Dendritic cells (DCs) are antigen (Ag)-presenting cells (APCs) characterized by a unique capacity to stimulate naïve T cells and initiate primary immune responses. Recent studies suggest that DCs also play critical roles in the induction of central and peripheral immunological tolerance, regulate the types of T cell immune responses, and function as sentinels in innate immunity against microbes. The diverse functions of DCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here we review recent progress in our understanding of the nature and classification of DCs.

View full abstract

Induction of different types of adaptive immune responses depending on the nature of antigens and the environmental context is crucial to cope with a variety of pathogens and concurrently to avoid pathological reaction to self antigens. Recent studies have been elucidating that the diversity of immune responses is critically controlled by dendritic cells (DCs). Two DC subsets have been identified in humans: myeloid DCs and plasmacytoid DCs. The DC subsets induce different types of adaptive immune responses depending on environmental factors. Interleukin (IL)-12 from myeloid DCs is a dominant factor for the induction of a Th1 response, whereas OX40 ligand on myeloid DCs is important for the induction of a Th2 response. Furthermore, inducible costimulator (ICOS) ligand on plasmacytoid DCs is critical for the induction of IL-10-producing regulatory T cells. Elucidating cellular and molecular mechanisms by which functions of the two DC subsets are modulated will lead to understanding the pathogenesis of various immune-related diseases and to developing novel immunological therapies.

View full abstract

In this review we discuss the role of dendritic cells (DC) in the pathogenesis of allergic contact hypersensitivity (ACH) and atopic disorders, such as asthma and atopic eczema. In ACH patients, DC recognize the invasion of simple chemicals such as haptens, and trigger antigen-specific T cell responses leading to the characteristic histological and clinical changes such as spongiosis and papulovesicular eruptions. During atopic disorders, it is well known that the Th2-deviated immune response plays a crucial role in their pathogenesis. DC provide T cells with antigen and costimulatory signals (signals 1 and 2, respectively), as well as with a polarizing signal (signal 3). When studying ACH, it is important to understand how simple chemicals induce the activation of DC and their migration to the draining lymph nodes where they supply signals 1 and 2 to naïve T cells. The mechanisms by which DC induce the Th2-deviated immune response, namely via the Th2-deviated signal 3, are central topics in the pathogenesis of atopic disorders.

View full abstract

After taking up pathogen-derived antigens, dendritic cells (DCs) leave peripheral organs and migrate into sentinel lymph nodes via afferent lymphatic vessels. During this process, they undergo maturation and produce proinflammatory cytokines, which leads to efficient antigen (Ag) presentation and activation of the innate and acquired immune systems. Recent evidence indicates that DC subsets cooperate to activate the innate immune system. It is becoming clear that the total DC population is composed of a network of DC subsets with distinct functions that are critical for sensing pathogens and orchestrating immune responses.

View full abstract

Dendritic cells (DC) play key rolls in various aspects of immunity. The functions of DC depend on the subsets as well as their location or activation status. Understanding developmental lineages, precursors and inducing factors for various DC subsets would help their clinical application, but despite extensive efforts, the precise ontogeny of various DC, remain unclear and complex. Because of their many functional similarities to macrophages, DC were originally thought to be of myeloid-lineage, an idea supported by many in vitro studies where monocytes or GM-CSF (a key myeloid growth factor) has been extensively used for generating DC. However, there has been considerable evidence which suggests the existence of lymphoid-lineage DC. After the confusion of myeloid-/lymphoid-DC concept regarding DC surface markers, we have now reached a consensus that each DC subset can differentiate through both myeloid- and lymphoid-lineages. The identification of committed populations (such as common myeloid- and lymphoid progenitors) as precursors for every DC subsets and findings from various knockout (KO) mice that have selected lymphoid- or myeloid-lineage deficiency appear to indicate flexibility of DC development rather than their lineage restriction. Why is DC development so flexible unlike other hematopoitic cells? It might be because there is developmental redundancy to maintain such important populations in any occasions, or such developmental flexibility would be advantageous for DC to be able to differentiate from any "available" precursors in situ irrespective of their lineages. This review will cover ontogeny of conventional (CD8^+/- DC) DC, plasmacytoid DC and skin Langerhans cells, and recently-identified many Pre-DC (immediate DC precursor) populations, in addition to monocytes and plasmacytoid DC, will also be discussed.

