[A MULTICENTER CLINICAL SURVEY ABOUT THE PREVALENCE OF JAPANESE CYPRESS POLLINOSIS AND THE EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH JAPANESE CEDAR POLLEN EXTRACT DURING JAPANESE CYPRESS POLLEN DISPERSAL PERIOD].

BACKGROUND: Little is known whether sublingual immunotherapy using Japanese cedar pollen extract (cedar SLIT) is effective for not only Japanese cedar pollinosis but also Japanese cypress pollinosis. We investigated the prevalence rate of Japanese cypress pollinosis, efficacy of cedar SLIT on cypress pollinosis and patients' wish to receive cypress SLIT. METHODS: We investigated a multi-center (31 institutions), cross-sectional survey using a self-administrated questionnaire with four questions for patients received cedar SLIT aged from 5 to 69 years old. RESULTS: 2523 subjects were enrolled for analysis. 83.4% of them had pollinosis symptoms during cypress season before cedar SLIT. In such patients, 37.4% experienced lessened efficacy of cedar SLIT during cypress season. Both the prevalence of cypress pollinosis and the lessened efficacy of cedar SLIT on cypress pollinosis were significantly seen in western Japan as compared to eastern Japan. 76.1% of the subject having cypress pollinosis before SLIT wished to receive cypress SLIT if it is available. CONCLUSION: A lessened efficacy of cedar SLIT during cypress season was broadly seen in Japan, and further showed a regional difference. Together with the finding of high wish by patients, these results suggest a development of cypress SLIT is desirable.

Japanese cedar and cypress pollinosis updated: New allergens, cross-reactivity, and treatment.

Pollen from many tree species in the Cupressaceae family is a well-known cause of seasonal allergic diseases worldwide. Japanese cedar pollinosis and Japanese cypress pollinosis, which are caused by pollen from Japanese cedar (Cryptomeria japonica) and Japanese cypress (Chamaecyparis obtusa), respectively, are the most prevalent seasonal allergic diseases in Japan. Recently, the novel major Japanese cypress allergen Cha o 3 and the homologous Japanese cedar allergen Cry j cellulase were identified, and it was shown, for the first time, that cellulase in plants is allergenic. Although the allergenic components of pollen from both species exhibit high amino acid sequence identity, their pollinosis responded differently to allergen-specific immunotherapy (ASIT) using a standardized extract of Japanese cedar pollen. Pharmacotherapy and ASIT for Japanese cedar and cypress pollinosis have advanced considerably in recent years. In particular, Japanese cedar ASIT has entered a new phase, primarily in response to the generation of updated efficacy data and the development of new formulations. In this review, we focus on both Japanese cypress and cedar pollinosis, and discuss the latest findings, newly identified causative allergens, and new treatments. To manage pollinosis symptoms during spring effectively, ASIT for both Japanese cedar and Japanese cypress pollen is considered necessary.

Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.

Characterization of a 7 kDa pollen allergen belonging to the gibberellin-regulated protein family from three Cupressaceae species.

BACKGROUND: Severe allergy to fruits mediated by a 7 kDa allergen belonging to the gibberellin-regulated protein (GRP) family is known to be associated with Cupressaceae pollinosis. OBJECTIVE: To identify and characterize Cupressaceae pollen allergens involved in GRP-related fruit allergy. METHODS: Pru p 7-related proteins from pollen of Cupressus sempervirens, Juniperus ashei and Cryptomeria japonica were identified using a rabbit anti-Pru p 7 antiserum, purified chromatographically and sequenced by mass spectrometry and bioinformatic comparisons. The C sempervirens protein was produced as a recombinant allergen in Pichia pastoris. IgE antibody binding to pollen GRP proteins was analysed in a peach allergic (n = 54) and a cypress pollen allergic (n = 88) patient population from southern France using ImmunoCAP. RESULTS: In each of the three Cupressaceae species studied, a 7 kDa pollen protein related to Pru p 7 was identified and found to comprise an amino acid sequence of 63 residues in length, 92%-98% identical to each other and 67%-68% identical to Pru p 7. The C sempervirens, J ashei and C japonica GRP allergens have been officially recognized by the WHO/IUIS Allergen Nomenclature Sub-Committee and named Cup s 7, Jun a 7 and Cry j 7, respectively. Recombinant Cup s 7 showed IgE antibody binding capacity comparable to that of the purified natural allergen. Among 51 peach allergic subjects sensitized to Pru p 7, substantially higher levels of IgE to Cup s 7 than to Pru p 7 were found. Further, the pollen protein was able to completely outcompete IgE binding to Pru p 7, while the reverse competition effect was modest, consistent with primary sensitization by the pollen allergen. CONCLUSION AND CLINICAL RELEVANCE: Pru p 7-related pollen allergens from three Cupressaceae species have been characterized and may become useful for the identification of pollinosis patients at risk of developing severe fruit allergy.

