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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., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Cha o 3 is a newly found glycosylated allergen from Chamaecyparis obtusa (Japanese cypress) pollen. The deduced amino acid sequence of Cha o 3 indicates that this glycoallergen contains a cellulase domain and a number of putative N-glycosylation sites. However, the structures of N -glycans linked to Cha o 3 remain to be determined. In this study, therefore, we analyzed the glycoform of Cha o 3 and found that this glycoallergen carries exclusively plant complex-type N-glycans; major structures were GlcNAc 2 Man 3 Xyl 1 Fuc 1 GlcNAc 2 (39%), Gal 1 Fuc 1 GlcNAc 2 Man 3 Xyl 1 Fuc 1 GlcNAc2 (14%), and Gal 2 Fuc 2 GlcNAc 2 Man 3 Xyl 1 Fuc 1 GlcNAc 2 (25%). The glycoform of Cha o 3 bearing the Le a epitope is similar to those of Cry j1, Jun a 1, or Cup a 1, major glycoallergens in cedar or cypress pollens, and the predominant occurrence of GlcNAc 2 Man 3 Xyl 1 Fuc 1 GlcNAc 2 is a common structural feature of glycoallergens from Cupressaceae pollens., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Sublingual immunotherapy (SLIT) appears to offer practical advantages for the treatment of allergic rhinitis (AR). Based on a review of the scientific literature, we present recommendations as guiding principles to administer SLIT safely., Methods: Clinical questions concerning SLIT were prepared. Literature published between January 2003 and December 2012 was searched from PubMed, the Cochrane Library, and Japana Centra Revuo Medicina. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. We answered 17 clinical questions and, based on this, presented evidence-based recommendations., Results: Sublingual immunotherapy improved symptoms (e.g., quality of life [QOL]) and reduced medication scores in seasonal AR and perennial AR. Most SLIT-induced adverse effects were local oral reactions, although systemic adverse effects such as gastrointestinal symptoms, urticaria, and asthma are occasionally reported. There have been no reports of lethal anaphylactic reactions by SLIT. When SLIT is continued for 3-4 years, its effect persists long after discontinuation., Conclusion: A correct diagnosis of AR and sufficient informed consent from patients are required before initiating SLIT. Sublingual immunotherapy should be continued for 3 years or longer. The initial administration of SLIT during the uptitration of an allergen vaccine and the general condition of patients are critical for the safe performance of SLIT., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: In anticipation of the development of guidelines for antigen-specific subcutaneous immunotherapy (SCIT), we present recommendations that can serve as guiding principles based on a review of the scientific literature., Methods: Clinical questions (CQs) concerning SCIT were prepared. Literature searches for publications between January 1990 and February 2011 were performed in PubMed, the Cochrane Library, and Japana Centra Revuo Medicina Web version 4. Qualified studies were analyzed and the results were evaluated, consolidated, and codified., Results: We present answers for 13 CQs on the indications, methods, effectiveness and mechanisms of SCIT, with evidence-based recommendations., Conclusion: The guiding principles are intended to be applied to children (≤15 years old) and adults (≥16 years old) with allergic rhinitis (AR). These principles can be used by otorhinolaryngologists for diagnosis of AR, evaluation of severity and rhinoscopic findings, performance of antigen challenge tests, and management of systemic anaphylactic reactions associated with SCIT., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: This study intended to assess the severity of Japanese cedar pollinosis using the Practical Guideline for the Management of Allergic Rhinitis in Japan (PG-MARJ) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guideline., Methods: An Internet questionnaire survey of patients with pollinosis was conducted in mid-May 2011 and responses were obtained from 3382 individuals who had potential symptoms of Japanese cedar pollinosis from February to early May 2011 and who had experienced such symptoms for at least two pollen seasons., Results: According to PG-MARJ, 23.5% of the respondents had severest rhinitis, 29.4% severe rhinitis, 31.3% moderate rhinitis, 13.8% mild rhinitis and 2.0% asymptomatic rhinitis. According to ARIA, 67.2% of them had moderate/severe persistent rhinitis, 23.8% moderate/severe intermittent rhinitis, 4.4% mild persistent rhinitis and 4.6% mild intermittent rhinitis., Conclusions: Moderate to severe rhinitis was diagnosed in more than 80% of the respondents according to PG-MARJ, while moderate/severe rhinitis was diagnosed in more than 90% of the respondents according to ARIA. Most of the respondents suffered relatively severe pollinosis. More than 80% of the respondents had all the three major symptoms (i.e., sneezing, rhinorrhea and nasal blockage). Disagreement in the severity assessment between the two guidelines was noted in approximately 20% of the respondents.

