Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease with unique and characteristic features. In 1994, the responsible gene for WAS, the WASP gene on X-chromosome, was identified. Since then, renewed clinical and basic researches of WAS have started and remarkably developed. I will comment on recent progress in the clinical and basic researches of WAS, including some topics reported by our and other groups.

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Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi. Atopic manifestations include atopic dermatitis-like skin lesion and extremely high serum IgE levels. Most of the extracellular bacterial infections are caused by Staphylococcus aureus, which is associated with milder inflammation compared to normal. Recent studies have revealed that the most cases of the HIES are caused by dominant negative mutations in STAT3 gene. Cutaneous manifestations of HIES includes newborn rash, eczematoid dermatitis, cold abscesses, mucocutaneous candidiasis, and coarse texture of the facial skin. Impaired Th17 cell development due to the defective IL-6 signaling in T cells and impaired induced regulatory T (iTreg) cell generation due to defective IL-10 signaling in dendritic cells may, at least in part, account for the cutaneous pathology of HIES.

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Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio-like rash, especially in winter. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint contractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one infant case in Wakayama. However, more cases are expected to be added in the near future. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the β5i subunit of immunoproteasome, has been identified to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally.

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Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized according to its various manifestations, which include ectodermal dysplasia, vascular anomalies, osteopetrosis, and diverse immunological abnormalities such as susceptibility to pathogens, impaired antibody responses to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome, impaired natural killer cell cytotoxicity, and autoimmune diseases. Two genes responsible for EDA-ID have been identified: nuclear factor-κB (NF-κB) essential modulator (NEMO) for X-linked EDA-ID (XL-EDA-ID) and IκBα for autosomal-dominant EDA-ID (AD-EDA-ID). Both genes are involved in NF-κB activation, such that mutations or related defects cause impaired NF-κB signaling. In particular, NEMO mutations are scattered across the entire NEMO gene in XL-EDA-ID patients, which explains the broad spectrum of clinical manifestations and the difficulties associated with making a diagnosis. In this review, we focus on the pathophysiology of EDA-ID and different diagnostic strategies, which will be beneficial for early diagnosis and appropriate treatment.

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Tulobuterol patch (Hokunalin^TM Tape), which contains a β₂-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. This drug delivery system ensures that the time at which the peak drug concentration in the blood is reached coincides with the morning dip in respiratory function. The use of the patch also prevents excessive increase in blood drug concentrations, thereby reducing the incidence of systemic adverse reactions. Since 1998, when it was first approved in Japan and worldwide, the tulobuterol patch has been used widely in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD), and evidence collected since it was approved has confirmed its clinical efficacy and safety. Because the patch is easy to use and requires only once-daily application, treatment adherence of patients using the patch is good. In this article, we discuss the rationale behind the development of the tulobuterol patch, evaluate data on its clinical efficacy and safety in the treatment of asthma and COPD, and examine the treatment adherence in individuals using the patch.

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Atopic dermatitis (AD) is a common, chronic or chronically relapsing, multifactorial skin disease that mainly occurs in children but affects also adults. AD usually begins early in life and often concerns people with a personal or family history of asthma and allergic rhinitis. AD is characterized by eczematous changes in the epidermis and originates from a late, T-cell mediated reaction associated to the formation and production of memory T-cell of TH2 type, occurrence of homing receptor at skin level and cutaneous lymphocyte-associated (CLA) antigens. Extrinsic or allergic AD, but not intrinsic AD, shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens. A pivotal role in the pathogenesis of AD is played by filaggrin, a protein contained in the granular layer of the epidermis regulating the aggregation of keratin filaments. Mutation in the filaggrin gene causes decreased barrier function of the corny layers of the epidermis. This favours the enter through the skin of environmental allergens, especially the house dust mite, that further facilitates such entering by the proteolytic activity of its major allergen Der p 1. In fact, recent advances suggest that the dust mite, more than foods, is the major cause of allergic AD. As far as the causal diagnosis of AD is concerned, there is notable evidence supporting the capacity of the atopy patch test (APT) to reproduce the pathophysiologic events of AD. This makes APT a valuable diagnostic tool for AD.

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Background: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear.
Methods: MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured.
Results: Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes.
Conclusions: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.

