As the key molecule of type-I-hypersensitivity, IgE provides specificity for the allergen and links it to the allergic effector functions. Antibodies are secreted by plasma cells and their precursors, the plasma blasts. The fate of plasma cells is a subject of controversy, with respect to their lifetime and persistence in the absence of allergen. In general, plasma cells were for a long time considered as short-lived end products of B-cell differentiation, and many of them are short-lived, although already for more than 20 years evidence has been provided that IgE-secreting plasma cells can persist over months. Today long-lived, "memory" plasma cells are considered to represent a distinct cellular entity of immunological memory, with considerable therapeutic relevance. Long-lived plasma cells resist current therapeutic and experimental approaches such as immunosuppression, e.g. cyclophosphamide, steroids, X-ray irradiation, anti-CD20 antibodies and anti-inflammatory drugs, while the chronic generation of short-lived plasma cells is sensitive to conventional immunosuppression. The seasonal variation in pollen-specific IgE can be suppressed by immunotherapy, indicating that component of the IgE response, which is stimulated with pollen allergen is susceptible to suppression. Targeting of the remaining long-lived, allergen-specific plasma cells, providing the stable IgE-titers, represents a therapeutic challenge.
Here we discuss recent evidence suggesting, why current protocols for the treatment of IgE-mediated allergies fail: Memory plasma cells generated by inhalation of the allergen become long-lived and are maintained preferentially in the bone marrow. They do not proliferate, and are refractory to conventional therapies. Current concepts target plasma cells for depletion, e.g. the proteasome inhibitor bortezomib, BAFF and APRIL antagonists and autologous hematopoietic stem cell transplantation.

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Although the current standard care for patients with food allergy is based on avoidance of the trigger foods with hope of possible gain of tolerance, increasing number of studies have shown that oral immunotherapy is a promising approach. Understanding the transcutaneous sensitization and oral immune tolerance to food antigens has shifted focus of treatment and prevention. However, more studies are warranted to elucidate the underlying mechanisms and to clarify the indication criteria to which type of patients this therapy should be applied. Easy and uncontrolled use of elimination diets for atopic dermatitis might have increased and exacerbated food allergy, and thorough innovation of our whole concept for food allergy is now required.

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Allergen immunotherapy targets Th2 cells activated by specific allergens, which constitutes the basis of allergic disease. Therefore, this approach has therapeutic potential for a variety of allergic diseases, including asthma, and may modify their natural course. Immunotherapy results in systemic immunological changes to allergens, thereby providing clinical benefits in allergic asthma. For example, immunotherapy attenuates T-cell-mediated airway inflammation by down-modulating Th2 and inducing Th1 differentiation. In addition, immunotherapy induces regulatory T cells, which produce IL-10. Meta-analysis has demonstrated that allergen immunotherapy improves clinical symptoms and non-specific airway hyperresponsiveness in asthma, and decreases drug requirements. Clinical studies have supported the usefulness if immunotherapy in mild to moderate asthma cases, particularly in patients with concomitant rhinitis. Several promising novel approaches have emerged as future immunotherapeutic strategies for the treatment of asthma. Current pharmacotherapy, including inhalational corticosteroids, provides powerful anti-symptomatic benefits in asthma; however, pharmacotherapy cannot cure or modify the natural course of asthma. As immunotherapy targets the background immunological state in asthma, it is expected to lead to long-term amelioration or cure. It is hoped that the positioning of allergen immunotherapy as a treatment option will allow the comprehensive management of symptoms in allergic individuals, and the modification of disease course.

