Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and have been shown to be major predisposing factors for atopic dermatitis (AD). Approximately 40 loss-of-function FLG mutations have been identified in patients with ichthyosis vulgaris (IV) and/or atopic dermatitis (AD) in Europe and Asia. Major differences exist in the spectra of FLG mutations observed between different ancestral groups. Notably, prevalent FLG mutations are distinct between European and Asian populations. Many cohort studies on FLG mutations in AD have revealed that approximately 25-50% of AD patients harbour filaggrin mutations as a predisposing factor. In addition, FLG mutations are significantly associated with AD-associated asthma. The risk for developing allergic rhinitis is also significantly higher with a FLG mutation, both with and without accompanying AD. Recent studies have hypothesized that skin barrier defects caused by FLG mutations allows allergens to penetrate the epidermis and to interact with antigen-presenting cells, leading to the development of atopic disorders including asthma. The restoration of skin barrier function seems a feasible and promising strategy for prophylactic treatment of AD patients with FLG mutations.

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The concept of "atopic march" has been well appreciated both by physicians and by dermatologists; eczema (atopic dermatitis) often precedes the development of airway diseases such as asthma and allergic rhinitis in atopic subjects. However, the underlying mechanisms for atopic march are less elucidated. It has been conceived that genetic susceptibility to atopy determines the phenotype of allergic diseases progressive from the skin to the airways, but recent discovery of filaggrin gene mutations that disturb the barrier function of the skin in patients with asthma and eczema now suggests the crucial role of epicutaneous sensitization as a precursory event for the development of asthma. In the present review, we describe updated genetic and immunological evidences that suggest the relationship between skin barrier-related molecules and the pathology of asthma.

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Antimicrobial Peptides and Proteins (AMPs) represent effector molecules of the innate defense system in all organisms. AMPs are either constitutively or inducibly produced mainly by various epithelial cells, including keratinocytes. This report reviews our current knowledge about the major yet known keratinocyte-derived AMPs, its role in healthy skin and atopic dermatitis.

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Skin barrier dysfunction has emerged as a critical driving force in the initiation and exacerbation of atopic dermatitis and the "atopic march" in allergic diseases. The genetically determined barrier deficiency and barrier disruption by environmental and endogenous proteases in skin and epithelium are considered to increase the risk of sensitization to allergens and contribute to the exacerbation of allergic diseases. Sources of allergens such as mites, cockroaches, fungi, and pollen, produce or contain proteases, which are frequently themselves allergens. Staphylococcus aureus, which heavily colonizes the lesions of atopic dermatitis patients and is known to trigger a worsening of the disease, also produces extracellular proteases. Environmental proteases can cause barrier breakdown in the skin, not only in the epithelium, and stimulate various types of cells through IgE-independent mechanisms. Endogenous protease inhibitors control the functions of environmental and endogenous proteases. In this review, we focus on the barrier dysfunction caused by environmental proteases and roles of endogenous protease inhibitors in the pathogenesis of allergic diseases. Additionally, we examine the subsequent innate response to Th2-skewed adaptive immune reactions.

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Background: Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite.
Methods: We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC).
Results:
1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts.
2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects.
3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group.
4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva.
Conclusions: In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

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Background: Allergen-specific immunotherapy (SIT) is currently used for several allergic disorders and IL-10-producing regulatory T cells (Tr1) induced by SIT suppress allergic reactions. We investigated the relation between IL-10 production and acquiring allergy.
Methods: A prospective study was undertaken to evaluate the effect of SIT on IL-10 production in T cells and other cell fractions in children with pollinosis. In addition, blood samples were collected from non-allergic healthy controls and patients with pollinosis to compare the levels of IL-10 production. PBMC were cultured with pollen peptides or control allergens, and the IL-10 production from monocyte and CD4 T cell was analyzed.
Results: Monocytes and CD4 T cells from SIT group of patients produced high levels of IL-10, suggesting that the induction of IL-10 is essential for inducing T cell tolerance. IL-10 production from monocytes and T cells was significantly increased in non-allergic controls compared to patients with pollinosis. This high IL-10 production was observed even when PBMC were stimulated with antigens other than pollen peptides.
Conclusions: IL-10 is critical for induction of specific T cell tolerance, and increased production of IL-10 by monocytes and T cells during inflammatory responses or after SIT may influence effector cells in allergy. Present data implicates that the low productivity of IL-10 by monocytes and T cells is closely related with sensitivity to multiple allergens, and resistance to allergic diseases. Augmentation of constitutive IL-10 production from immune system is a potential therapeutic approach for allergic disorders.