View full abstract

Background: Recently, some common foods in daily life have been found to have anti-allergic effects. We have reported that tomato extract (TE) could possibly inhibit histamine release and mouse ear-swelling responses. Moreover, it is reported that TE could relieve the symptoms for Japanese cedar pollinosis.
Methods: To evaluate the anti-allergic effect of TE, we performed a randomized, double-blind, placebo-controlled study in 33 patients with perennial allergic rhinitis (PAR) using oral administration of TE (360mg per day) or placebo for 8 weeks.
Results: We found that the sneezing score significantly decreased in the TE group at the end of the trial compared to the beginning (P < 0.05). There were decreasing tendencies of rhinorrhea and nasal obstruction in the TE group. The patients' quality of life was significantly improved in the TE group after 8 weeks of treatment (P < 0.05), but not in placebo group. A significant improvement in total symptom scores, combining sneezing, rhinorrhea and nasal obstruction, was observed after oral administration of TE for 8 weeks (P < 0.01). The safety of TE treatment was confirmed by laboratory tests and inspection of general conditions.
Conclusions: TE can be expected to safely improve the nasal symptoms of PAR.

View full abstract

Background: Viral infection of the respiratory tract in patients with asthma is one of the most frequent causes of exacerbation of asthmatic symptoms. Disodium cromoglycate (DSCG) is a commonly used anti-asthmatic medicine with many beneficial biochemical and physiological effects. The purpose of this study was to investigate the efficacy of DSCG against colds when used in clinical practice.
Methods: A questionnaire survey to determine the efficacy of DSCG was undertaken in 220 adult patients with asthma (81 male, 139 female; mean age: 54.1 ± 13.7 years and 60.1 ± 12.7 years, respectively) from April to September 2004 at the Miyatake Asthma Clinic.
Results: The duration of DSCG inhalation therapy was not less than 5 years in more than half of the patients. The mean daily DSCG dose at the time of the questionnaire survey was 40mg/day in over 50% of all patients. After DSCG was added to inhaled corticosteroid (ICS) combination therapy, 56.4% of the patients rated their condition as "improved", and 66.4% of the patients felt that the frequency of colds they had caught had decreased while DSCG was added to ICS.
Conclusions: DSCG inhalation therapy is a useful additional treatment following ICS to alleviate asthma symptoms, and to prevent colds in adult patients with asthma.

View full abstract

Background: β-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting β₂ selective drugs. Although anti-inflammatory effects of β₂ selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of β₂ selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation β₂-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma.
Methods: Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation.
Results: Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice.
Conclusions: Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.

View full abstract

Background: Perimenstrual asthma (PMA) has been documented in 30% to 40% of asthmatic women; the characteristics of PMA have also been well described. However, there have been few epidemiological investigations of PMA in practice. In this study, we analyzed PMA based on a questionnaire survey carried out in Japan and compared the results with those of studies reported previously.
Methods: For 8 weeks from September through October 2004, a questionnaire survey was administered to patients with bronchial asthma and their attending physicians. The questionnaire surveyed asthma control, asthma-related emergencies and satisfaction in daily life. The attending physicians were questioned about patient profiles and medications. All female patients who were menstruating during the survey period and who were known to have asthma exacerbation related to menstruation were allocated to the PMA group; those who were not were allocated to the non-PMA group.
Results: The rate of PMA in female patients who were menstruating during the survey period was 11.3% in this study. Characteristic features of the PMA group (n = 54) included more severe disease, worsened disease control and more aggressive patient management, including increased oral corticosteroid use compared with the non-PMA group. The rates of emergency episodes in the PMA group were higher than in the non-PMA group. There was a significant increase in aspirin intolerant asthma (AIA, 25.5%) in the PMA group compared with the non-PMA group (8.4%).
Conclusions: Attention should be paid to the lack of knowledge regarding PMA in patients with asthma in actual clinical settings. The low rate of PMA reported in this study may be due to the study method using self-reports of PMA by patients without sufficient knowledge, and may not be an accurate representation of the actual incidence of the disease. The clinical similarity of PMA to AIA in this study may also provide a new insight into the mechanism of PMA.

View full abstract

Background: Allergic reactions after ingestion of fermented soybeans have rarely been reported. Fermented soybeans were recently reported to be a causative food of IgE-mediated, late-onset anaphylaxis without early phase responses. The objectives of our study are to clarify the clinical and laboratory features and to characterize the allergens in allergy due to fermented soybeans.
Methods: Seven patients with suspected hypersensitivity to fermented soybeans, from whom informed consent had been obtained, underwent skin prick-prick tests with fermented soybeans and challenge test with fermented soybeans. Additionally, specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by ELISA and IgE-immunoblotting, respectively.
Results: Seven male patients, aged 26 to 42 years (mean age, 33.1 years), participated. All patients reported generalized urticaria and dyspnea; 5, loss of consciousness; 2, collapse; 2, vomiting; and 2, diarrhea after fermented soybean ingestion. The interval between fermented soybean ingestion and onset of symptoms was 5 to 14 hours (mean, 9.6 hours). All patients were positive on skin prick-prick tests with fermented soybeans. In 2 patients, oral challenge with fermented soybeans was positive 5.5 and 13 hours after ingestion. In ELISA, all 5 patients tested showed elevated IgE levels to the fermented soybean extract. Furthermore, IgE-immunoblotting using 5 patients' sera showed six bands, of which three bands at 38, 28, and 26-kd were bound to sera from 4 patients.
Conclusions: Cases with hypersensitivity after ingestion of fermented soybeans most frequently correspond to IgE-mediated, late-onset anaphylactic reactions due to fermented soybeans.