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Background: Angioedema with eosinophilia (AE) is mostly reported in Japanese patients, and only as case reports. In this study, we aimed to determine how prevalent AE cases appear, the characteristic features and the course of AE, and to evaluate whether corticosteroid therapy for AE is necessary or not.
Methods: The patients whose blood samples showed an eosinophil count of ≥2,000/μL, among the samples tested for blood cell counts and differential counts between January 2006 and December 2010, in Japanese Red Cross Medical Center, were firstly included. Among these, patients with AE were extracted.
Results: All of the 11 patients were Japanese young females. One patient with arthralgia showed radioisotope accumulation in the joints by bone scintigraphy. The peak peripheral blood eosinophil count was 7,839 ± 6,008 (2,130-23,170)/μL after visiting our hospital. An increase in white blood cell count was only due to an increase in eosinophil count. Serum C-reactive protein and IgE levels remained almost normal. Peripheral blood eosinophil count decreased steadily for 8 weeks, regardless of corticosteroid use. Edema in all of the patients and arthralgia in 6 patients improved within 12 weeks. As far as followed, none of the patients had a recurrence of AE.
Conclusions: AE developed in Japanese young females and likely showed a single course. In AE, the count of eosinophil of 10⁴/μL was observed. Only eosinophil count increased among leukocyte series. Serum C-reactive protein and IgE levels remained almost normal. The eosinophil count in AE patients will return to the normal level within 8 weeks even without corticosteroid therapy.

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Background: IL-33 is known to induce Th2-type cytokine production by various types of cells through its receptors, ST2 and IL-1RAcP. Polymorphism in the ST2 and/or IL-33 genes was found in patients with atopic dermatitis and asthma, implying that the IL-33/ST2 pathway is closely associated with susceptibility to these diseases. Exposure to allergens through damaged skin is suspected to be a trigger for allergen sensitization, resulting in development of such allergic disorders as asthma and atopic dermatitis.
Methods: To elucidate the role(s) of the IL-33/ST2 pathway in asthma in individuals who had been epicutaneously sensitized to an antigen, wild-type and ST2^-/- mice were epicutaneously sensitized with ovalbumin (OVA) and then were intranasally challenged with OVA. The degree of airway inflammation, the number of leukocytes and the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in bronchoalveolar lavage fluids (BALFs), The levels of cytokines and chemokines in lungs and OVA-specific IgE levels in sera were determined by histological analysis, a hemocytometer, colorimetric assay, quantitative PCR or ELISA, respectively.
Results: The number of eosinophils in BALFs, the levels of Th2 cytokines and chemoattractants in the lungs and OVA-specific IgE in sera from ST2^-/- mice were significantly reduced compared with wild-type mice. Although the number of neutrophils in BALFs and the pulmonary levels of IL-17 were comparable in both mice, the levels of MPO activity in BALFs and neutrophil chemoattractants in the lung were reduced in ST2^-/- mice.
Conclusions: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.

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Background: To estimate the efficacy and safety of 0.1% tacrolimus ophthalmic suspension based on the blood level of tacrolimus in patients with severe allergic conjunctivitis.
Methods: Fifty-two patients in whom topical anti-allergic agents had been ineffective were treated with 0.1% tacrolimus ophthalmic suspension twice daily for 12 weeks. Adverse drug reactions were monitored, as well as ocular symptoms and signs. The blood concentration of tacrolimus was measured before the initiation of treatment and 4 and 12 weeks later.
Results: About 75% of the patients without concomitant using of tacrolimus ointment had blood levels of tacrolimus below the detection limit of the assay (0.5ng/mL). On the other hand, 71% (week 4) and 57% (week 12) of patients with concomitant using of tacrolimus ointment had blood levels above the detection limit of the assay. However, the maximum blood concentration was less than 2ng/mL. Adverse drug reactions occurred in 16 patients. These were disorders of the eye such as warmness, irritation, and a burning sensation. However, all of the patients could continue treatment with tacrolimus for 12 weeks. There were no serious adverse events such as increased intraocular pressure or ocular infection during the study. All symptoms and signs improved over time.
Conclusions: The good safety profile of 0.1% tacrolimus ophthalmic suspension based on the low blood concentration of tacrolimus, coupled with demonstrated efficacy, make it an important tool for treating severe allergic conjunctivitis.