PGD(2) is the major prostanoid produced during the acute phase of allergic reactions. Two PGD(2) receptors have been isolated, DP and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), but whether they participate in the pathophysiology of allergic diseases remains unclear. We investigated the role of CRTH2 in the initiation of allergic rhinitis in mice. First, we developed a novel murine model of pollinosis, a type of seasonal allergic rhinitis. Additionally, pathophysiological differences in the pollinosis were compared between wild-type and CRTH2 gene-deficient mice. An effect of treatment with ramatroban, a CRTH2/T-prostanoid receptor dual antagonist, was also determined. Repeated intranasal sensitization with Cry j 1, the major allergen of Cryptomeria japonica pollen, in the absence of adjuvants significantly exacerbated nasal hyperresponsive symptoms, Cry j 1-specific IgE and IgG1 production, nasal eosinophilia, and Cry j 1-induced in vitro production of IL-4 and IL-5 by submandibular lymph node cells. Additionally, CRTH2 mRNA in nasal mucosa was significantly elevated in Cry j 1-sensitized mice. Following repeated intranasal sensitization with Cry j 1, CRTH2 gene-deficient mice had significantly weaker Cry j 1-specific IgE/IgG1 production, nasal eosinophilia, and IL-4 production by submandibular lymph node cells than did wild-type mice. Similar results were found in mice treated with ramatroban. These results suggest that the PGD(2)-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice.

Background: Signal transducer and activator of transcription (STAT) 1 signaling pathway mediates biological functions of interferon (IFN) gamma, which is a key cytokine-regulating T helper 1 (Thl) differentiation. Although constitutive activation of STAT1 has been reported in the airway epithelium of patients with chronic asthma, its in vivo role in the pathogenesis of allergic rhinitis is not clear. We determined the role of STAT1 in the pathogenesis of allergic rhinitis in vivo using STAT1 gene-deficient (STAT1-/-) mice and a murine model of Schistosoma mansoni egg antigen (SEA)-induced allergic rhinitis., Methods: STATI -/- BALB/c and wild-type (WT) mice were sensitized by intranasal administration of SEA, and their immunologic responses were examined., Results: STATI-1- mice showed impaired nasal eosinophilia and markedly reduced histamine-induced nasal hyperresponsiveness after SEA sensitization. Moreover, levels of Th2-associated SEA-specific IgG1 and IgE antibodies were lower in STAT1-/- mice. Anti-CD3stimulated nasal lymphocytes from STAT1-/-mice also produced less amounts of Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 compared with WT mice, but both produced comparable levels of IFN-gamma., Conclusion: These results show that STAT1 is involved in the pathogenesis of SEA-induced allergic rhinitis in BALB/c mice. Furthermore, they reveal a surprising role of STAT1 in induction of nasal eosinophilia, and Th2-type cytokine production from nasal lymphocytes during allergic rhinitis.

In our previous study (Y. Kimura et al., Biosci. Biotechnol. Biochem., 69, 137-144 (2005)), we found that plant complex type N-glycans harboring Lewis a epitope are linked to the mountain cedar pollen allergen Jun a 1. Jun a 1 is a glycoprotein highly homologous with Japanese cedar pollen glycoallergen, Cry j 1. Although it has been found that some plant complex type N-glycans are linked to Cry j 1, the occurrence of Lewis a epitope in the N-glycan moiety has not been proved yet. Hence, we reinvestigated the glycoform of the pollen allergen to find whether the Lewis a epitope(s) occur in the N-glycan moiety of Cry j 1. From the cedar pollen glycoallergen, the N-glycans were liberated by hydrazinolysis and the resulting sugar chains were N-acetylated and then coupled with 2-aminopyridine. Three pyridylaminated sugar chains were purified by reversed-phase HPLC and size-fractionation HPLC. The structures were analyzed by a combination of exo- and endo-glycosidase digestions, sugar chain mapping, and electrospray ionization mass spectrometry (ESI-MS). Structural analysis clearly indicated that Lewis a epitope (Galbeta1-3(Fucalpha1-4)GlcNAcbeta1-), instead of the Galbeta1-4(Fucalpha1-6)GlcNAc, occurs in the N-glycans of Cry j 1.