View full abstract

Background: We investigated the possibility of preventing common cold-like symptoms as a previously unknown benefit of leukotriene receptor antagonists (LTRAs).
Methods: A total of 279 adult patients with bronchial asthma referred to our hospital between June and December 2004 were retrospectively analyzed. Patients were divided into LTRA treated and untreated groups. Frequency of acute exacerbations and number of visits to emergency rooms and of hospital admissions were analyzed as indicators of frequency of infections and asthma exacerbation over the previous 12 months.
Results: Irrespective of inhaled corticosteroid (ICS) use, frequency of infections was significantly lower in the LTRA treated group (0.3 ± 0.7 times/year) than in the LTRA untreated group (1.6 ± 4.2 times/year) (P < 0.05), suggesting that LTRA therapy prevents common cold-like symptoms. Frequency of acute exacerbations and number of hospital admissions were significantly lower in the LTRA treated versus LTRA untreated group (0.4 ± 0.8 versus 2.7 ± 4.3 times/year and 0.0 ± 0.2 versus 0.4 ± 0.7 times/year, respectively; both P < 0.01). When the patients were divided into ICS treated and untreated groups, none of the parameters analyzed differed significantly between the two groups, although all parameters tended to be lower in the ICS treated group.
Conclusions: Adult asthma patients undergoing treatment with LTRAs exhibit lower incidence rates of common cold-like symptoms than those not receiving LTRAs. LTRAs play an important role in reducing the incidence of common cold-like symptoms among asthma patients and in suppressing exacerbation of asthma symptoms possibly associated with these symptoms.

View full abstract

Background: Combination of suplatast tosilate with tacrolimus ointment was reported to reduce the dose of tacrolimus ointment with maintained treatment efficacy for refractory facial erythema in atopic dermatitis (AD), however these were only case-controlled studies and the number of cases was not sufficiently large. Thus, the efficacy of a combination therapy of tacrolimus ointment and suplatast tosilate for treating AD including refractory facial erythema was investigated using a method of meta-analysis on the basis of published papers collected by database search.
Methods: We searched the literature on the efficacy of a combination of topical tacrolimus and suplatast tosilate for refractory facial erythema in patients with adult atopic dermatitis, and related data were collected for meta-analysis.
Results: Our meta-analysis study showed that suplatast/tacrolimus combination therapy revealed better improvement in skin symptom scores and significantly decreased the dose of tacrolimus compared with topical tacrolimus monotherapy. In addition, a significantly greater number of patients could stop using tacrolimus ointment by using the combination with suplatast tosilate than by tacrolimus monotherapy for refractory facial erythema.
Conclusions: The combination therapy with suplatast tosilate decreased the effective dosage of tacrolimus ointment supporting use of the combination therapy for refractory facial erythema.

View full abstract

Background: Some patients with Japanese cedar (JC) pollinosis already show pollinosis symptoms before the first day of the pollen season as determined by microscopic pollen counts.
Methods: Airborne pollen allergen (Cry j 1) levels were measured by electron spin resonance radical immunoassay, a highly-sensitive method for Cry j 1 with a sensitivity 10-100-fold higher than conventional enzyme-linked immunosorbent assay. The symptom data from patients with JC pollinosis were collected from a mobile phone site, "pollen check sheet", and the onset times of the patients' symptoms were analyzed.
Results: The relationship between airborne Cry j 1 levels and the onset time of pollinosis symptoms was investigated. The symptoms of some patients began at the time airborne Cry j 1 levels fluctuated at 1 to 3pg/m³ and symptom scores increased at the time of sudden increase in Cry j 1 levels. About 40% of patients began to show symptoms until the first day of the pollen season and the time nearly corresponds to the time of sudden increase in Cry j 1 levels.
Conclusions: Pollinosis symptoms of some patients began at the time airborne Cry j 1 levels fluctuated at 1 to 3pg/m³ and symptom scores increased at the time of sudden increase in Cry j 1 levels. The latter time nearly corresponds to the first day of the pollen season.

