Cytokines are important regulatory mediators secreted by T cells and other immunoactive cells. Based on the cytokine synthesis patterns, CD4 T cells can often be classified into at least two populations with different immune regulatory functions. The Th1 cells, producing interleukin (IL)-2 and interferon (IFN)-γ, are often associated with cell-mediated immune responses such as delayed type hypersensitivity (DTH), whereas Th2 cells, secreting IL-4, IL-5 and IL-13, usually provide B cell help and enhance allergic reactions. Naïve CD8 T cells, similar to CD4 T cells, can differentiate into at least two subsets of cytolytic effector cells with distinct cytokine patterns. The Tc1 cells secrete a Th1-like cytokine pattern, including IL-2 and IFN-γ. The Tc2 cells produce Th2 cytokines, including IL-4, IL-5 and Il-10. There is increasing evidence that Th1/Th2 and Tc1/Tc2 cytokine imbalance has been of pathogenetic importance in various diseases, such as allergic and autoimmune diseases. The present review article focuses on the evidence that the imbalance of Th1/Th2 and Tc1/Tc2 cytokines plays an important role in various otolaryngological diseases, such as Kimura's disease, Wegener's granulomatosism, acute perceptive hearing loss and Meniere's disease. It is concluded that the predominance of Th1 or Th2 and Tc1 or Tc2 cells may contribute to the mechanism in the pathogenesis of these otolaryngological diseases.

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Recent asthma deaths were examined from yearly reports of the Ministry of Health, Labor and Welfare of Japan and from reports published by the Japan Asthma Death Investigation Committee on 811 deaths over the period 1992-2000. The rate and number of recent asthma deaths in Japan have been decreasing rapidly. Most asthma deaths were of patients aged 70-90 years and there has been a marked trend for increased asthma deaths in the elderly. As for the circumstances surrounding the deaths, sudden death, unstable sudden aggravation and intermittent aggravation were mainly noted. Respiratory infections, fatigue and stress were the major courses of fatal attacks contributing to deaths due to asthma. Many of the patients who died from asthma had been diagnosed as having as moderate to severe asthma and many had non-atopic asthma. There are some reports that suggest that the recent decrease in asthma deaths in Japan is correlated with the use of inhaled corticosteroids.

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Bronchial asthma is a chronic inflammatory disease of the conducting airways. Current asthma treatment guidelines recommend inhaled corticosteroids (ICS) as the first-line maintenance therapy for mild to severe persistent asthma, because ICS are the most efficacious anti-inflammatory medication. Despite treatment with ICS, suppression of inflammation is often incomplete and blockade by ICS of cysteinyl leukotriene (CysLT) and thromboxane (TX) A₂ biosynthesis is limited. The addition of a CysLT₁ receptor antagonist to an ICS represents a reasonable alternative therapeutic approach for the treatment of asthma patients whose symptoms remain uncontrolled on ICS alone. Indeed, CysLT₁ receptor antagonists are demonstrated both to have an additive effect to ICS therapy and to allow the reduction of ICS dosage. Thromboxane modifiers also have an additive effect with low- to moderate-dose ICS. Although the long-term usefulness of add-on therapy of CysLT or TX modifiers (vs long-acting β₂-adrenergic receptor agonists) to ICS is unclear, these alternatives are worthy of further consideration.

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Considerable evidence supports the role of dendritic cells (DC) in the pathogenesis of allergic diseases. Dendritic cells, as the most potent antigen-presenting cells (APC) for the induction of primary immune response to antigen, are deeply involved in the differentiation of naïve T cells into Th2 cells, thereby developing the development of allergic sensitization. After sensitization, DC may also function as a major APC to control the activation and clonal expansion of memory Th2 cells. In addition, DC are able to produce chemokines to recruit Th2 cells into inflammatory sites, indicating DC are important agents in various phases of allergic inflammation. Recently, we have demonstrated that monocyte chemotactic protein-1 not only regulates the homing of DC, but also modulates DC function. The present paper reviews the role of DC in the regulation of the Th2 response in allergic diseases and discusses the possibility of a new therapeutic strategy targeting chemokine-mediated regulation of DC function.

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Mast cells express high-affinity IgE receptors (FcεRI) on their surface and can be activated to secrete a variety of biologically active mediators by cross-linking of receptor-bound IgE. Recent studies in animal models indicate that mouse mast cells may play a protective role in host defense against bacteria through the production of tumor necrosis factor-α, mainly as a result of Toll-like receptor (TLR) 4- or CD48-mediated activation. Moreover, several recent observations in animal models have indicated that mast cells may also play a pivotal role in coordinating the early phases of autoimmune diseases, particularly those involving auto-antibodies. We recently identified functional TLR4 and FcγRI on human mast cells, in which their expression had been upregulated by interferon-γ. We compared each of the receptor-mediated gene expression profiles with the FcεRI-mediated gene expression profile using high-density oligonucleotide probe arrays and discovered that human mast cells may modulate the immune system in a receptor-specific manner.

