harness the nucleic acid sensing machinery for the intervention of allergic disorders., (© 2019 Elsevier Inc. All rights reserved.)

Background: Kindergarteners frequently encounter various infectious diseases, so surveillance of viral infectious diseases would provide information for their health promotion., Methods: We enrolled kindergarten attendees, age 2-5 years, during the academic years of 2006 and 2007 in a Taipei City kindergarten. Daily monitoring of illness and regular biweekly physical examinations were undertaken. Multiple infections were defined as one child having two or more laboratory-confirmed viral infections with different viruses or different serotypes during one academic year., Results: The overall laboratory-confirmed incidence rate of respiratory viral infection was 239 per 100 person-years in the 2006 academic year and 136 per 100 person-years in the 2007 academic year. The attack rate for seasonal influenza was 17% in the 2006 academic year and 27% in the 2007 academic year. Boys and children with allergies had significantly higher risks to get multiple viral infections [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.20-2.75; OR 1.56, 95% CI 1.00-2.39, respectively]. Boys also tended to get enterovirus infections (OR 1.56, 95% CI 1.02-2.38) while children with allergies tended to acquire adenovirus infections (OR 1.71, 95% CI 1.12-2.66)., Conclusion: Boys and children with allergies were more susceptible to multiple viral infections, so they should be more cautious about viral infections., (Copyright © 2017. Published by Elsevier B.V.)

Thymic stromal lymphopoietin (TSLP) is associated with several allergic diseases including asthma. Two isoforms of TSLP exist in humans, a long form (lfTSLP) and a short form (sfTSLP), displaying distinct immunological functions. Recently, TSLP was found to be upregulated in human airway cells upon human metapneumovirus (hMPV) infection, yet it remains unclear if the two isoforms are regulated differently during hMPV infection. Importantly, the molecular mechanisms underlying hMPV-mediated TSLP induction remain undescribed. In this study, we characterized the expression and regulation of TSLP in hMPV-infected human airway cells. We demonstrated that hMPV strongly induced the expression of pro-inflammatory lfTSLP in human airway epithelial cells and lung fibroblasts. Further, knockdown of pattern recognition receptors retinoic acid-inducible gene I (RIG-I) or Toll-like receptor 3 (TLR3), as well as downstream signal transducers, abrogated hMPV-mediated lfTSLP induction. Importantly, silencing of TANK-binding kinase 1 (TBK1) also impaired hMPV-mediated lfTSLP induction, which could be attributed to compromised NF-κB activation. Overall, these results suggest that TBK1 may be instrumental for hMPV-mediated activation of NF-κB downstream RIG-I and TLR3, leading to a specific induction of lfTSLP in hMPV-infected human airway cells.

Background: Viruses are important triggers of asthma exacerbations. They are also detected outside of exacerbation. Alteration of anti-viral response in asthmatic patients has been shown although the mechanisms responsible for this defect remain unclear. The objective of this study was to compare in virus-infected and not-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response and especially the expression of pattern recognition receptor (PRR) and their function., Methods: Virus identification was performed both during the exacerbation and at steady state (eight weeks later). Data assessed at both periods included clinical features, anti-viral response and inflammation (in sputum and plasma), and PRR expression/function in blood mononuclear cells., Results: Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-β, IFN-γ and IL-29 levels in sputum and plasma were similar between infected and not infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. Airway inflammation in infected patients was characterized by significantly higher IL-5 concentration and eosinophil count. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-γ in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state., Conclusion: Our results reports in asthmatic children that impaired anti-viral response during virus-induced exacerbation is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function and a different pattern of airway inflammation., Trial Registration: This multicenter prospective study was approved by the regional investigational review board (ref: 08/07).

Background: Tonsils have an active role in immune defence and inducing and maintaining tolerance to allergens. Vitamins A, D, and E, and antimicrobial peptide LL-37 may have immunomodulatory effects. We studied how their serum levels were associated with allergy status, intratonsillar/nasopharyngeal virus detection and intratonsillar expression of T cell- and innate immune response-specific cytokines, transcription factors and type I/II/III interferons in patients undergoing tonsillectomy., Methods: 110 elective tonsillectomy patients participated. Serum levels of vitamins A, 25(OH)D, and E, LL-37 and allergen-specific IgE as well as nasopharyngeal/intratonsillar respiratory viruses were analyzed. The mRNA expression of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2 and Tbet in tonsils were analyzed by quantitative RT-PCR., Results: The median age of the patients was 16 years (range 3-60), 28% of subjects had atopy, and 57% carried ≥1 respiratory virus in nasopharynx. Detection of viruses decreased by age. Higher vitamin A levels showed borderline significance with less viral detection (P = 0.056). Higher 25(OH)D was associated with less allergic rhinitis and atopy (P < 0.05) and higher vitamin E with less self-reported allergy (P < 0.05). In gene expression analyses, 25(OH)D was associated with higher IL-37, vitamin A with higher IFN-γ and vitamin E with less IL-28 (P < 0.05). LL-37 was associated with less FOXP3, RORC2 and IL-17 in tonsils (P < 0.05)., Conclusions: Vitamin D and E levels were associated with less allergic disorders. Vitamin A was linked to antiviral and vitamin D with anti-inflammatory activity. LL-37 and was linked to T regulatory cell effects.

