Local mucosal immunoglobulin E production: does allergy exist in non‐allergic rhinitis?

In this review, we critically evaluate the evidence for local IgE production in allergic rhinitis mucosa and the concept of local allergy in non-atopic idiopathic rhinitis. Significantly, fewer studies have focused on the disease pathways associated with non-allergic rhinitis compared with their allergic counterparts. Recently, there's been a revival of the hypothesis concerning the existence of local tissue-specific allergic disease confined to the nasal mucosa of some systemically non-atopic rhinitis subjects. Providing the evidence for local mucosal IgE production in allergic rhinitis is a pre-requisite to reviewing its existence in non-allergic rhinitis. In addition, practical and theoretical approaches useful in the detection of allergy in non-allergic rhinitis will be discussed. Furthermore, successful therapeutic regimens used in the treatment of non-allergic rhinitis will be examined as these could provide an insight into the underlying pathophysiology of this common but poorly understood disease.     

Cultural adaptation is associated with atopy and wheezing among children of Turkish origin living in Germany

BACKGROUND: Turkish children have been found to suffer less from atopic diseases than their German peers. The underlying causes are unknown. OBJECTIVE: To evaluate rates of sensitization and atopic disease among children in Germany with German or Turkish ethnicity and different degrees of cultural adaptation. METHODS: This was a cross-sectional study. The setting was screening for school eligibility in an inner-city district of Berlin/Germany. The participants were preschool children born in Germany with double German or double Turkish parental citizenship. Cultural adaptation of Turkish children was assessed by the language parents used to communicate with their child: only Turkish (n = 60, group A); Turkish and German (n = 269, group B); and only German (n = 103, group C). Group D contained children from German parents (n = 383). The main outcome measures were specific sensitization to common aeroallergens (CAP-System, Pharmacia Phadiatop >or= 0.35 kU/L), and lifetime and 1-year prevalences of allergic disease symptoms (ISAAC questionnaire in German and Turkish, Mantel-Haenszel test for trend). RESULTS: Sensitization rates for groups A, B, C and D were 8.0%, 6.8%, 18.9% and 18.3%, respectively (P = 0.004). The corresponding prevalence rates for wheeze ever were 6.7%, 9.3%, 12.6% and 21.3% (P < 0.001), wheeze in the past year 3.3%, 3.7%, 9.7% and 10.2% (P = 0.001), itchy rash ever 3.3%, 6.3%, 8.7% and 13.7% (P < 0.001), itchy rash in the past year 1.7%, 3.7%, 4.9% and 9.5% (P < 0.001), respectively. No significant differences were found for hay fever symptoms. CONCLUSIONS: Higher cultural adaptation is correlated with higher rates of allergic sensitization and disease among children of Turkish origin living in Berlin. This correlation suggests that environmental rather than genetic differences are responsible for the differences observed.     

Patch test reactions in atopic patients

Patch testing was carried out in 851 atopic patients; 181 atopic dermatitis (AD) patients were additionally tested with 50% dilutions of the test substances. The occurrence of allergic and irritant reactions was frequent, being 57% and 33% for AD patients aged 28-41 years and 19-27 years, respectively. Among age-matched allergic rhinitis (AR)/allergic conjunctivitis (AC) or asthma (A) patients, the number of allergic reactions varied from 25 to 30%, and for irritant reactions was 24%. In all groups, nickel, fragrance-mix, balsam of Peru and neomycin were the commonest allergens. Contact allergy to ingredients of topical medicaments was common among AD patients and patients with severe and long-lasting dermatitis were most frequently sensitized. However, sensitivity to multiple substances was not common among those patients. The number of irritant reactions was considerable, but 50% dilution of the test substances did not solve the problem.     

