Basophils comprise the smallest population in human peripheral blood leukocytes. The role of basophils in the pathogenesis of allergic diseases has long been obscure, although their accumulation and activation in tissues have suggested their potential importance. Recent advances in the field of basophil biology have indicated that cytokines and chemokines are the primary regulators of basophil functions. In addition, various functions of these cells seem differently modulated. The evidence strongly supports the notion that basophils exposed to these substances and allergens will behave as unique effector cells that presumably play proinflammatory roles in type I allergic reactions.
Basophils represent less than 1% of peripheral blood leukocytes. They are often recruited to the site of allergic inflammation, albeit in small numbers. However, it remained uncertain whether basophils play any significant role in allergic reactions or act as minor and redundant 'circulating mast cells'. We have recently demonstrated that basophils play critical roles in systemic anaphylaxis and chronic allergic inflammation, distinctively from mast cells. Basophils are one of the major players in the IgG- but not IgE-mediated systemic anaphylaxis, in contrast to mast cells. In response to the allergen-IgG immune complexes, basophils release the platelet-activating factor rather than histamine as the major chemical mediator to induce the systemic anaphylaxis. The depletion of basophils protects mice from death due to anaphylactic shock. Basophils also play a crucial role in the development of the IgE-mediated chronic allergic inflammation with massive eosinophil infiltration in the skin, independently of T cells and mast cells, even though basophils account for only ∼2% of the infiltrates. The basophil depletion shows a therapeutic effect on on-going allergic inflammation. Accumulating evidence suggests that basophils function as initiators rather than effectors of the chronic allergic inflammation. Thus, basophils and their products seem to be promising therapeutic targets for allergic disorders.
Basophils and mast cells are major players in the progression of allergic disorders. Although both cell types originate from hematopoietic stem cells, their lineage commitment pathways and mechanisms have been unsolved issues in hematology. Recent advances in the multicolor FACS system enable the prospective isolation of progenitor populations whose readouts are restricted to basophil and/or mast cell lineages. These newly-isolated progenitor subsets are helpful to understand the developmental machinery of basophil and mast cell lineages, leading to the possible exploitation of a novel therapeutic strategy for allergic and autoimmune disorders. In this review, we summarize the recent progress in our understanding of the basophil/mast cell ontogeny on a cellular basis.
Background:Dermatophagoides farinae (Der f) is one of the most frequently implicated allergens in several allergic diseases. Several genome-wide screens have identified a linkage between chromosome 6p21 and mite-specific IgE responsiveness. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily and, on the basis of its homology to B7-1, has been implicated as a costimulatory molecule involved in T-cell activation. BTNL2 resides in the HLA region on chromosome 6p21, and significant associations between BTNL2 gene polymorphisms and several inflammatory diseases have been reported. Objective: The aim of this study was to examine whether BTNL2 gene polymorphisms are associated with specific IgE responses to Der f. Methods: Three single nucleotide polymorphisms (SNPs), including 2 coding SNPs and 1 intron SNP, were studied. One of the coding SNPs was the rs2076530 A > G, which has a functional consequence. A total of 863 unrelated Japanese subjects (447 positive and 416 negative for IgE to Der f) were recruited for a case-control study. Results: Controlling for gender, age, smoking, and the presence of asthma, multiple logistic regression analyses showed that homozygosity of the rs2076530 A allele, which has been reported to be a risk allele for sarcoidosis, was associated with a risk of sensitization towards Der f (Odds ratio; 1.55, p = 0.0060). Conclusions: Although an association which may be due to the linkage disequilibrium with other genes in 6p21 needs to be ruled out, the present findings suggest that the BTNL2 gene might be one of the candidate genes that is responsible for the pathogenesis of Der f-specific IgE responsiveness.