Increased viral replication and cytokine production may be associated with the pathogenesis of asthma attacks in rhinovirus (RV) infections. However, the association between increased RV replication and enhanced expression of intercellular adhesion molecule-1 (ICAM-1), a receptor for a major RV group, in airway epithelial cells has remained unclear. Furthermore, the inhibitory effects of mucolytics, which have clinical benefits in asthmatic subjects, are uncertain. Human nasal epithelial (HNE) cells were infected with type 14 rhinovirus (RV14), a major RV group. RV14 titers and cytokine concentrations, including interleukin (IL)-6 and IL-8, in supernatants, RV14 RNA replication and susceptibility to RV14 infection were higher in HNE cells obtained from subjects in the allergic group (allergic subjects) than in those from subjects in the non-allergic group (non-allergic subjects). ICAM-1 expression and the number and fluorescence intensity of acidic endosomes from which RV14 RNA enters the cytoplasm were higher in HNE cells from allergic subjects, though substantial amounts of interferon (IFN)-γ and IFN-λ were not detected in the supernatant. The abundance of p50 and p65 subunits of transcription factor nuclear factor kappa B (NF-κB) in nuclear extracts of the cells from allergic subjects was higher compared to non-allergic subjects, and an inhibitor of NF-κB, caffeic acid phenethyl ester, reduced the fluorescence intensity of acidic endosomes as well as RV titers and RNA. Furthermore, a mucolytic agent, L-carbocisteine, reduced RV14 titers and RNA levels, cytokine release, ICAM-1 expression, the fluorescence intensity of acidic endosomes, and NF-κB activation. The increased RV14 replication observed in HNE cells from allergic subjects might be partly associated with enhanced ICAM-1 expression and decreased endosomal pH through NF-κB activation. L-Carbocisteine inhibits RV14 infection by reducing ICAM-1 and acidic endosomes and may, therefore, modulate airway inflammation caused by RV infection in allergic subjects.

Purpose: Recent studies have employed animal models to investigate links between rhinovirus infection and allergic airways disease, however, most do not involve early life infection, and none consider the effects of sex on responses., Materials and Methods: Here, we infected male and female mice with human rhinovirus 1B (or control) on day 7 of life. Mice were then subjected to 7 weeks of exposure to house-dust-mite prior to assessment of bronchoalveolar inflammation, serum antibodies, lung function, and responsiveness to methacholine., Results: There were significant differences in responses between males and females in most outcomes. In males, chronic house-dust-mite exposure increased bronchoalveolar inflammation, house-dust-mite specific IgG1 and responsiveness of the lung parenchyma, however, there was no additional impact of rhinovirus infection. Conversely, in females, there were additive and synergistic effects of rhinovirus infection and house-dust-mite exposure on neutrophilia, airway resistance, and responsiveness of the lung parenchyma., Conclusions: We conclude that early life rhinovirus infection influences the development of house-dust-mite induced lung disease in female, but not male mice.

IFN-α/β was first described as a potent inhibitor of viral replication, but it is now appreciated that IFN signaling plays a pleiotropic role in regulating peripheral T cell functions. Recently, IFN-α/β was shown to block human Th2 development by suppressing the transcription factor GATA3. This effect is consistent with the role for IFN-α/β in suppressing allergic inflammatory processes by blocking granulocyte activation and IL-4-mediated B cell isotype switching to IgE. With the consideration of recent studies demonstrating a defect in IFN-α/β secretion in DCs and epithelial cells from individuals with severe atopic diseases, there is an apparent reciprocal negative regulatory loop in atopic individuals, whereby the lack of IFN-α/β secretion by innate cells contributes to the development of allergic Th2 cells. Is it possible to overcome these events by treating with IFN-α/β or by inducing its secretion in vivo? In support of this approach, case studies have documented the therapeutic potential of IFN-α/β in treating steroid-resistant allergic asthma and other atopic diseases. Additionally, individuals with asthma who are infected with HCV and respond to IFN therapy showed a reduction in symptoms and severity of asthma attacks. These findings support a model, whereby allergic and antiviral responses are able to cross-regulate each other, as IgER cross-linking of pDCs prevents IFN-α/β production in response to viral infection. The clinical importance of upper-respiratory viruses in the context of allergic asthma supports the need to understand how these pathways intersect and to identify potential therapeutic targets., (© Society for Leukocyte Biology.)