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Background: Signal transducers and activators of transcription 6 (Stat6) is involved in the interleukin (IL)-4 and IL-13 signaling pathway. The aim of the present study was to evaluate whether polymorphisms in the 5'-flanking region of the Stat6 gene are associated with allergic diseases in Japanese children.
Methods: The Stat6 gene polymorphisms were genotyped by polymerase chain reaction (PCR) fragment length polymorphism analysis and the IL-4 receptor Ile50Val polymorphism was examined using PCR methods.
Results: Novel dinucleotide repeat polymorphisms were found in the 5'-flanking sequences, positioning at -865 (Pro A) and -690 (Pro B) of the Stat6 gene starting codon. The GT repeats in the 5'-flanking sequences were highly polymorphic (Pro A: 14-29 repeats; ProB: 14-20 repeats) with no significant differences in the frequency of allelic and genotypic distributions observed between allergic subjects and controls. In the GT repeat polymorphism of Stat6 exon 1, there was a significant difference in the frequency of genotypic distribution between the two groups (P = 0.003). The Stat6 exon 1 variant had significant linkage disequilibrium with Pro B variants, but not with Pro A. The GT repeat polymorphism was not associated with the IL-4 receptor Ile50Val polymorphism.
Conclusions: Variants of the Stat6 gene may be useful markers for predicting allergic diseases in Japanese children.

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Background: Signal transducers and activators of transcription 6 (Stat6) is a key transcription factor involved in interleukin (IL)-4 and IL-13-mediated biological responses. Recently, we reported the association between the dinucleotide (GT) repeat polymorphism in the first exon of Stat6 and allergic subjects in a Japanese population. The aim of the present study was to evaluate whether this GT repeat polymorphism is associated with bronchial asthma, including childhood asthma and atopic and non-atopic adult asthma.
Methods: Stat6 gene polymorphisms were genotyped by polymerase chain reaction (PCR) fragment length polymorphism analysis.
Results: In the first exon of Stat6, polymorphic PCR products were classified into six alleles (12-17 GT repeats). A significant difference was found in the genotypic frequency of the GT repeat polymorphism between controls and child asthmatics (P = 0.015), but not atopic or non-atopic adult asthma. The frequency of the 15 repeat allele (wild type) was lower in child asthmatics than in controls (P = 0.0047; odds ratio (OR) 1.6, 95% confidence interval (CI) 1.16-2.23), whereas shorter repeat alleles (12, 13 and 14 GT repeat) were higher in child asthmatics than in controls (P = 0.0064; OR (95%CI) 1.66 (1.15-2.39)).
Conclusion: Genetic variations in the Stat6 gene may be associated with a predisposition for childhood asthma.

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Background: The aim of the present survey was to investigate the changes associated with fexofenadine administration in the quality of life (QOL) of Japanese cedar pollinosis patients.
Methods: After obtaining informed consent, volunteers suffering from Japanese cedar pollinosis were divided into two groups: (i) the fexofenadine group (2 × 60 mg/day); and (ii) the placebo group. Changes in QOL were examined after administration for 14 days (randomized, double-blind comparison study). The study period was from 27 February to 13 March 2003. Subjects were recruited from the Tokyo metropolitan area; 104 were randomized to the fexofenadine group and 103 were randomized to the placebo group. The QOL was evaluated using the Japanese Allergic Rhinitis Standard QOL Questionnaire (JRQLQ no. 1). The JRQLQ is structured to evaluate six domains of usual daily activities, outdoor activities, social functioning, sleep problems, general physical problems and emotional function, as well as the overall QOL.
Results: On the 14th day after the start of fexofenadine or placebo administration, the QOL was improved in all domains of the JRQLQ in the fexofenadine group, whereas it had worsened in all domains, except outdoor activities, in the placebo group. The overall evaluation of QOL was significantly more favorable in the fexofenadine group on the 14th day after the start of administration.
Conclusions: The present study showed that fexofenadine administration suppressed the deterioration of overall QOL and alleviated the interference with daily life in patients suffering from Japanese cedar pollinosis.

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Background: Grass pollen immunotherapy is highly effective in reducing seasonal hay fever symptoms and medication requirements. Clinical improvement is accompanied by a reduction in nasal mucosal eosinophils, although the mechanism is unknown.
Methods: Nasal biopsies were taken from 37 adults before immunotherapy and during the peak pollen season following 2 years treatment. Biopsies were processed for immunohistochemistry for CCR3, adhesion molecules (intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1) and apoptotic cells (terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling; TUNEL), as well as for interleukin (IL)-4 and IL-13 mRNA-positive cells. Results were compared with eosinophil numbers in the nasal mucosa.
Results: Analysis of the clinical data confirmed that the proportion of patients who showed greater than 60% improvement in symptoms (47 and 15%) and in rescue medication (79 and 10%) were significant for the immunotherapy group compared with placebo group (P < 0.03 and P < 0.02, respectively). Seasonal increases were observed for VCAM-1 expression (P = 0.05) and IL-13 mRNA-expressing cells (P < 0.05) in the placebo group, but not in the immunotherapy group. The differences for VCAM-1 expression achieved significance between groups (P = 0.05). There was no significant difference in either ICAM-1 expression or in the number of CCR3⁺ cells, TUNEL⁺ apoptotic cells and IL-4 mRNA-expressing cells.
Conclusion: Successful grass pollen immunotherapy was associated with inhibition of seasonal increases in nasal eosinophils, IL-13 mRNA-expressing cells and VCAM-1 expression, but no change in CCR3 expression or in the number of apoptotic cells. The reduction in eosinophils after immunotherapy may be due to suppression of eosinophil recruitment to the nasal mucosa rather than enhanced apoptosis.