Background: We conducted and reported the first (1982; 55,388 subjects), and second (1992; 45,674 subjects), epidemiological surveys conducted on bronchial asthma in elementary students across 11 prefectures in western Japan. The 2 surveys were conducted in the same regions using the same methodology employing a modified Japanese version of the American Thoracic Society-Division of Lung Diseases (ATS-DLD) Epidemiology Questionnaire. We conducted the third survey in 2002, and compared the findings to those of previous studies. Methods: In the third survey, 37,036 students attending the same schools as in previous surveys (in 11 prefectures) were given the questionnaire. A total of 35,582 responses (96.1%) were collected. An ATS-DLD Epidemiology Questionnaire was also used in this study, and the findings were compared to those of previous studies. Results: 1. The prevalence of bronchial asthma (BA) in boys, girls, and all students was 3.8%, 2.5%, and 3.2%, respectively, for the first survey; 5.6%, 3.5%, and 4.6% for the second survey; and 8.1%, 4.9%, and 6.5% for the third survey. 2. A decline in the BA prevalence in older subjects which could be seen in the first survey was absent in the second and third surveys. There were no regional differences in the third survey. 3. The boys-to-girls ratio in the first, second, and third surveys was 1.5, 1.6, and 1.6, respectively. 4. BA was more prevalent among subjects with a past history of respiratory disease in infancy and those with a family history of allergic disease. 5. The prevalence of asthma symptoms and wheezing in the first, second, and third surveys was 7.1%, 9.8%, and 11.8%, respectively. 6. A comparison of the prevalence of other allergic diseases between the second and third surveys revealed a decrease in atopic dermatitis and an increase in allergic rhinitis, allergic conjunctivitis, and cedar pollinosis. Conclusions: BA prevalence in the third survey increased 2.1 and 1.4 times respectively compared to the first survey and second survey, indicating an upward trend in all regions and age groups surveyed.
Background: Bronchial asthma (BA) and allergic rhinitis (AR) are thought to share a common pathogenesis. However, reports concerning the comorbidity of the two diseases in a large-scaled population are rare in Japan. In the present study, we performed an analysis on the two diseases using questionnaires that addressed the diagnosis, symptoms and period of occurrence in more than 10,000 patients with BA or AR. Methods: Patients with BA (adult: n = 2,781, childhood: n = 3,283) and AR (n = 3,945) were enrolled in the present study during the 3 months from August 1, 2006 to October 31, 2006. Results: Sixty one percent of the patients with adult BA showed symptoms of AR. Among them, 68% of the patients were diagnosed with AR. Among the patients with childhood BA, 68% showed AR symptoms and 60% were diagnosed with AR. On the other hand, 49% of AR patients showed BA symptoms and 35% of them were diagnosed with BA. The symptoms of both BA and AR in the BA and AR patients were frequent in two seasons, March and April, and September and October. In addition, BA and AR symptoms often co-occurred in the patients with BA and AR. Conclusions: Comorbidity of BA and AR was high in both populations of BA and AR. The symptoms of both BA and AR co-occurred on both a daily and seasonal basis. These results suggested that BA and AR share a common immuno-pathogenesis in the airway and need to be treated as a single airway disease.
Background: Allergen specific immunotherapy is highly effective, but adverse events may occur during treatment. Peptide-based immunotherapy has been proposed as one of new strategies for reduction of allergic adverse reactions. We examined the possibility of candidate peptides for the development of peptide-based immunotherapy for Japanese cedar pollinosis. Methods: Twelve Cry j 1-specific T-cell lines were established from peripheral blood mononuclear cells (PBMC) of 12 patients with Japanese cedar pollinosis. Using these T-cell lines, 37 Cry j 1-derived overlapping peptides were assessed for their proliferative responses and cytokine production. Results: Four peptides corresponding to the Cry j 1 sequence were able to induce proliferative responses to more than one T-cell line: p61-80 (3/12; 25.0%); p115-132 (2/12; 16.6%); p206-225 (4/12; 33.3%); and p337-353 (5/12; 41.7%). Furthermore, T-cell lines generated from 11 of 12 donors (91.7%) responded to at least one of these four peptides. On the other hand, the pattern of cytokine production from Cry j 1-specific T-cell lines varied. Moreover, cytokine production patterns by stimulation with Cry j 1 peptide did not reflect those by stimulation with Cry j 1 protein. Conclusions: Our results suggest four Cry j 1-derived peptides (p61-80, p115-132, p206-225 and p337-353) may be considered to be the immunodominant T-cell epitopes of the Cry j 1 molecule, and can be useful for the design of peptide-based immunotherapy for the management of Japanese cedar pollinosis.