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Background: Sphingosine-1-phosphate (S1P), a lysophospholipid released from inflammatory cells, causes cell migration by increasing cytokines and chemokines. This study was designed to determine whether S1P causes adherence of eosinophils to pulmonary endothelial cells via enhancement of adhesion molecule expression.
Methods: Expression of VCAM-1 and ICAM-1 was assessed by RT-PCR and Western blot analysis in human pulmonary microvasucular endothelial cells (HPMVECs). The number of adherent eosinophils to HPMVECs was calculated according to adhesion assay.
Results: Pre-treatment of HPMVECs with S1P increased mRNA and protein expression of VCAM-1, in contrast, did not dramatically increase those expression of ICAM-1. The maximal expression of these adhesion molecules in mRNA and protein was observed 4 and 8h after exposure to S1P, respectively. Pre-treatment with S1P also activated RhoA, a monomeric G protein; the ability of S1P to enhance the expression of VCAM-1 was attenuated by RhoA related inhibitors such as Y-27632, C3 exoenzyme, and GGTI-286. The effects of S1P on VCAM-1 were attenuated by pre-incubation with pertussis toxin, which catalyzes the ADP-ribosylation of G_i, a heterotrimeric G protein.
After HPMVECs were treated with S1P, adhesion of human eosinophilic leukemic cell line (EoL-1) cells to HPMVECs was enhanced in a concentration-dependent manner. Augmented adherence of EoL-1 cells by S1P was also attenuated by Y-27632 and pertussis toxin. S1P causes adherence of eosinophils to pulmonary endothelium via RhoA activation.
Conclusions: S1P may act as a lipid mediator in asthma. The RhoA/Rho-kinase pathway may be a therapeutic target for preventing eosinophil infiltration to the airway.

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Background: Little is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP).
Methods: A total of 50 JCCP patients received MFNS (200μg once daily: n = 25) or placebo (n = 25) starting on February 1, 2010. Treatments continued until the end of April. The primary endpoint was the comparison of the total nasal symptom score (TNSS) between the MFNS and placebo groups. The secondary endpoints included comparisons of QOL, daytime sleepiness, nasal ECP levels, and safety.
Results: Continuous dispersion of Japanese cedar pollen began on February 22. Although the placebo group showed a significant worsening of symptoms after the start of the continuous dispersion, no worsening occurred in the MFNS group. A significant difference in the TNSS between the two groups was seen starting at 4 weeks after the treatment. Similar results were seen for QOL and sleepiness. Nasal ECP levels in March were significantly lower in the MFNS group. A total of 56% of the MFNS group progressed to a persistent allergic rhinitis state in accordance with the ARIA classification, as opposed to 84% of the placebo group. MFNS was well tolerated, and the plasma cortisol concentrations were similar between the two groups.
Conclusions: EIT with MFNS for JCCP is both safe and effective. This treatment can potentially lessen symptoms and help pollinosis patients remain in the intermittent state.

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Background: Mannose-binding lectin (MBL) encoded by the MBL2 gene, is an important component of the innate immunity. Low levels have been linked with respiratory infections and both high and low levels with allergy and asthma. The aims of the study were to evaluate the connection between polymorphisms of the MBL2 gene and viral findings, clinical characteristics and subsequent wheezing in young infants with bronchiolitis.
Methods: In all, 129 full-term infants hospitalized for bronchiolitis at age less than 6 months have been followed-up until the mean age of 1.5 years. The genotyping of the MBL2 gene mutations was made by pyrosequencing for a simultaneous detection of three single nucleotide polymorphisms (SNP).
Results: The MBL genotypes or allele frequencies had no significant associations with clinical characteristics of bronchiolitis. The 41 children with variant genotypes were more often infected by multiple viruses (21.9%, p = 0.047) than children with wild-type A/A genotypes (9.1%). In addition, more children with variant genotypes (31.7%, p = 0.016) had used corticosteroids because of post-bronchiolitis wheezing, compared to those with wild-type A/A genotypes (13.6%). No other significant associations with viral findings or post-bronchiolitis outcomes were found.
Conclusions: Preliminary evidence was found that the variant non-A/A genotypes may be associated with susceptibility to multiple viral infections and more severe post-bronchiolitis wheezing requiring treatment with corticosteroids.