The aim of study was to evaluate various risk in patients who were hospitalized with moderate to severe virus-induced wheezing. Infants hospitalized with virus-induced wheezing were enrolled in the study. Respiratory viruses were detected in nasopharyngeal swab and total IgE levels and skin prick tests were performed in all patients. The mean age of the patients was 11.2±9 months. The most common detected viral agents were Respiratory Syncytial Virus, (33.6%), Influenza virus (16.3.%). Children with positive family history of atopy had their first virus-induced wheezing at an earlier age (9.0 ±7.8 months) than the others (14.2±10.8 months), (p=0.007). Atopy and viral etiology did not significantly influence clinical severity of the disease. Although children with positive parental history of atopy experience first virus-induced wheezing at an earlier age, personal atopy was not found as a risk factor for predicting the severity of the first virus-induced wheezy episode.

Background: Epstein-Barr virus (EBV)-associated T/natural-killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors., Objectives: To elucidate the prognostic factors of HV and HMB., Methods: We studied clinicopathological manifestations, routine laboratory findings, anti-EBV titres, EBV DNA load and EBV-encoded gene expression, including expression of BZLF1, in 50 patients with classical HV (cHV), sHV, HMB only and HMB with HV (HMB + HV), and further analysed 30 patients who were available for follow-up., Results: The median age of disease onset was 5 years (range 1-74). A follow-up study indicated that fatal outcomes were observed in three of eight patients with sHV, two of six patients with HMB only, and two of five patients with HMB + HV. The main causes of death were complications from haematopoietic stem-cell transplantation and multiorgan failure. There were no fatalities among the 11 patients with cHV. Univariate analysis revealed two poor prognostic indicators: (i) onset age > 9 years and (ii) the expression of an EBV-encoded immediate-early gene transcript, BZLF1 mRNA, in the skin lesions (P < 0·001 and P = 0·003, respectively)., Conclusions: No prognostic correlation was observed in EBV-infected lymphocyte subsets, anti-EBV antibody titres or EBV DNA load. Late onset and EBV reactivation are both related to more severe phenotypes of the disease, and thus may predict a poor prognosis., (© 2014 British Association of Dermatologists.)

Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation., (Copyright © 2014, American Association for the Advancement of Science.)

Pulmonary viral infections can exacerbate or trigger the development of allergic airway diseases via multiple mechanisms depending upon the infectious agent. Respiratory vaccinia virus transmission is well established, yet the effects of allergic airway disease on the host response to intra-pulmonary vaccinia virus infection remain poorly defined. As shown here BALB/c mice with preexisting airway disease infected with vaccinia virus developed more severe pulmonary inflammation, higher lung virus titers and greater weight loss compared with mice inoculated with virus alone. This enhanced viremia was observed despite increased pulmonary recruitment of CD8(+) T effectors, greater IFNγ production in the lung, and high serum levels of anti-viral antibodies. Notably, flow cytometric analyses of lung CD8(+) T cells revealed a shift in the hierarchy of immunodominant viral epitopes in virus inoculated mice with allergic airway disease compared to mice treated with virus only. Pulmonary IL-10 production by T cells and antigen presenting cells was detected following virus inoculation of animals and increased dramatically in allergic mice exposed to virus. IL-10 modulation of host responses to this respiratory virus infection was greatly influenced by the localized pulmonary microenvironment. Thus, blocking IL-10 signaling in virus-infected mice with allergic airway disease enhanced pulmonary CD4(+) T cell production of IFNγ and increased serum anti-viral IgG1 levels. In contrast, pulmonary IFNγ and virus-specific IgG1 levels were reduced in vaccinia virus-treated mice with IL-10 receptor blockade. These observations demonstrate that pre-existing allergic lung disease alters the quality and magnitude of immune responses to respiratory poxviruses through an IL-10-dependent mechanism.

Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

Background: Herpetic dermatitis due to herpes simplex virus (HSV) and varicella zoster virus (VZV) can present with similar clinical and histopathologic features. Further confounding matters, viral cytopathic changes are not always observed in biopsy specimens. Therefore, use of polymerase chain reaction (PCR) analysis can play an integral role in the definitive diagnosis of herpetic dermatitis and in the distinction of HSV-1/HSV-2 from VZV., Methods: Forty patients with skin biopsies (2004-2011) had PCR analysis performed to detect HSV-1/2 or VZV. Patient demographics, clinical impression and histopathologic characteristics were reviewed and correlated with PCR findings., Results: Overall, there was complete correlation between clinical impression, histopathology and PCR results in 21 of 40 cases. In 19 cases, clinical impression and histopathology were discrepant and in 15 of these cases PCR confirmed HSV or VZV infection. We also describe 3 cases of herpetic dermatitis without viral change that histopathologically demonstrate the pattern of a dermal hypersensitivity reaction., Conclusions: The results of this study suggest that routine use of PCR for definitive diagnosis of herpetic dermatitis should be considered when there is a clinical suspicion of herpes virus infection, even when there is a lack of specific histopathologic findings. Additionally, a dermal hypersensitivity reaction should be recognized as one histopathologic manifestation of herpes incognito., (Copyright © 2012 John Wiley & Sons A/S.)

Distal symmetrical polyneuropathy is the most common form of HIV infection-associated peripheral neuropathy and is often associated with pain. C57BL/6 (B6) mice infected with LP-BM5, a murine retroviral isolate, develop a severe immunodeficiency syndrome similar to that in humans infected with HIV-1, hence the term murine AIDS. We investigated the induction of peripheral neuropathy after LP-BM5 infection in B6 mice. Infected B6 mice, like HIV-infected humans, exhibited behavioral (increased sensitivity to mechanical and heat stimuli) and pathological (transient loss of intraepidermal nerve fibers) signs of peripheral neuropathy. The levels of viral gag RNA were significantly increased in all tissues tested, including spleen, paw skin, lumbar dorsal root ganglia, and lumbar spinal cord, postinfection (p.i.). Correlated with the development of peripheral neuropathy, the tissue levels of several cytokines, including IFN-γ, IL-1β, IL-6, and IL-12, were significantly elevated p.i. These increases had cytokine-specific and tissue-specific profiles and kinetics. Further, treatment with the antiretroviral agent zidovudine either significantly reduced or completely reversed the aforementioned behavioral, pathologic, and cytokine changes p.i. These data suggest that LP-BM5 infection is a potential mouse model of HIV-associated distal symmetrical polyneuropathy that can be used for investigating the roles of various cytokines in infection-induced neuropathic pain. Further investigation of this model could give a better understanding of, and lead to more effective treatments for, HIV infection-associated painful peripheral neuropathy.

Background: Individuals with allergies have a heightened Th2 (T helper 2) immunity, which may provide advantages in controlling tumor growth. Inverse associations have been reported among individuals with allergies and risk of brain and pancreatic cancers., Methods: We examined the relationship between allergies and risk of head and neck squamous cell carcinoma (HNSCC) in a population-based case-control study with 1,014 cases and 1,193 frequency-matched controls. Logistic regression models were used to estimate odds ratios (OR) and 95 % confidence intervals (95 % CI) controlling for age, sex, race, smoking history, alcohol consumption, and education. In addition, in a subset of the population, models were adjusted for HPV16 status., Results: Individuals with allergies had a 19 % lower risk of HNSCC (OR = 0.81, 95 % CI = 0.67-0.98). Associations with allergies were stronger for laryngeal (OR = 0.66, 95 % CI = 0.45-0.97) and oropharyngeal (OR = 0.73, 95 % CI = 0.57-0.92) cancers, while no association was observed for oral cavity cancers (OR = 0.98, 95 % CI = 0.76-1.26). History of asthma was not associated with overall HNSCC, but the association was statistically significant for oropharyngeal cancer (OR = 0.67, 95 % CI = 0.44-0.99). HPV16 status did not confound or modify the associations with allergies., Conclusions: Elevated Th2 immunity in individuals with history of allergies and asthma may reduce the risk of HNSCC. Additional research into related mechanisms may provide new insights into how to treat HNSCC., Impact: These findings may provide new insight into biological pathways that could lead to a better understanding of the etiology of this disease.

Epidemiological studies suggest that viral infections during childhood are a risk factor for the development of asthma. However, the role of virus-specific pattern recognition receptors in this process is not well defined. In the current study, we compare the effects of the inhaled viral TLR ligands polyinosinic-polycytidylic acid (TLR3) and resiquimod (TLR7/8) on sensitization to a model allergen (OVA) in a murine model. Both compounds enhance the migration, activation, and Ag-processing of myeloid dendritic cells from the lung to the draining lymph nodes comparable to the effects of LPS. Application of polyinosinic-polycytidylic acid [poly(I:C)] or LPS induces production of allergen-specific IgE and IgG1, whereas resiquimod (R848) had no effect. In addition, rechallenge of mice with OVA resulted in airway inflammation and mucus production in animals that received either poly(I:C) or LPS but not after application of R848. In summary, these results show that activation of TLR3 in combination with inhaled allergen results in induction of dendritic cell activation and migration similar to the effects of LPS. This leads to the development of allergic airway disease after allergen rechallenge, whereas mice treated with R848 did not develop allergic airway disease. These findings give further insight into the effects of stimulation of different TLRs on the development of asthma.