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Allergic rhinitis is the most prevalent type I allergy in industrialized countries. Pollen scattering from trees or grasses often induces seasonal allergic rhinitis, which is known as pollinosis or hay fever. The causative pollen differs across different areas and times of the year. Impaired performance due to pollinosis and/or medication used for treating pollinosis is considered to be an important reason for the loss of concentration and productivity in the workplace. Antigen-specific immunotherapy is an only available curative treatment against allergic rhinitis. Subcutaneous injection of allergens with or without adjuvant has been commonly used as an immunotherapy; however, recently, sublingual administration has come to be considered a safer and convenient alternative administration route of allergens. In this review, we focus on the safety and protocol of subcutaneous and sublingual immunotherapy against seasonal allergic rhinitis. We also describe an approach to selecting allergens for the vaccine so as to avoid secondary sensitization and adverse events. The biomarkers and therapeutic mechanisms for immunotherapy are not fully understood. We discuss the therapeutic biomarkers that are correlated with the improvement of clinical symptoms brought about by immunotherapy as well as the involvement of Tr1 and regulatory T cells in the therapeutic mechanisms. Finally, we focus on the current immunotherapeutic approach to treating Japanese cedar pollinosis, the most prevalent pollinosis in Japan, including sublingual immunotherapy with standardized extract, a transgenic rice-based edible vaccine, and an immunoregulatory liposome encapsulating recombinant fusion protein.

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Background: This study investigated the variations in the clinical efficacy and drug cost following the introduction of the Asthma Prevention and Management Guidelines in Japan (JGL2003).
Methods: The medical charts of fifty outpatients treated continuously for asthma, aged 16-50 years, from October 2002 to October 2004 at Showa University Hospital were analyzed for physicians' compliance with asthma guidelines, symptom severity, episodes in various occasions, prescriptions and drug costs.
Results: Physicians' compliance with the guidelines, which were defined as the number of patient visits treated in conformity with the JGL over the total number of patient visits, was found to be high before (89.4%) and after (90.3%) the introduction of JGL2003, without a statistical difference. On the other hand, the distribution of asthma symptom severity varied significantly (P < 0.0001). Fewer patients were recognized as having more severe asthma symptoms after the introduction of JGL2003. Significantly more patients with severe asthma symptoms were detected in the physicians' noncompliant group than in the compliant group (P < 0.0001). The number of patients prescribed with oral corticosteroids, long-acting β₂-agonists containing patches, long-acting oral β₂-agonists, short-acting inhaled β₂-agonists, sustained-released theophylline and leukotriene receptor antagonists decreased after the introduction of JGL2003. Furthermore, the total annual drug cost per patient decreased significantly by an average of 16,259 yen (P = 0.006).
Conclusions: The JGL2003 was judged to have improved criteria, which thus resulted in the high compliance of physicians with the guidelines, in the remission of asthma symptoms and in the reduction in the total annual drug cost per patient.

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Background: At present, the only treatment for food allergy is to avoid the allergy-causing food. Some trials of specific oral tolerance induction (SOTI) have been carried out, but the rate of tolerance induction was low despite long treatment periods, at least 3 months to several years. A new type of treatment is long desired. The objectives of this study are to perform our rush SOTI for school-age patients with severe egg allergy, and to evaluate the safety and efficacy of this method for one year.
Methods: Six school-age children (7-12 years of age) with severe IgE-mediated egg allergy confirmed by double-blind, placebo-controlled food challenge (DBPCFC) underwent rush SOTI, in which patients ingested increasing doses of egg several times every day. After rush SOTI, patients ingested the maintenance dose of egg at least twice a week.
Results: In DBPCFC, the median threshold dose of egg white inducing allergic reactions was 0.152g(0.012-0.360g). All subjects acquired tolerance to more than one whole egg (60g). It took only 12 days (9-18 days). None experienced any serious reaction. We observed a decrease in IL-10 and an increase in TGF-β1 at 6 months and a decrease in egg-specific IgE and an increase in egg white-specific IgG₄ at 12 months after rush SOTI in blood. All subjects have been able to ingest more than one whole egg ever since.
Conclusions: Our rush SOTI is a safe and effective treatment for severe food allergy since only a few weeks are needed to acquire tolerance. It would replace allergen avoidance as the treatment for food allergy.