Background: People suffering from asthmatic symptoms have a lower quality of life than those without. The aim of this study is to clarify the association of quality of life with the severity of asthma, perceived stress, and other factors such as the comorbidity of allergic diseases among young adults with asthma. Methods: The study participants were 695 asthma patients, aged 20-44 years, from 29 medical centers in Japan. We excluded from the analysis of the result of the study 116 patients with complications of serious diseases, cough-variant asthma or aspirin-intolerant asthma. The patients completed the 8-Item Short-Form Health Survey (SF-8), the Airways Questionnaire 20 (AQ20), and the Japanese version of the Perceived Stress Scale (JPSS) and their doctors also provided clinical information including diagnosis, complications, severity of asthma, and results of pulmonary function and immunological tests. Results: There was a weak correlation between the generic quality of life (SF-8) and the disease-specific quality of life (AQ20). The AQ 20 revealed almost no association with the results of pulmonary function and immunological tests, and only a slight association with comorbidity of allergic rhinitis and food allergy. The AQ20 showed a moderate relation with perceived stress (JPSS) but a weak association with the severity of asthma. The multiple logistic models demonstrated that there was no relationship between the severity of asthma and the AQ20 in females, and in the age group of 20-34 years. Conclusions: A major variable related to the disease-specific quality of life was perceived stress, followed by the severity of asthma. Stress management of patients with asthma may improve their quality of life.
Background: The therapeutic use of Kampo medicine, Sho-seiryu-to (SST) in allergic disorders is well known. As histamine plays a central role in allergic diseases, it is possible that SST affects the allergy-related histamine signaling. In this study, we investigated the effect of SST on allergy-related histamine signaling in the nasal mucosa of toluene 2, 4-diisocyanate (TDI)-sensitized nasal allergy model rats. Methods: Six-week-old male, Brown Norway rats were sensitized for 2 weeks with 10μl of 10% TDI, and after a 1 week interval, provocation was initiated with the same amount of TDI. SST (0.6g/rat) was given orally 1 hour before TDI treatment began for a period of 3 weeks. Nasal symptoms were scored for 10 minutes immediately after TDI-provocation. The genes expression in nasal mucosa was determined using real-time quantitative RT-PCR. Results: SST significantly suppressed TDI-induced nasal allergy-like symptoms. TDI provocation showed a significant up-regulation of histamine H1 receptor (H1R) and histidine decarboxylase (HDC) gene expressions. Prolonged pre-treatment of SST significantly suppressed the mRNA levels of H1R and HDC that was up-regulated by TDI. SST also suppressed TDI-induced interleukin (IL)-4 and IL-5 mRNA elevation. However, SST showed no significant effect for TDI-induced mRNA elevation of IL-13. Conclusions: These results demonstrate that SST alleviates nasal symptoms by the inhibition of histamine signaling through suppression of TDI-induced H1R and HDC gene up-regulation. SST also suppresses cytokine signaling through suppression of IL-4 and IL-5 gene expression. Suppression of histamine signaling may be a novel mechanism of SST in preventing allergic diseases.
Background: The addition of leukotriene modifier (LM) may be a useful approach for uncontrollable asthma despite treatment with inhaled corticosteroid (ICS), especially in asthmatics comorbid with allergic rhinitis (AR), although little is known about its molecular mechanism. We evaluated the additive effects of LM with ICS on pulmonary function and airway inflammation in asthmatics with or without AR. Methods: Eighteen uncontrolled steroid-treated asthmatics, nine with and nine without AR, were enrolled. Spirometry, peak expiratory flow (PEF) measurements, and exhaled breath condensate sampling were performed before and 8 weeks after LM administration. The lowest PEF over the course of one week, expressed as a percentage of the highest PEF (Min%Max PEF), was used as an index of fluctuation of the airway caliber. Airway cytokine expression was analyzed with a protein array. Results: A significant improvement in forced expiratory volume in one second as a percentage of the predicted value (%FEV1) and Min%Max PEF was seen in the subgroup of asthma with AR. Although there was no significant difference in the baseline cytokine values between the groups, the exhaled RANTES level was significantly reduced by LM in the asthma with AR group. The changes in the RANTES level were significantly related to the changes in the %FEV1 and Min%Max PEF values. Conclusions: LM caused a greater improvement in pulmonary function and airway inflammation in asthmatics with AR. The RANTES-mediated pathway may be involved in the improvement of the airflow limitation and airway lability by LM additive therapy in asthmatics receiving steroid therapy.