Purpose of Review: Information is accumulating which implicates airway inflammation resulting from respiratory viral infections, acting against a background of atopy, in both the cause and pathogenesis of atopic asthma. This review brings together the most recent publications relevant to this rapidly evolving area, particularly those focusing on underlying pathogenic mechanisms., Recent Findings: Salient findings from the recent literature include increased respiratory infection-associated symptom severity/duration and loss of asthma control in atopic relative to nonatopic children; up-regulation of FcεR1 expression on circulating monocytes/dendritic cells occurs during virus-associated atopic asthma exacerbations, providing a mechanism for transient amplification of underlying allergic airways inflammation; high potency of hRV-type C in induction of infection-associated wheeze; Th2-polarized immunity to mucosal dwelling bacteria and protection against asthma; a role for IL-15 in viral-associated airways inflammation; vitamin D and protection against infection-associated asthma exacerbations; strategies for reduction of infection-associated wheezing severity by boosting mucosal Treg cell activity via immunostimulation of the gut mucosa., Summary: Research in this area is pointing towards new rationales for development of early intervention strategies for prevention of asthma initiation and progression in childhood, based on control of respiratory infections and/or sensitization to aeroallergens.

Among other infectious agents, enteroviruses have been associated with protection against allergic diseases. The aim of the present study was to confirm these findings using a highly sensitive and specific neutralization antibody assay and to investigate whether the protective effect is related to certain enterovirus serotypes. Antibodies against 12 enterovirus serotypes were measured in 60 children who were positive for allergen-specific IgE and in 190 control children. Echoviruses seemed to be more protective than coxsackie-B-viruses and echovirus 11 had the strongest independent protective effect (P = 0.001; OR = 0.35, 95% CI: 0.18-0.67). The results support previous observations suggesting that infections by certain enterovirus types are associated with protection against IgE sensitization., (Copyright © 2011 Wiley Periodicals, Inc.)

Severe respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17(-/-) knockout mice resulted in significant inhibition of mucus production during RSV infection. RSV-infected animals treated with anti-IL-17 had reduced inflammation and decreased viral load, compared with control antibody-treated mice. Blocking IL-17 during infection resulted in significantly increased RSV-specific CD8 T cells. Factors associated with CD8 cytotoxic T lymphocytes, T-bet, IFN-γ, eomesodermin, and granzyme B were significantly up-regulated after IL-17 blockade. Additionally, in vitro analyses suggest that IL-17 directly inhibits T-bet, eomesodermin, and IFN-γ in CD8 T cells. The role of IL-17 was also investigated in RSV-induced exacerbation of allergic airway responses, in which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hepatitis A virus (HAV) usually results in asymptomatic infection or mild disease, but in a small subset of patients it can lead to severe disease and even liver failure. In this issue of the JCI, Kim et al. identify a polymorphism associated with this increased disease risk in the gene that encodes the HAV receptor--TIM1. Importantly, this TIM1 gene polymorphism protects from the development of atopic diseases in HAV-seropositive individuals.

Background: An increased prevalence of asthma/recurrent wheeze (RW), clinical allergy and allergic sensitisation up to age 13&emsp14;years has previously been reported in subjects hospitalised with respiratory syncytial virus (RSV) bronchiolitis in their first year of life compared with matched controls. A study was undertaken to examine whether these features persist into early adulthood, to report longitudinal wheeze and allergy patterns, and to see how large and small airway function relates to RSV infection and asthma., Methods: Follow-up at age 18 years was performed in 46 of 47 subjects with RSV and 92 of 93 controls. Assessments included questionnaire, clinical examination, skin prick tests, serum IgE antibodies to inhaled allergens, blood eosinophils, fraction of exhaled nitric oxide (FeNO), spirometry, multiple breath washout (lung clearance index, LCI) and dry air hyperventilation challenge., Results: Increased prevalence of asthma/RW (39% vs 9%), clinical allergy (43% vs 17%) and sensitisation to perennial allergens (41% vs 14%) were present at age 18 in the RSV cohort compared with controls. Persistent/relapsing wheeze associated with early allergic sensitisation predominated in the RSV cohort compared with controls (30% vs 1%). Spirometric function was reduced in subjects with RSV with or without current asthma, but not in asthmatic controls. LCI was linked only to current asthma, airway hyperresponsiveness and FeNO., Conclusions: Severe early RSV bronchiolitis is associated with an increased prevalence of allergic asthma persisting into early adulthood. Small airway dysfunction (LCI) is related to current asthma and airway inflammation but not to RSV bronchiolitis. Reduced spirometry after RSV may reflect airway remodelling.