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Background: The 1/f fluctuations of heart rate (HR) have been used as a novel index of autonomic function from a chronobiological viewpoint. The autonomic function of asthma sufferers differs from that of normal children. Therefore, we investigated whether there are 1/f fluctuations in asthmatic children during an asthma attack and whether asthmatic children have a different rhythm of 1/f fluctuations in the 24 h after an asthma attack.
Methods: We recorded 24 h electrocardiographs of eight asthmatic children (three females, five males; median age 8.5 years; range 7-11 years) at the time of an asthma attack and during a non-attack period and examined the 1/f^β fluctuations on HR and its rhythm over a 24 h period using the MemCalc system (GMS, Tokyo, Japan). The 1/f fluctuations on HR were calculated by the expression on a log₁₀(frequency) - log₁₀(power density) scale of the HR variability.
Results: The values of β (1/f^β fluctuations of HR) for asthma attack and non-attack periods were 0.9 ± 0.07 and 0.96 ± 0.08, respectively (t = 1.59; P = 0.13). During the asthma attack period, the rhythm was median 7.9 h (range 6.1-11.1 h), compared with 22.7 h (range 12.2-36.4 h) during the non-attack period (t = 0; P < 0.001).
Conclusion: During an asthma attack, the rhythm of 1/f fluctuations is ultradian (cycle length under 20 h), compared with various rhythms during a non-attack period. In future, we will clarify the relevance of the ultradian rhythm of 1/f fluctuations over a 24 h period and the biological life-support system at a point of time of an asthma attack.

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Background: Parvalbumin is the major and cross-reactive allergen in fish. Sufficient amounts of IgE-reactive recombinant fish parvalbumin are needed for diagnosis and immunotherapy of fish allergy.
Methods: A DNA fragment corresponding to parvalbumin of the Pacific mackerel Scomber japonicus was synthesized and cloned into the expression vector pGEX-6p-3 to produce glutathione S-transferase (GST)-fusion parvalbumin in Escherichia coli. The GST-free recombinant parvalbumin was purified using the RediPack GST Purification Module (Amersham Pharmacia Biotech, Buckinghamshire, UK). Parvalbumins of seven species of fish (Japanese eel, horse mackerel, red sea bream, Pacific mackerel, skipjack, bigeye tuna and Japanese flounder) were purified by gel filtration and reverse-phase HPLC. The IgE-binding capacity was examined by ELISA and antigenic cross-reactivity by inhibition ELISA.
Results: The GST-free recombinant Pacific mackerel parvalbumin was obtained in an electrophoretically pure state. Data from ELISA and inhibition ELISA revealed that the recombinant parvalbumin contains most of the IgE-binding epitopes of the natural counterpart. In addition, the recombinant parvalbumin inhibited the IgE reactivities of the pooled patient serum to parvalbumins purified from six species of fish in almost the same magnitude as the natural Pacific mackerel parvalbumin.
Conclusions: Because the recombinant Pacific mackerel parvalbumin bearing the IgE-binding capacity of the natural counterpart is cross-reactive with various fish parvalbumins, it can be a useful tool for the diagnosis and immunotherapy of fish allergy.

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Background: Approximately 16.2% of the Japanese population suffers from pollinosis. One of the forms of management is self-care (preventive care), which can be categorized as 'indoor' and 'outdoor'. Outdoor self-care is usually emphasized, but indoor self-care is also important. Considerable pollen is found in indoor dust and this is thought to be one of the factors that worsens pollinosis and enables it to persistent for a long time, even after the pollinating period has finished. Taking this into consideration, we investigated the dynamic state of indoor pollen.
Methods: Floating indoor house dust was collected in Petri dishes. The amount of pollen in the house dust samples collected was measured using an LCD laboratory highly sensitive Cry j1 assay kit.
Results: The results showed that, indoors, a lot of Japanese cedar pollen (JCP) was found on the floor (tatami mats, carpets), sofas and curtains. The number of JCP in living rooms peaked in April after the pollinating period and decreased gradually; however, JCP was still found indoors, even as late as the following February. Floating JCP in the house was one-tenth of the JCP levels on the floor. Floating JCP increased on days with low humidity. Air conditioning temporarily increased levels of floating JCP in houses with an air conditioner, but the level of floating JCP decreased rapidly compared with the level of that in houses without an air conditioner. Nasal signs and symptoms disappeared completely at a level of 30 floating pollen counts/day per Petri dish.
Conclusion: Considerable JCP was found floating indoors with house dust after a pollinating season.

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