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Background: The prevalence of bronchial asthma (BA) in youth is increasing in Japan, but very few athletes are reported to be affected with BA. The aim of this study is to analyze pulmonary function test (PFT) in athletes from the aspect of BA retrospectively.
Methods: Medical history questionnaires of 2111 athletes (male: 1549, female: 562) were reviewed. All athletes participated in the institute's athletic test for the first time, from April 2003 through March 2006. Athletes were categorized into three groups; current-BA confirmed and treated by the physician, possible-BA according to the allergic history and/or BA symptoms, and non-BA that is neither of the above two groups. The PFT data were then analyzed.
Results: There were 24 current-BA (1.1%), 137 possible-BA (6.5%), and 183 cases with a past history of BA (PH; 8.7%). Percent of predicted forced expiratory volume in 1 second (%FEV₁) and of predicted peak expiratory flow rate (%PEF) in current-BA (86.2 ± 17.7% and 81.6 ± 19.1%, respectively) and possible-BA (84.7 ± 14.6% and 81.2 ± 17.3%, respectively) were significantly lower than those in non-BA (93.9 ± 13.7% and 93.8 ± 19.8%, respectively), without any significant difference between current-BA and possible-BA. Athletes with PH show impaired obstructive indices; even in non-BA with PH showed lower %FEV₁ (91.3 ± 13.9%, p < 0.05) and %PEF (86.8 ± 17.8%, p < 0.001) than non-BA without PH (94.0 ± 13.7% and 94.2 ± 19.9%, respectively).
Conclusions: The incidence of BA in Japanese athletes may be higher than currently recognized. More intervention is encouraged for the diagnosis of BA, to avoid any fatal asthma during sports by initiating preventive therapy.

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Background: Inhaled corticosteroids (ICS) are the mainstay of asthma treatment, but conventional ICS may have limited effectiveness in inflammation and patency of small airways. Ciclesonide is delivered and deposited in the peripheral region of the lung as a small particle corticosteroid. The aim of the study is to compare the effects of ciclesonide with fluticasone propionate on small airway function in asthma.
Methods: Thirty mild persistent asthma patients treated with 200μg of fluticasone propionate were randomized to receive either ciclesonide 200μg once daily or fluticasone propionate 100μg twice daily for 8 weeks. Small airway function was assessed by impulse oscillometry (IOS) and percentage of eosinophil induced sputum.
Results: We observed that ciclesonide significantly improved IOS measured resistance of small airways (R5-R20; p < 0.05), distal reactance (X5; p < 0.01), reactance area (AX; p < 0.01), and decreased late-phase sputum eosinophil level (p < 0.01) compared with fluticasone propionate. There were no significant changes in spirometry indices in either group during the study.
Conclusions: These findings suggest that ciclesonide improves small airway function and inflammation compared with fluticasone propionate in mild asthma. This study provides evidence that IOS and late-phase induced sputum allows detection of changes in the small airways that can not be detected by spirometry.

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Background: Some polyphenols possess anti-allergic activities. Naringenin chalcone is one of the polyphenols that is present in the skin of red tomatoes. In this study, we investigated the effect of naringenin chalcone in allergic responses in vivo using an experimental mouse model system of allergic asthma.
Methods: Allergic airway inflammation was induced in mice by sensitization and challenge with ovalbumin. Naringenin chalcone was orally administrated every day during the course of the experiment. Airway hyperreactivity, the eosinophilic infiltration in the bronchioalveolar lavage fluid and Th2 cytokine production from splenic CD4 T cells were assessed.
Results: Eosinophilic airway inflammation, airway hyperreactivity and Th2 cytokine production from CD4 T cells were significantly suppressed in mice that were treated with naringenin chalcone. Hyperproduction of mucus was slightly reduced.
Conclusions: The results of this study suggest that naringenin chalcone suppresses asthmatic symptoms by inhibiting Th2 cytokine production from CD4 T cells. Thus, naringenin chalcone may be a useful supplement for the suppression of allergic symptoms in humans.