Background: Data on the link between atopy and viral wheeze are limited., Aim: To evaluate the association between IgE sensitization and viral infection in wheezing children., Methods: This is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). Eighteen respiratory viral infections were studied using all available methods. A specific immunoglobulin E (IgE) sensitization for common food and aeroallergens and other atopy-related variables including total IgE, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology., Results: Atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. The number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total IgE level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13)., Conclusions: According to our data, allergic sensitization is positively linked to rhinovirus-, but not other virus-, associated wheezing and calls attention for studies to test rhinovirus-associated wheezing as a part of asthma risk indices., (© 2010 John Wiley & Sons A/S.)

Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-γ production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma.

Allergy and allergens have been implicated in asthma and it has historically been assumed that deteriorating asthma is related to allergen exposure. In the current pro/con debate some leading academics and researchers in the field consider this notion in the light of recent evidence. They conclude that allergy does not directly cause exacerbations but suggest that it may contribute to acute asthma in a different fashion. Possibilities that are proposed by the authors include specific allergy phenotypes acting as risk factors for virus-associated exacerbations or alternatively that allergy may be implicated in the blunted innate immune responses detected in asthma., (© 2010 The Authors. Respirology © 2010 Asian Pacific Society of Respirology.)

Background: We have previously shown that Epstein-Barr virus (EBV) seropositivity, at 2 years of age, was inversely related to IgE-sensitization and that this effect was enhanced when EBV is combined with cytomegalovirus (CMV) seropositivity. We hypothesize that early exposure to EBV or CMV will affect the cytokine balance in the individual., Objective: The aim of this study was to relate the cytokine profile in peripheral blood mononuclear cells (PBMC) to the EBV and CMV serostatus and IgE-sensitization in children at 2 years of age., Methods: Seventy-five children were followed prospectively from birth until 2 years of age. Their EBV and CMV serostatus was correlated to the numbers of IFN-gamma, IL-4, IL-10 and IL-12-producing PBMC following PHA stimulation in vitro. Skin prick tests and allergen-specific IgE antibodies were used to assess IgE-sensitization., Results: In the study cohort, there was an inverse association between EBV seropositivity and IgE-sensitization but not with CMV seropositivity. Following linear regression analysis, we did not detect any statistically significant associations between children with IgG antibodies against EBV at 2 years of age and the investigated cytokines. However, there was a non-significant tendency to a positive association between high numbers of all individual cytokine-producing cells and EBV seropositivity. Children who were CMV seropositive had significantly higher numbers of IFN-gamma and lower numbers of IL-4-producing cells compared with CMV negative children. There was a significant, positive association between the number of IL-4-producing cells and IgE-sensitization., Conclusion: Taken together our results indicate that infections with EBV and CMV in different ways will interact with the immune system and may protect children from developing early atopy.

The impact of respiratory viral infections on the emergence of the asthmatic phenotype is a subject of intense investigation. Most experimental studies addressing this issue have used the inert Ag OVA with controversial results. We examined the consequences of exposure to a low dose of the common aeroallergen house dust mite (HDM) during the course of an influenza A infection. First, we delineated the kinetics of the immune-inflammatory response in the lung of mice following intranasal infection with influenza A/PR8/34. Our data demonstrate a peak response during the first 10 days, with considerable albeit not complete resolution at day 39 postinfection (p.i.). At day 7 p.i., mice were exposed, intranasally, to HDM for 10 consecutive days. We observed significantly enhanced eosinophilic inflammation, an expansion in Th2 cells, enhanced HDM-specific IgE and IgG1 responses and increased mucous production. Furthermore, lung mononuclear cells produced enhanced IFN-gamma and IL-5, unchanged IL-13, and reduced IL-4. These immunologic and structural changes lead to marked lung dysfunction. This allergic phenotype occurs at a time when there is a preferential increase in plasmacytoid dendritic cells over myeloid dendritic cells, activated CD8(+) T cells, and increased IFN-gamma production, all of which have been proposed to inhibit allergic responses. In contrast, the inflammatory response elicited by HDM was reduced when exposure occurred during the resolution phase (day 40 p.i.). Interestingly, this was not associated with a reduction in sensitization. Thus, the proinflammatory environment established during an acute influenza A infection enhances Th2-polarized immunity to a low dose of HDM and precipitates marked lung dysfunction.