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Background: The correlation between inflammatory cells and airway smooth muscle plays fundamental roles in the pathophysiology of asthma. This study was designed to determine whether pre-exposure of airway smooth muscle to sphingosine-1-phosphate (S1P), which is released from mast cells by allergic reactions, causes a deterioration of β-adrenoceptor function.
Methods: Isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F₃₄₀/F₃₈₀), an indicator of intracellular Ca²⁺ levels, were simultaneously measured using fura-2 loaded guinea-pig tracheal tissues. Intracellular cAMP levels were also measured.
Results: Pre-exposure to S1P caused a reduction in the inhibitory effects of 0.3μM isoprenaline, a β-adrenoceptor agonist, and 10μM forskolin, a direct activator of adenylyl cyclase, against 1μM methacholine-induced contraction in concentration- and time- dependent manners. In contrast, the values of F₃₄₀/F₃₈₀ were not augmented under this experimental condition. After incubation with S1P in the presence of 0.001-1μM Y-27632, a Rho-kinase inhibitor, the reduced responsiveness to forskolin induced by S1P was reversed in a concentration-dependent manner. Moreover, pre-treatment with pertussis toxin (PTX), an inhibitor of G_i, suppressed the loss of forskolin-induced relaxation induced by S1P. Pre-exposure to S1P markedly inhibited the augmentation of cAMP accumulation induced by forskolin. However, addition of Y-27632 and pre-exposure to PTX returned forsokin-induced cAMP accumulation to the control level.
Conclusions: Pre-exposure to S1P causes heterologus desensitization of β-adrenoceptors by increasing the sensitivity of airway smooth muscle to intracellular Ca²⁺. Ca²⁺ sensitization regulated by G_i and Rho-kinase is involved in this phenomenon.

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Background: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β₂-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen.
Methods: This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250μg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160μg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV₁, and fractional exhaled nitric oxide (FeNO) at the end of treatment period.
Results: Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score ≤0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV₁ values improved significantly, but not FeNO values, after switching from SFC to FBC.
Conclusions: Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled.

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Background: The purpose of this study is to conduct a histopathological research of the conjunctival findings and eosinophilic inflammation of novel atopic keratoconjunctivitis in a NC/Nga mouse model using crude Dermatophagoides farina.
Methods: NC/Nga mice were sensitized by repeated topical applications of an ointment containing Dermatophagoides farinae body (Dfb). They were then divided into 4 groups depending on the following topical ophthalmic treatment: DFb group undergoing topical ophthalmic ointment containing Dfb; DFco group undergoing topical instillation of allergen extracts of Dermatophagoides farinae; Ba group undergoing topical ointment with substrate alone and NT group without after-topical ophthalmic treatment. At 24 hours after the last ophthalmic treatment, histopathological examination was performed. The density of the subepithelial infiltration of the eosinophils was determined. Serum total IgE and house-dust-mite (HDM)-specific IgE antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA).
Results: In the DFb group, the conjunctiva showed similar findings to those of atopic keratoconjunctivitis, i.e. intraepithelial pseudotubular formation, Torus-form infiltration due to massive lymphocytes in the palpebral conjunctiva and gelatinous hyperplasia in the limbus with subepithelial granuloma composed of lymphocytes and eosinophils. Subepithelial infiltration of eosinophil density in the DFb group [878.4 ± 399.7cells/mm² (mean ± SD)] was significantly higher than in the other 2 groups (DFco 85.6 ± 40.1 Ba 49.2 ± 32.3) (P < 0.001). Total serum IgE concentration and HDM-specific serum IgE antibody concentration in the DFb group and the DFco group were significantly higher compared with those in the NT group.
Conclusions: Topical application of an ointment containing DFb to both the skin and eyes of NC/Nga mice can induce an atopic keratoconjunctivitis (AKC) model in these mice.

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Background: Grasses belong to major sources of inhaled allergens. The knowledge of particular molecules responsible for hypersensitivity is of crucial importance for better understanding of individual differences among single allergic subjects and allergic populations living in various world-areas.
Methods: Specific-IgE-antibodies against Phl p 1, Phl p 5, Phl p 7, Phl p 12 were detected in a group of 130 Phleum-allergic-subjects (82 children, 48 adults).
Results: Phl p 1 antibodies were detected in most pediatric and adult patients, however, the children were associated with higher RAST classes more often. Anti-Phl p 5-antibodies were found more frequently in adults. An increase was observed in the number of pediatric patients reacting to Phl p 7 and Phl p 12. There were no differences in concentrations of specific-IgE against Phl p 5, Phl p 7 and Phl p 12 depending on age. Almost 10% of allergic children produced antibodies directed exclusively against minor allergens or did not produce specific-IgE-antibodies against tested molecules. Part of the patients reacted to profilin and calcium-binding protein originating from only one source (Phl p 12/Bet v 2 and Phl p 7/Bet v 4).
Conclusions: Antibodies against Phl p 1 and Phl p 5 can be used as a marker of allergy to grasses in adult patients. Children reacted exclusively to minor allergens more frequently than adults. Prolonged allergen exposure is evidently necessary to induce sensitization to Phl p 5. A high level of homology between profilins and calcium-binding proteins enables only one allergen to be used for diagnostic purposes but a possibility of a reaction to species-bound epitopes should be taken into account.

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