Pru p 7 sensitization is a predominant cause of severe, cypress pollen-associated peach allergy.

BACKGROUND: Peach is a common elicitor of food allergic reactions. Peach-induced immediate reactions may occur as benign pollen-food syndromes, usually due to birch pollen-related PR-10 cross-reactivity in temperate climates, and as potentially severe primary food allergies, predominantly related to nsLTP Pru p 3 in Mediterranean regions. The newly described peach allergen Pru p 7 has gained recent attention as a potential peach allergy severity marker. Sensitization to Pru p 7 and its allergenic homologues of the gibberellin-regulated protein family occurs in areas with high Cupressaceae tree pollen exposure. OBJECTIVE: We sought to investigate the distribution, clinical characteristics and molecular associations of Pru p 7 sensitization among subjects with suspected peach allergy in different regions of France. METHODS: Subjects with suspected peach allergy (n = 316) were included. Diagnostic work-up was performed according to current guidelines, including open food challenge when required. IgE antibody measurements and competition experiments were performed using the ImmunoCAP assay platform. RESULTS: Sensitization to Pru p 7 was present in 171 (54%) of all subjects in the study and in 123 of 198 (62%) diagnosed as peach allergic, more than half of whom were sensitized to no other peach allergen. Frequency and magnitude of Pru p 7 sensitization were associated with the presence of peach allergy, the clinical severity of peach-induced allergic reactions and the level of cypress pollen exposure. Cypress pollen extract completely outcompeted IgE binding to Pru p 7. Pru p 7 was extremely potent in basophil activation tests. CONCLUSION AND CLINICAL RELEVANCE: A subtype of Cupressaceae pollinosis, characterized by Pru p 7 sensitization, can be an underlying cause of severe peach allergy.

Genome-wide association study for pollinosis identified two novel loci in interleukin (IL)-1B in a Japanese population.

The number of pollinosis patients in Japan has significantly increased over the past 20 years. The majority of genome-wide association studies (GWAS) on pollinosis have been conducted in subjects of European descent, with few studies in Japanese populations. The aim of our GWAS was to identify genetic loci associated with self-reported pollinosis in a Japanese population and to understand its molecular background using a combination of single nucleotide polymorphisms (SNPs) and gene- and pathway-based analyses. A total of 731 and 560 individuals who were recruited as participants of the Japan Multi-Institutional Collaborative Cohort Study participated in the discovery and replication phases, respectively. The phenotype of pollinosis was based on the information from a self-administered questionnaire. In the single-SNP analysis, four SNPs (rs11975199, rs11979076, rs11979422, and rs12669708) reached suggestive significance level (P < 1 × 10-4) and had effects in the same direction in both phases of the study. The pathway-based analysis identified two suggestive pathways (nucleotide-binding oligomerization domain -like receptor and tumor necrosis factor signaling pathways). Both rs1143633 and rs3917368 in the interleukin-1B gene showed associations in the retrace (from pathway to gene and SNP) analysis. We performed single-SNP, gene, and pathway analysis and shed light on the molecular mechanisms underlying pollinosis in a Japanese population.

Cypress pollen allergy is responsible for two distinct phenotypes of allergic rhinitis different from other pollinosis.