Background: The increase in incidence of atopic diseases (ADs) in the developed world over the past decades has been associated with reduced exposure of childhood infections., Objective: To investigate the relation between early intestinal viral infections in relation to the development of atopic symptoms (eczema, wheeze and atopic sensitization) in the first and second year(s) of life., Methods: In the KOALA Birth Cohort Study, we assessed IgG seropositivity for rota- and norovirus (GGI.1 and GGII.4) at 1 year of age. This was related to allergic sensitization [specific immunoglobulin E (IgE)] at 1 and 2 years, and parent reported eczema and wheeze in the first 2 years, using logistic regression analysis adjusted for confounders., Results: Rotavirus seropositivity (39%) was associated with an unexpected higher risk of recurrent wheeze in the first and second year of life [adjusted odds ratio (OR) 3.1 and 95% confidence intervals (CI) 1.1-9.1] and persistent and new recurrent wheeze (adjusted OR 2.7 and 95% CI 1.1-6.2). No further associations were found between intestinal viral seropositivity and atopic manifestations., Conclusion: Our data did not show a clear protection by enteric viral infections in young children on development of IgE response to allergens, but rotavirus infection in the first year was a risk factor for wheeze. However, this needs to be followed up to older ages in order to establish the true importance of intestinal viral infections and especially cumulative effects in AD aetiology. Exposure to rotavirus may offer a new and interesting focus on infant wheeze and later asthma development.

Atopic asthma pathogenesis is driven by the combined effects of airway inflammation generated during responses to viral infections and aeroallergens, and both these pathways are regulated by dendritic cells (DC) that differentiate locally from monocytic precursors. These DCs normally exhibit a sentinel phenotype characterized by active Ag sampling but attenuated presentation capability, which limits the intensity of local expression of adaptive immunity. How this tight control of airway DC functions is normally maintained, and why it breaks down in some atopics leading to immunopathological changes in airway tissues, is unknown. We postulated that signals from adjacent airway epithelial cells (AEC) contribute to regulation of local differentiation of DC. We tested this in a coculture model containing both cell types in a GM-CSF-IL-4-enriched cytokine milieu characteristic of the atopic asthmatic airway mucosa. We demonstrate that contact with AEC during DC differentiation up-regulates expression of the function-associated markers MHC class II, CD40, CD80, TLR3, and TLR4 on DCs with concomitant up-regulation of Ag uptake/processing. Moreover, the AEC-conditioned DCs displayed increased LPS responsiveness evidenced by higher production of IL-12, IL-6, IL-10, and TNF-alpha. The Th2 memory-activating properties of AEC-conditioned DCs were also selectively attenuated. Data from microarray and blocking experiments implicate AEC-derived type 1 IFNs and IL-6 in modulation of DC differentiation. Collectively, these findings suggest that resting AECs modulate local DC differentiation to optimize antimicrobial defenses in the airways and in the process down-modulate capacity for expression of potentially damaging Th2 immunity.

Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.

CC chemokine receptor 1 (CCR1) is found on a variety of cells in the immune system and has been shown to play an important role in the host response to pathogens. These studies used a murine model of virus-induced exacerbation of allergic airway disease to examine the role of CCR1 on T cells associated with immune responses taking place in the lung. Lungs of virally exacerbated allergic animals contained elevated levels of interferon-gamma and interleukin-13 and increased levels of CCR1 ligands CCL3 and CCL5. CCR1 expression on T cells was increased in virally exacerbated allergic animals over the level observed in mice sensitized to allergen or exposed to viral infection alone. Using mice deficient for CCR1, we observed decreased airway hyperreactivity and Th2 cytokine production from CD4(+) T cells when this receptor was absent. Transfer studies demonstrated that neither CD4(+) nor CD8(+) T cells from CCR1(-/-) mice migrated to the lymph node as efficiently as wild-type T cells. Intracellular cytokine staining in wild-type mice revealed that CCR1(+) CD4(+) and CD8(+) T cells are associated with interleukin-13 production. Thus, these studies identify CCR1 as a potential target for alleviating T-cell accumulation during exacerbation of asthmatic disease.

Hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms, such as high fever, lymphadenopathy and hepatosplenomegaly. Half of the patients reported died of hemophagocytic syndrome or lymphocyte proliferative disorders. Clinical and laboratory studies have revealed that HMB occurs in association with natural killer (NK) cell lymphocytosis related to chronic Epstein-Barr virus (EBV) infection. Recent studies have clarified the unique pathogenic mechanism of this mysterious disease, and demonstrated the close relationship between HMB and EBV-carrying NK cell lymphocytosis; i.e., CD4(+) T cells from the patients markedly responded to mosquito salivary gland extracts, and the CD4(+) T cells stimulated by mosquito bites may play a key role in the development of HMB and NK cell oncogenesis via the induction of EBV reactivation and EBV-oncogene expression, respectively.