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Background: Recent studies suggest that Tc1/Tc2 imbalances are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The purpose of this study was to clarify the relationship between peripheral blood T-cell profiles and pulmonary function or inflammatory parameters.
Methods: Thirty-one patients with stable COPD (median age 70 years, 30 males, 15 current smokers and 16 ex-smokers) and 30 healthy control subjects were enrolled in this study. The subjects underwent blood tests, exhaled nitric oxide (eNO) measurement, pulmonary function tests, and sputum induction. Tc1/Tc2 and Th1/Th2 were determined by analyzing intracellular cytokine staining for IFN-γ and IL-4 in peripheral blood CD8⁺ and CD4⁺ T cells using flow cytometry after stimulation with phorbol 12-myristate 13-acetate and ionomycin.
Results: There was a significantly increased proportion of IFN-γ-producing and IL-4-producing CD8⁺ T cells in patients with COPD compared with control subjects (median [IQR] 73.6% [63.9%-80.7%] vs 62.0% [45.6%-73.8%], p = 0.004; and 2.6% [1.1%-6.9%] vs 1.1% [0.6%-2.2%], p = 0.002, respectively). In addition, the proportion of IFN-γ-producing CD4⁺ T cells was significantly higher in patients with COPD compared with control subjects (25.7% [21.2%-38.0%] vs 22.8% [15.6%-29.2%], p = 0.027). The proportion of IFN-γ-producing CD8⁺ T cells was correlated negatively with single-breath carbon monoxide transfer coefficient (Kco)(ρ = -0.45, p = 0.033) and positively with eNO (ρ = 0.50, p = 0.012). The proportion of IL-4-producing CD8⁺ T cells was positively correlated with body mass index (ρ = 0.42, p = 0.023) and Kco (ρ = 0.47, p = 0.026).
Conclusions: It is suggested that Tc1 cells have a detrimental role and that Tc2 cells have a protective role in disease progression.

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Background: Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disorder due to a systemic hypersensitivity reaction. We report on a case with DIHS-like symptoms following human herpes virus 6 (HHV-6) infection complicated with encephalopathy.
Case Summary: An 11-month-old girl suffered from a human herpes virus 6 (HHV-6) infection (exanthema subitum) complicated with encephalopathy. We treated the patient with continuous infusion of thiopental, assisted mechanical ventilation, methylprednisolone pulse therapy, and γ-globulin infusion therapy starting on the fifth day of the illness and started phenobarbital administration on the eleventh day. The patient developed a fever, systemic erythematous exanthema, lymphadenopathy, and eosinophilia two weeks after the start of phenobarbital administration. Steroid therapy, methylprednisolone (4mg/kg/day) followed by oral prednisolone (1mg/kg/day), was started on the 28th day and was tapered off on the 72nd day after admission. Serum anti-HHV-6 IgG antibody elevation and the presence of HHV-6 DNA in the peripheral blood detected by polymerase chain reaction (PCR) analysis suggested reactivation of HHV-6 after the primary infection of HHV-6. Lymphocyte transformation test for phenobarbital was positive three weeks after the DIHS crisis.
Discussion: HHV-6 reactivation is a unique feature in DIHS. In general one develops DIHS accompanied by reactivation of HHV-6 which has been residing in the body since the initial infection (exanthema subitum) in early childhood. This is the first report of a patient with DIHS-like symptoms which developed immediately following the primary infection of HHV-6.

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A 56-year-old woman was referred to our hospital because of dyspnea, wheezing, and a productive cough. Eight years before presentation, bronchial asthma was diagnosed and the patient received inhaled corticosteroids plus antiasthmatic agents (a long-acting inhaled β2-agonist, leukotriene modifiers, and theophylline). Chest radiography showed small diffuse nodular shadows, and a computed tomographic scan showed thickening of the bronchi and bronchioles, with diffuse centrilobular nodules in both lung fields. A blood test and microscopic examination of the bronchoalveolar fluid revealed marked eosinophilia. Transbronchial lung biopsy and transbronchial biopsy showed eosinophilic bronchitis and bronchiolitis. After treatment with oral prednisolone (40mg daily) and inhaled corticosteroids, the symptoms, blood eosinophilia, and radiographic findings improved. Recently, several similar cases of eosinophilic bronchiolitis have been reported. Studies of further cases and elucidation of the pathophysiology of eosinophilic bronchiolitis are necessary to establish a concept for this disease and to determine whether it should be classified as a subtype of bronchial asthma or as a distinct entity.

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