Summary: Different phenotypes of allergic rhinitis have been identified based on the seasonality of the allergen involved. Within pollinosis, importance has to be paid to the responsible pollen species. Guidelines for clinical management are mostly based on studies performed in patients with grass pollen allergy. Only few data is available on tree pollen allergy and more specifically on cypress pollen allergy. We focused on the clinical and biological features of cypress pollen allergy to determine whether it is associated with a specific phenotype of allergic rhinitis or not. Our results suggest that cypress pollen can be responsible for two distinct phenotypes of rhinitis, both different from other pollinosis. In the most common phenotype, cypress pollen was not responsible for bronchial hyperresponsiveness or systemic inflammation. Close attention has to be paid to the allergen involved in allergic rhinitis. Different phenotypes leading to different pharmacological strategies may apply.

Cha o 3, a cypress pollen allergen, does not activate basophils in Japanese cypress pollinosis.

Background: In Japan, pollinosis caused by the Japanese cypress (JCy) Chamaecyparis obtusa is among the very common seasonal allergies. In JCy pollinosis, Cha o 1 is the first major allergen, and Cha o 2 is the second major allergen. Recently, Cha o 3 was identified as a new JCy pollen allergen in JCy pollinosis. However, the relative contribution of Cha o 3 to JCy pollinosis compared with that of Cha o 1 and that of Cha o 2 has not been fully elucidated. Objective: This study aimed to clarify the allergenicity of Cha o 3 compared with that of Cha o 1 and Cha o 2 in JCy pollinosis. Methods: We recruited 27 patients with JCy pollinosis and performed the basophil activation test (BAT) with native (n) Cha o 1, Cha o 2, and Cha o 3 purified from JCy pollen. In addition, we a performed JCy-specific IgE suppression test. Results: In the BAT, 26 of 27 patients (96%) and 18 of 27 patients (67%) showed positive basophil activation in response to n Cha o 1 and n Cha o 2, respectively, as judged by CD203c expression. Little CD203c expression in response to n Cha o 3 was seen. The presence of n Cha o 3 marginally reduced the titer levels of JCy-specific IgE. Conclusion: Cha o 3 showed little ability to activate basophils and suppress JCy-specific IgE titers compared with Cha o 1 or Cha o 2 in patients with JCy pollinosis. Thus, Cha o 3 may not be a major allergen in JCy pollinosis.

Histamine antagonist Bepotastine suppresses nasal symptoms caused by Japanese cedar and cypress pollen exposure.

Objective: To determine the efficacy of the antihistamine bepotastine on treating nasal symptoms in patients with Japanese cedar and cypress pollinosis, based on two previous studies that looked at bepotastine OD's inhibitory effect on symptom onset after exposure. Design and methods: Randomized double-blind placebo controlled, parallel study. Twenty-eight volunteers with Japanese cedar and cypress pollinosis were randomly assigned into two experimental groups: a bepotastine-treated or a placebo control group. Subjects received either 10 mg bepotastine tablets or placebo tablets 1 day before entering an artificial exposure pollen chamber (OHIO Chamber) and also for three or more consecutive days. They were exposed to Japanese cedar and cypress pollen for 3 h per day for 2 days. Nasal and ocular symptoms were self-rated by each patient at regular intervals in addition to being objectively measured. Possible cognitive impairment was assessed by using the digit cancellation test (D-CAT). Results: In Study 1, under controlled conditions, there were no significant differences (p > .05) between subjects exposed to Japanese cedar pollen and those exposed to cypress pollen in terms of total nasal symptom score (TNSS). In Study 2, in the placebo group, the amount of nasal discharge and the number of sneezes did not diminish before cypress pollen exposure on the second day (p < .05). This suggests that an antihistamine can suppress the symptoms of hang over. No deterioration of work performance was observed in the bepotastine group after pollen exposure for 2 days, as measured by D-CAT (p > .05). Conclusion: We conclude that bepotastine can suppress allergy-related symptoms without impairing work performance in subjects with seasonal allergic rhinitis caused by Japanese cedar pollen or cypress pollen.