Background: Transforming growth factor β1 (TGFβ1) is an important factor in immunomodulation. The expression of TGFβ1 has been shown to be influenced by the C-509T polymorphism in the TGFβ1 gene. We investigated age-related changes of plasma TGFβ1 levels in a birth-cohort study. In addition, the genotypes of the C-509T polymorphism were investigated in allergic and non-allergic subjects. Methods: Sixty-four neonates who met the following criteria were enrolled in this cohort study: 1) full-term vaginally delivery; 2) underwent DNA polymorphism analysis; and 3) questionnaire forms were filled out by parents at 0, 6 and 14 months of age. The umbilical cord blood at 0 months and peripheral blood at 6, and 14 months were collected. Plasma TGFβ1 levels were measured at 0, 6 and 14 months of age. Genomic DNA was extracted from their umbilical cord blood. The genotype of the subjects was examined for the presence of C-509T. Results: The plasma TGFβ1 level at 6 months was the highest of the 3 measurements (at 0, 6, and 14 months of age). The TGFβ1 levels at 14 months in allergic subjects were significantly higher than those in non-allergic subjects (p = 0.03). All subjects with bronchial asthma (n = 3) had the TT genotype of the C-509T polymorphism. Conclusions: The plasma TGFβ1 levels change with age. In addition, TGFβ1 may play a role in the pathogenesis of bronchial asthma.
Background: Interactions between eosinophils and monocytes after lipopolysaccharide inhalation are yet to be investigated. The mechanism of eosinophil activation induced by lipopolysaccharide in the presence of monocytes was investigated. Methods: Expression of ICAM-1 and Mac-1 on eosinophils was evaluated after lipopolysaccharide stimulation in the presence of monocytes or monocyte culture supernatants. Cytokines in the supernatant of lipopolysaccharide-stimulated monocytes were measured using a cytokine array. Results: Expression of ICAM-1 and Mac-1 on eosinophils was up-regulated after lipopolysaccharide stimulation in the presence of monocytes or monocyte culture supernatant. Lipopolysaccharide induced secretion of ENA-78, GMCSF, GRO, IL-1beta, IL-6, IL-10, MCP-1, TNF-alpha and MIP-3 alpha from monocytes. The up-regulation of ICAM-1, but not Mac-1, on eosinophils was attenuated by anti-TNF-alpha neutralizing antibody. Conclusions: Monocyte-derived TNF-alpha plays an important role in the up-regulation of ICAM-I on eosinophils induced by lipopolysaccharides.
Background: IgA deficiency (IgAD) is the most common immunodeficiency, however the pathogenesis in most cases of IgAD is unknown. There are 2 subclasses of IgA, IgA1 and IgA2, and its heavy chains are encoded by 2 different genes, the α1 and α2 genes. To investigate the molecular pathogenesis of IgA deficiency, it is important to evaluate each of the expressions of IgA1 and IgA2 separately. Methods: In this study, we report on the reverse transcriptase (RT)-PCR method in which α1 and α2 mRNAs can be separately evaluated. This method is based on electrophoretic separation using the difference of 39 bases between α1 and α2 mRNAs. Three selective, 5 partial and 2 secondary IgAD patients were examined. Results: In the 3 selective IgAD patients, no α1 or α2 mRNA expression was detected. In the 5 partial IgAD patients, various α1 and α2 mRNA expression patterns were found. One of the partial IgAD patients showed only α2 gene expression, but not α1 gene expression, and was found to show an α1 gene deletion together with γ2 and ε gene deletions. His plasma IgA2 level was within the normal range. Conclusions: Patients with an α1 gene deletion can be considered as having partial IgAD. Using this method, we identified the second case of α1 gene deletion in Japan, and classified IgAD patients on the basis of α1 and α2 expression.