View full abstract

Background: Although procaterol is used clinically as a β₂-adrenergic receptor agonist to relax airway smooth muscle, it has not yet been clarified whether procaterol has inotropic effects on respiratory muscles.
Methods: Three intervention groups were investigated: a procaterol inhalation only group; a procaterol inhalation plus endotoxin injection group (in vivo); and a procaterol incubation group (in vitro). The diaphragm muscle in all groups was dissected and measurements of its contractile properties were performed.
Results: The effects of procaterol inhalation shifted the force-frequency curves upward at 30 minutes after inhalation, and inhibited the decline of force-frequency curves due to endotoxin injection in vivo. In vitro administration of procaterol resulted in an increase in the force-frequency curves in a dose-dependent manner.
Conclusions: It can be concluded that procaterol has an inotropic effect on the diaphragmatic muscles taken from normal animals as well as on the diaphragm muscles in a septic animal model.

View full abstract

Background: There is growing interest in probiotics such as lactic acid bacteria (LAB), not only for treatment of T helper type (Th) 1-mediated diseases but also for Th2-mediated diseases, including allergic diseases, since lactic acid bacteria may be able to modulate the Th1/Th2 balance, in addition to having an immunomodulative effect through induction of Th1 bias.
Methods: The effect of oral administration of heat-killed Lactobacillus acidophilus Strain L-92 (L-92) on ovalbumin (OVA)-specific immunoglobulin (Ig)E production was investigated in BALB/c mice. L-92 was orally administered to mice for 8 weeks from 2 weeks after initiation of OVA-immunization. Patterns of cytokine and Ig production in splenocytes and cells from Peyer's patches (PPs) from these mice were examined after restimulation with OVA in vitro.
Results: L-92 significantly suppressed serum OVA-specific IgE levels for a long period. Cytokines such as interferon (IFN)-γ, interleukin (IL)-4 and IL-10 and Igs such as total IgE and OVA-specific IgE were produced at significantly lower levels by splenocytes of L-92-treated mice, compared with those of control mice. In contrast, transforming growth factor (TGF)-β and IgA levels produced by PPs from L-92-treated mice were significantly higher than in those from control mice.
Conclusions: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-β production in PPs. TGF-β is known to be associated with activation of regulatory T (Treg) cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-β activity.

View full abstract

Background: Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after prolonged exposure to certain drugs and may be related to reactivation of herpes viruses. There have been few reports regarding the clinical association of DIHS with pathogens other than herpes viruses.
Case Summary: We report a case of scleroderma with DIHS associated with paramyxovirus infection. A 61-year-old man with early diffuse cutaneous scleroderma with myositis and progressive interstitial pneumonia developed generalized erythema with high fever 3 weeks after taking sulfamethoxazole/trimethoprim. The diagnosis of DIHS was made based on the patient's history of using an offending drug, clinical manifestations and laboratory data showing peripheral eosinophilia with the presence of atypical lymphocytes. Virological tests showed significant increases of antibody titers against mumps virus and parainfluenza virus type 2, which strongly suggested that paramyxovirus infection occurred during the clinical course of DIHS.
Discussion: These findings suggest that paramyxovirus infection had contributed to the development of DIHS in this patient and that there is a need to seek evidence of other viral infections in some cases of DIHS, especially those without herpes virus reactivation/infection.

View full abstract

Background: We report a case of a 31-year-old woman who began to notice swelling of her arms at age 20. She was once given a diagnosis of cellulitis, but her symptoms spontaneously resolved. The patient had swelling of the left forearm and palm and was referred to our department for evaluation. She had slight pain but no obvious weight gain.
Case Summary: Antinuclear antibody and other autoantibodies, including anti-ds-DNA antibody, anti-RNP antibody, anti-Sm antibody, and anti-SS-A antibody were not detected. C1 inhibitor activity was low, C3 was normal, C4 was low, CH₅₀ was low, and C1q was normal.
Discussion: Based on the presence of the typical clinical features and the positive results on the complement tests, we diagnosed hereditary angioedema. A decrease in C1 inhibitor activity and an increase in specific protein concentrations indicated type 1.

View full abstract

Background: Ortho-phthalaldehyde (OPA) has recently been used as a disinfectant for various medical apparatuses. OPA is not generally recognized as a potential allergen.
Case Summary: Subsequent to our recent report describing a patient presenting with OPA-induced anaphylaxis following laryngoscopy, we experienced two more such cases. In all three cases, the basophil histamine release test was useful for identifying the allergen as OPA. OPA-specific IgE was successfully detected in the serum of the patients by ELISA.
Discussion: Physicians and co-medical workers need to be aware of potential allergens to which patients may be exposed during routine medical procedures.

View full abstract