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Background: In children, exhaled nitric oxide (eNO) is usually confounded by factors such as age and height. We evaluated the relationship between eNO and lung function by minimizing the effects of aging and height.
Methods: In Study 1, the subjects comprised 738 elementary school children and junior high school children (aged 6 to 15 years, 366 males and 372 females). They were divided into two groups according to age (6-10 years and 11-15 years). A height range was determined by a histogram of height in each group. In Study 2, lung function, respiratory resistance and eNO level were measured in age- and height-limited groups.
Results: In Study 1, total of 148 younger children ranging in height from 120 to 130cm and 180 older children ranging in height from 148 to 158cm participated in Study 2. The level of eNO among asthmatic children was higher than that of normal children in both the younger and the older groups. The decrease in forced expiratory volume in 1 second (FEV₁) and other parameters of central airway resistance did not correlate with the eNO level. However, the small airway parameters of MMEF and V₂₅/HT in older asthmatic children, and V₂₅/HT and R₅-R₂₀ in younger asthmatic children inversely correlated with eNO.
Conclusions: Our data suggest that eNO level inversely correlates with small airway narrowing, and airway inflammation has a significant effect on small airway lung function in asthmatic school children.

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Background: Oral allergy syndrome resulted from plant-derived foods is frequent among adults. Allergy to melon (cucumis melo) is one of the most frequent fruit allergies in Iran. Three different major allergens have been found in Cucumis melo that Cuc m 1 (cucumisin) has been identified as the major allergen of melon. Cucumisin is an alkaline serine protease that it is found as a 78kDa protein in precursor form. The aim of this study was production of recombinant Cuc m 1 in Escherichia coli (E. coli) cells and characterization of its allergenicity property.
Methods: Production of recombinant Cuc m 1 was carried out by cDNA cloning technique into the pET32b(+) vector using specific primers designed based on cucumisin nucleotide sequence available in Genebank database, cucumisin encoding gene and directional cloning method. Cloned plasmid into E. coli TOP10 was transformed into E. coli BL21 and expression of the protein was induced by IPTG. The recombinant protein was purified via Ni-NTA affinity chromatography using histidine tag in recombinant protein. IgE binding of this protein was assessed by IgE-immunoblotting, ELISA and inhibition ELISA.
Results: The directional cloning was resulted in expression of a fusion Cuc m 1. Immunoblotting with sera of patients allergic to melon showed strong reactivity with purified protein band. Inhibition assays demonstrated that purified rCuc m 1 could be the same with natural form of Cuc m 1 in total extract.
Conclusions: In the present study, we have provided a functional recombinant cucumisin allergen, rCuc m 1 with 86kDa, which may be used as a standard allergen for clinical diagnosis and study of allergy to melon.

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Background: Among the gramineae species, orchard grass is a typical causative pollen that provokes seasonal rhinitis. The purpose of this study was to examine the protective efficacy of epinastine hydrochloride for signs and symptoms caused by repeated nasal provocation with discs containing orchard grass pollen.
Methods: A single-dose, placebo-controlled, double-blind, crossover clinical study was conducted in subjects with orchard grass pollinosis. The pollen challenge was conducted with the use of provocation discs containing orchard grass pollen.
Results: Epinastine hydrochloride suppressed nasal symptoms caused by nasal provocation tests using orchard grass pollen discs. Among the nasal symptoms, the number of sneezing was significantly inhibited 30 minutes and 60 minutes after the administration of epinastine hydrochloride, as compared with placebo. There were no adverse reactions to the study drugs.
Conclusions: Our results suggest that nasal provocation tests with discs containing orchard grass pollen is a useful method for evaluating the onset of action of antiallergic drugs. As compared with placebo, epinastine hydrochloride decreased early-phase sneezing and the total nasal symptom score after repeated nasal provocations with orchard grass pollen discs.

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Background: Angiogenesis is one pathogenesis of allergic airway disease.
Methods: A potent angiogenic factor is platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP) in the field of cancer-associated research. Vascular endothelial growth factor (VEGF) is another representative angiogenic factor. Both factors were added to the culture system of human peripheral blood mononuclear cells (PBMC) with IL-4 and anti-CD40 monoclonal antibody (mAb). Total IgE levels in the supernatants and signal transduction of stimulated PBMC were evaluated.
Results: Addition of PD-ECGF enhances in vitro IgE production by PBMC in the presence of IL-4 and anti-CD40 mAb, but VEGF does not enhance IgE production. Although PD-ECGF catalyzes the reversible phosphorolysis of thymidine to 2-deoxy-D-ribose-1-phosphate (2DDR), treatment of 2DDR has no effect on IgE production by human PBMC. Both IL-4 and anti-CD40 mAb induce PD-ECGF by human PBMC. Thymidine phosphorylase inhibitor (TPI), 5-chloro-6-[1- (2-iminopyrrolidinyl) methyl] uracil hydrochloride reduce IgE production via blocking of STAT6- phosphorylation.
Conclusions: Taken together, these results suggest TP involvement in the enhancement of IgE production and suggest that TPI is a novel strategy against IgE-related allergic disease.