Respiratory infections by bacteria and viruses often trigger symptoms of asthma in both adults and children. This observation and subsequent mechanistic studies have demonstrated important interactions among allergens, microbes and the atopic host. The mechanisms responsible for microbe-induced asthma exacerbations are only incompletely understood. A focal point of current research is the inflammatory response of the host following an encounter with a pathogenic microbe, including variations in chemokine and cytokine production and resulting in changes in bronchial hyper-responsiveness and lung function. Direct bronchial infection, exposure of nerves with resulting neurogenic inflammation and a deviated host immune response are among the mechanisms underlying these functional disorders. Lately, suboptimal innate immune responses, expressed as defective interferon production, have gained attention as they might be amenable to intervention. This review describes the suggested mechanisms involved in the complex interactions between 'asthmagenic' microbes, the immune system and atopy, based on in-vitro and in-vivo experimental models and epidemiological evidence. In addition, it provides a synopsis of potential therapeutic strategies either directly against the microorganisms or in respect to the associated inflammation.

Based on the hypothesis that respiratory syncytial virus (RSV) sG protein causes allergy in patients, it is suggested that treatment of RSV patients with antagonists of IL-4 and FKN early in infection will prevent the increased level of IL-4 in the serum. Together with CpG ODNs that induce Toll-like receptor 9(+) (TLR9(+)) plasmacytoid dendritic cells to release type I IFN-alpha and -beta will reactivate the inhibited Th1 cells and the antiviral cytotoxic T leukocytes. In addition, binding of CpG ODNs to TLR9(+) B cells will stop IgE synthesis and antiviral IgG and IgA will continue. Together, the IL-4 and FKN antagonists and CpG ODNs reactivate the adaptive immune response to clear the virus and protect the patient from a second RSV infection. It is also suggested that the less-pathogenic RSV strain Long may be a candidate for vaccine development after deletion of the FKN and superantigen domains from the G gene.

About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact might confer protection against the development of allergic illnesses. The so-called hygiene hypothesis has ever since undergone numerous more or less subtle modifications by various researchers in the fields of epidemiology, clinical science, and immunology. Three major tracts have developed exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and the effect of both on underlying responses of the innate and adaptive immunity. To date, a truly unifying concept has not yet emerged, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures becomes apparent. These influences are discussed as determinants for a number of complex allergic illnesses in this review, while we attempt to pay attention to the importance of different phenotypes, namely of the asthma syndrome. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future.

Background: Evidence of the influence of pathogen exposure on the development of atopy and atopic disease is not unequivocal. We investigated the association between markers of infections and occurrence of atopy among adults in eastern Finland and western Russia, two adjacent areas with profound differences in living conditions and lifestyles., Methods: Randomly selected adults aged 25-54 years from Finland (n = 790) and from Russia (n = 387) participated in the study. Skin prick tests were performed to 11 common airborne allergens, and at least one positive prick reaction was considered to indicate atopy. Antibodies to different pathogens including hepatitis A virus (HAV), Helicobacter pylori, Toxoplasma gondii, herpes simplex virus (HSV), Chlamydia pneumoniae and the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were measured., Results: In Finland 34.3% and in Russia 23.3% of the study population was atopic (p < 0.001). Seroprevalences to all these pathogens were significantly higher among the Russians. In multivariate logistic regression analysis, only H. pylori was inversely associated with atopy in Russia. A further stepwise analysis revealed that H. pylori alone can explain 32% of the difference in atopy between the countries, and T. gondii, A. actinomycetemcomitans, HSV and C. pneumoniae had a slightly additive effect, whereas, unexpectedly, seropositivity to HAV and, to a lesser extent, P. gingivalis had an opposite effect. The net result of the stepwise analysis showed that 44% of the difference in atopy between the countries could be explained by seropositivity to these seven pathogens., Conclusions: Seropositivity to select pathogens, particularly to H. pylori, could explain a substantial part of the difference in atopy prevalence between Finland and Russia. Exposure to HAV was not associated with protection against atopy in this adult population.

Epidemiological and experimental data suggest that infections or the exposure to non-pathogenic bacteria protect individuals from developing some autoimmune and atopic disorders. Generally, these findings support the 'hygiene hypothesis', which attributes the rise in autoimmune and atopic disorders to a lack of infections that normally keep the immune system balanced by inducing immunoregulation. The suspected key players for infection-mediated immune suppression of autoimmunity and atopy are T regulatory cells and dendritic cells, which produce immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-beta. However, there is also solid evidence suggesting that infections can exacerbate or even directly cause autoimmune and allergic disorders. In this Review, we discuss which type of infections induce, exacerbate or inhibit allergic and autoimmune diseases and point at infection-induced immunological mechanisms influencing the development of autoimmunity and atopy.