Background: We have recently found that exposure to acute restraint stress suppresses antigen-specific antibody production, including IgE, in a murine model of allergic rhinitis. Although age-related alterations in immune responses are known, it remains unclear whether aging modulates the antibody production under stressful conditions. In this study, we set out to determine the effects of aging on antibody production under acute restraint stress in mice. Methods: Both young and aged CBA/J mice were repeatedly sensitized intranasally with phospholipase A2 (PLA2) without adjuvants. Restraint stress was applied using uniform cylinders once a week for a continuous 8h period, on 5 occasions in total. Blood samples were taken at 0, 20 and 30 days after primary sensitization, and production of PLA2-specific antibodies and levels of IL-4, IFN-γ, IL-10 and IL-1β in sera were determined by ELISA. Results: Repeated intranasal sensitization with PLA2 induced PLA2-specific IgE, IgG1 and IgG2a production in aged mice. We found that exposure to restraint stress significantly inhibited production of PLA2-specific IgE, IgG1 and IgG2a in aged mice. In addition, antibody production under restraint stress decreased significantly in aged mice when compared with young mice. No IL-4, IFN-γ, IL-10 or IL-1β were detected in sera from non-stressed or stressed aged mice. Conclusions: Aging exacerbates the immunosuppressive role of acute restraint stress in antigen-specific antibody production in mice.
Background: Histamine is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 (H1R), H2R, H3R and H4R. However, its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified. Objective: This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice (Hdc-/- mice) with allergic airway inflammation. Methods: Wild-type and Hdc-/- C57BL/6 mice were sensitized with ovalbumin (OVA). After a 2-week exposure to OVA, goblet cell hyperplasia was evaluated. Cell differentials and cytokines in BALF were analyzed. The mRNA levels of MUC5AC and Gob-5 gene were determined quantitatively. Results: The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc-/- mice with OVA inhalation. In addition, the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc-/- mice with OVA inhalation compared to the wild-type mice under the same conditions. The concentrations of Interleukin-4 (IL-4), IL-5, IL-13, Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and IL-2 in the BALF all increased significantly in both groups compared to those exposed to saline. In particular, the concentration of TNF-α in the Hdc-/- mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions. The mRNA levels of Gob-5 and MUC5AC, and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc-/- mice exposed to OVA compared to wild-type mice. Conclusions: These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation.
Background: A type-IV-allergic reaction to German camomile (Matricaria chamomilla) in a form of allergic contact dermatitis is not unusual. However, only a few cases of anaphylactic reaction to camomile have been described in the literature. Case Summary: We present the case of a 38-year-old Caucasian man who developed an episode of severe anaphylaxis with generalized urticaria, angioedema and severe dyspnoea one hour after consuming camomile tea. Laboratory examination demonstrated a total serum IgE of 123kU/l with specific IgE against camomile (4.94kU/l, class 3). Skin prick test and labial provocation test with camomile showed a strong positive reaction. Discussion: Our case confirms the presence of a type-I allergy to orally ingested camomile and indicates that the incidence and risk may be underestimated. Additonal response to mugwort and pollen-derived food allergens should be evaluated in patients sensitised to camomile due to a higher incidence of allergic cross-reactivity.
We encountered two patients with severe cow's milk allergy who reacted strongly to an injection of methylprednisolone sodium succinate (Sol-Medrol 40mg® Pfizer, Japan). They came to our hospital because of an asthmatic attack or urticaria and were treated with Sol-Medrol 40mg®. After the injection, the allergic reaction was immediate. Skin prick tests demonstrated that the β-lactoglobulin contaminating the lactose of the drug preparation caused the immediate allergic reaction.
Background: As patients share in the decision-making process regarding treatments they receive, it is important that they can discriminate between reliable and unreliable sources of information about potential treatments. Methods: In this study, health professionals and patients were asked to assess the reliability of information contained in pamphlets on treatments for asthma and atopic dermatitis using a new Japanese translation of an instrument called DISCERN. The scores given by both groups were analyzed to assess inter-rater agreement. The same DISCERN instrument was used by health professionals to evaluate websites on treatments for atopic dermatitis and the degree of inter-rater agreement was assessed again. Results: There was a greater inter-rater agreement between health professionals than between patients. When health professionals used the instrument to evaluate websites, the final rankings given were consistent between different raters, showing good inter-rater agreement. Conclusions: We conclude that DISCERN is useful for evaluating the reliability of medical information both in pamphlets and on the internet, although it is used more effectively by health professionals than by patients. Further studies are needed on the use of DISCERN by patients in evaluating websites containing medical information.