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Background: Seasonal allergic rhinitis (SAR) to Japanese cedar (Cryptomeria japonica; JC) is an IgE-mediated type I allergy affecting the nasal mucosa. However, the molecular mechanisms that underlie SAR are only partially understood. The aim of the study was to identify novel genes related to SAR during natural exposure to pollens, by using microarray analysis.
Methods: Subjects were 32 SAR patients and 25 controls. Total RNA was extracted from CD4⁺ T cells isolated from peripheral blood mononuclear cells and subjected to microarray analysis with Illumina Human Ref8 BeadChip arrays. The Mann-Whitney test was performed to identify genes whose expression was altered during allergen exposure. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed on samples collected from SAR patients and controls to verify the microarray results.
Results: Microarray analysis showed that the expression of 3 genes was significantly altered during allergen exposure. Among these 3 genes, the expression of interleukin 17 receptor beta (IL17RB) was confirmed to be upregulated in SAR patients compared to that of the IL17RB gene in healthy, non-allergic controls. The average fold change of IL17RB expression in the real-time RT-PCR experiment was 3.9 (P = 0.003).
Conclusions: The present study identified upregulation of IL17RB during natural allergen exposure in patients with SAR, which may further elucidate the molecular mechanisms underlying SAR.

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Background: Microscopic polyangiitis is a vasculitic disease that may result in a pulmonary renal syndrome. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis is strongly associated with infection.
Case Summary: We describe a case of microscopic polyangiitis that developed in a patient with MPO-ANCA positive pulmonary fibrosis following infection with mycoplasma. A renal biopsy was undertaken following the detection of microscopic hematuria during follow-up but no abnormal findings were evident. The MPO-ANCA titer increased following infection with mycoplasma pneumonia and a second renal biopsy demonstrated crescentic glomerulonephritis. The degree of pulmonary fibrosis was unaffected.
Discussion: The present case suggests that the mycoplasma infection triggered the elevation of MPO-ANCA titer and provoked glomerulonephritis in a patient with MPO-ANCA positive IPF. This case indicates the importance of testing for MPO-ANCA at the time of initial diagnosis, performing urinalysis and examining the urine sediment during follow-up and being alert to the potential onset of vasculitis in cases of pulmonary fibrosis.

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A 13-year-old girl who had had pollinosis since the age of eight began to experience itching of the ears and vomiting after eating fresh fruits such as peach, apple and watermelon. This occurred at 10 years of age. The girl displayed positive reactions to six kinds of pollens, eleven kinds of fruits, numerous vegetables and to recombinant: rBet v2 present in specific IgE antibodies. She also reacted positively to several pollens, fruits and rBet v2 in the skin prick test. In the component-resolved diagnosis (CRD) using microarray technology, she also tested positive for profilin, a pan-allergen among plants. It is reported that profilin cross-reacts between pollen, fruits, vegetables and latex. From these results, we concluded that the allergic reactions to multiple kinds of foodstuff and pollens observed in this subject were due to cross-reactivity induced by profilin. Our results demonstrate that CRD by microarray is a reliable test in the diagnosis of PFAS.

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Background: It has been suggested that gene-environmental interactions play crucial roles in the development of allergy, especially in early life. Analysis of twin cases may provide novel insights into the pathogenesis and pathophysiology of allergy. Though several studies have indicated the importance of a genetic contribution to the expression of allergic diseases based on twin analyses, very few data are available regarding twins with Food Protein-Induced Gastrointestinal Syndrome (FPIGS). Two pairs of identical and fraternal twins with FPIGS are presented.
Case Summary: The twins were born with no abnormalities and fed breast milk and supplemental formula. The identical twins developed vomiting and bloody stool simultaneously. The fraternal twins developed prolonged vomiting and loose stools at different times. Since their symptoms disappeared with when formula feeding was stopped, the symptoms were thought to indicate the presence of an allergy to cow's milk. The clinical symptoms and laboratory findings of the four patients were highly suggestive of FPIGS. The identical and fraternal twins showed very similar symptoms, including their onset and clinical courses. However, a substantial clinical disparity existed in the clinical features of the two pairs of twins.
Discussion: Comparisons of the twins' similarities and disparities suggest a profound genetic effect on the patients' clinical features, along with individual environmental factors. The prevalence of FPIGS is increasing, and it is now a major topic of public concern in Japan. Further accumulation of data on twins with FPIGS is needed to clarify the genetic contributions to this disease.

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