IgE and atopy in perinatally HIV-infected children

Elevated serum immunoglobulin E (IgE) and increased prevalence of atopy is reported in patients infected with human immunodeficiency virus (HIV). The elevated serum IgE may be attributed to polyclonal stimulation of B cells or IgE production against allergens, viruses, fungi and bacteria. This study investigates the prevalence of atopy in perinatally HIV-infected children, and the relationships between serum IgE (and other serum immunoglobulins) with atopy, CD4+ cell count and HIV-disease stage. Serum immunoglobulin levels, epicutaneous skin test for common aeroallergens, clinical Centers for Disease Control and Prevention (CDC) classification, CD4+ cell counts and allergy history were extracted from the charts of perinatally HIV-infected children on highly active antiretroviral therapy. The prevalence of atopy (52%) and the pattern of aeroallergen sensitivity were comparable with the US pediatric population. Serum IgE levels did not correlate with clinical disease stage. However, in non-atopic patients, serum IgE levels increased with disease progression (p = 0.02). There was an inverse relationship between the prevalence of elevated serum IgE levels and atopy with progression of disease (p = 0.019). Serum IgE did not correlate with atopy, CD4+ cell count, or duration of HIV infection or levels of serum immunoglobulins. This is the first study to show no increased prevalence of atopy in perinatally HIV-infected children compared with the general population. In advanced stages of HIV, elevated serum IgE may be specific for antigens other than those known as allergens.     

Polyclonal and allergen-induced cytokine responses in children with elevated immunoglobulin E but no atopic disease

BACKGROUND: Reduced Th1 and elevated Th2 cytokine responses are considered to be a principal mechanism in the generation of the inflammation leading to the manifestations of atopic disease in the skin of atopic dermatitis and in the airways of asthma. If reduced Th1 and elevated Th2 responses are principal determinants of the manifestation of atopic disease it might be expected that subjects with established disease would exhibit differences in their cytokine profiles as compared with atopic patients without clinical disease. OBJECTIVE: To determine whether asymptomatic atopic children exhibit a cytokine imbalance similar to that seen in patients with established atopic disease or if they behave like non-atopic controls. Cytokine responses in a group of children with elevated IgE but no clinical manifestations of disease, atopic children with established disease and non-atopic controls were compared. METHODS: We examined allergen-induced (house dust mite, HDM, rye grass pollen and RYE) cytokine responses in parallel with polyclonal (staphylococcal enterotoxin B, SEB) cytokine responses in a group of children with elevated serum IgE levels without current or past evidence of atopic disease (median age 6.6 years) and compared these with a non-atopic control group (median age 6.5 years) and a group of children with atopic disease (median age 6.7 years). RESULTS: Symptomatic atopic children had reduced SEB-induced IFN-gamma and increased SEB-induced IL-4 and IL-5 as compared with non-atopic controls. In contrast, SEB-induced IFN-gamma, IL-4 and IL-5 production in asymptomatic atopics was not significantly different from the non-atopic control subjects. Allergen-induced Th1 (IFN-gamma) and Th2 (IL-5 and IL-13) cytokine production was increased in both symptomatic atopics and asymptomatic atopics when compared with non-atopic controls. CONCLUSION: The defect in polyclonally induced IFN-gamma production was associated with the clinical manifestation of atopic disease but not the atopic stateper se. This suggests that the global reduction in IFN-gamma is the key determinant of the development of overt atopic disease. In contrast, elevated allergen-induced Th2 cytokine responses in children related to the atopic state per se irrespective of the presence of clinical atopic disease.     

Does previous infection protect against atopic eczema and recurrent wheeze ininfancy?

BACKGROUND: Frequent infection in infancy and early childhood has been hypothesized to explain the low prevalence of asthma and other atopic disease among children in developing countries (the so-called 'hygiene hypothesis'), but the low prevalence in Eastern Europe remains unexplained. OBJECTIVE: To test the hygiene hypothesis in the Republic of Belarus by examining the relationship between gastrointestinal (GI) and respiratory infection and two potentially atopic outcomes in the first 12 months of life: atopic eczema and recurrent wheeze. METHODS; We carried out two case-control studies nested within a large (n=17 046) randomized trial in Belarus, with cases defined as (1) first occurrence of atopic eczema (n=819) and (2) second episode of wheezing (n=112). Incidence density sampling was used to select four matched controls born within 1 month at the same hospital as the case. Exposure was defined as one or more episodes of GI or respiratory infection (examined separately) with onset >7 days before onset of the case's atopic outcome. Analyses controlled for family atopic history, duration of exclusive breastfeeding, sex, birth weight, maternal education, and (for recurrent wheeze) maternal smoking. RESULTS: For atopic eczema, prior GI infection occurred in 7.4% of cases vs. 6.0% of controls [adjusted OR=1.27 (0.94-1.72)] and prior respiratory infection in 35.2% vs. 32.6% [adjusted OR=1.14 (95% CI=0.94-1.37)]. For recurrent wheeze, prior GI infection occurred in 9.8% of cases vs. 7.4% of controls [adjusted OR=1.30 (0.60-2.82)]. CONCLUSION: Our results do not support the hypothesis that infection protects against atopic eczema or recurrent wheezing in the first 12 months of life.     

Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV ₁, MEF₂₅ and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.     

Role of interleukin-17F in chronic inflammatory and allergic lung disease

IL-17 family members belong to a distinct category of cytokines that coordinate local tissue inflammation by inducing the release of pro-inflammatory and neutrophil-mobilizing cytokines. The importance of the IL-17 family in inflammatory and autoimmune disease is becoming increasingly apparent. IL-17F is a recently discovered member of the IL-17 family that has a number of biological activities through induction of various cytokines, chemokines, and mediators. IL-17A, the founding member of the IL-17 family, and IL-17F are produced by several inflammatory cells, including activated T cells, in response to infectious and antigenic stimuli. Overexpression of IL-17A or IL-17F in the lungs results in induction of CXC chemokines and neutrophil recruitment. In a case-control study of 1125 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL17F gene was shown to be associated with asthma and chronic obstructive pulmonary disease (COPD). Functionally, this variant failed to induce cytokines and chemokines, and interestingly, was able to antagonize the activity of wild-type IL-17F. These results provide an experimental basis for the observed genetic association with chronic inflammatory lung diseases, and also suggest the potential therapeutic utility of this antagonistic variant of IL-17F. Given that asthma and COPD are complex diseases involving a number of genetic and environmental factors, the genetic impact of IL-17F H161R with regard to the development of chronic airway inflammation likely varies among individuals with different genetic backgrounds and environmental exposures.     

Characterization of T cell epitopes in αs1-casein in cow''s milk allergic, atopic and non-atopic children

BACKGROUND: One to two percent of infants suffer from IgE-mediated allergic reactions against cow's milk proteins. Most children develop clinical tolerance, but approximately 15% are still allergic by the age of 10 years. Little is known about the T cell epitopes in individual cow's milk protein in relation to allergy and tolerance. OBJECTIVE: To identify T cell epitopes in alphas1-casein, the most abundant milk protein, and to investigate T cell responses toward these epitopes in allergic, atopic and non-atopic children. METHODS: Allergen-specific T cell lines (TCLs) were derived from peripheral blood mononuclear cells of 11 cow's milk allergic, nine atopic and nine non-atopic children. T cell responses were measured to alphas1-casein and to overlapping peptides (18-mers), spanning the alphas1-casein molecule. Proliferation was determined by incorporation of (3)H-thymidine, and cytokine production (IL-10, IL-13 and IFN-gamma) was measured by ELISA. RESULTS: Four main regions (amino acid (AA) residues 43-66, 73-96, 91-114 and 127-180) in the alphas1-casein molecule were immunogenic to T cells, among which the AA residues 133-156 spanned the immunodominant part. Only subtle differences were found in peptide recognition between the subject groups. Some of the peptides induced slightly Th1- or Th2-skewed cytokine responses. The increased levels of IL-10 in response to alphas1-casein observed in TCLs from atopic children appeared not to be linked to recognition of specific IL-10-inducing epitopes. CONCLUSIONS: The immunodominant sequence in alphas1-casein is spanned by AA residues 133-156. Tolerance towards alphas1-casein in atopic children may be mediated by an overall induction of IL-10 and not by recognition of certain T cell epitopes. The identified T cell epitopes in children with cow's milk allergy may be useful targets in developing peptide immunotherapy.