We have determined the structures of N-glycans linked to major allergens in the mountain cedar (Juniperus ashei) pollen, Jun a 1. First, two kinds of the pollen glycoallergen (Jun a 1-A and Jun a 1-B) were purified from partially purified Jun a 1 by cation exchange chromatography. The N-glycans were liberated by hydrazinolysis from the two glycoallergens and the resulting sugar chains were N-acetylated and then coupled with 2-aminopyridine. Three pyridylaminated sugar chains were purified by reversed-phase HPLC and size-fractionation HPLC from Jun a 1-A and Jun a 1-B respectively. The structures were determined by a combination of exo- and endo-glycosidase digestions, two dimensional sugar chain mapping, and electrospray ionization mass spectrometry (ESI-MS) analysis. Structural analysis indicated that Lewis a epitope (Galbeta1-3(Fucalpha1-4)GlcNAcbeta1-) occurs in the N-glycans of the pollen allergens.

Summary In Japan, pollen from Japanese cedar ( Cryptomeria japonica) and Japanese cypress ( Chamaecyparis obtusa), species that have been planted in approximately 4.5 and 2.6 million ha, respectively, is spread wide through aerial dispersion in spring. Consequently, Japanese cedar/cypress pollinosis ( JCCP) is the major phenotype of allergic rhinitis ( AR) in Japan, and significantly impairs the quality of life ( QOL). Compared with Japanese cedar pollinosis, the pathogenesis and management of Japanese cypress pollinosis remain unclear. Cha o 1 and Cha o 2 are major allergens in Japanese cypress pollen, and have considerable homology with Cry j 1 and Cry j 2, respectively, in Japanese cedar pollen. Several other components were recently identified in Japanese cypress pollen, and may facilitate allergic inflammation via IgE-independent mechanisms. Allergen-specific CD4+ Th2 cells producing interleukin ( IL)-4, IL-5, IL-13 and IL-31 are believed to play central roles in the pathogenesis of AR. The major human T cell epitopes in Cha o 1 and Cha o 2 have been identified. Compared with those in Cry j 1 and Cry j 2, both common and unique T cell epitopes in the cypress allergens have been characterized. Peripheral blood mononuclear cells ( PBMCs) produced these Th2-type cytokines in response to a crude extract of Japanese cypress pollen. Among these cytokines, induction of antigen-specific IL-5 and IL-31 production is closely associated with the onset and exacerbation of Japanese cypress pollinosis, respectively. Allergen-specific immunotherapy using a standardized extract of Japanese cedar pollen is effective in controlling both naso-ocular symptoms and QOL during the period of cedar pollen dispersion, although the significant efficacy tends to be reduced during the period of cypress pollen dispersion, especially when the pollen dispersion is high. IL-5 production by PBMCs in response to the crude extract of Japanese cypress pollen did not differ significantly between patients with and without the immunotherapy, suggesting that unique component(s) in Japanese cypress pollen can induce IL-5 production, which is not fully suppressed by immunotherapy with the standardized extract of cedar pollen. The Practical Guideline for Management of Allergic Rhinitis in Japan recommends that patients who experience severe symptoms of pollinosis every year should receive early interventional treatment. Although early interventional treatment with a histamine H1 receptor antagonist ( H1RA) is effective for Japanese cedar pollinosis, especially at the beginning of the season, this treatment has limitations for Japanese cypress pollinosis when exposure to the pollen is high. Combined therapy with a leukotriene receptor antagonist and/or intranasal corticosteroids may be required to fully control the worsening of JCCP during the cypress pollen season. [ABSTRACT FROM AUTHOR]

The article reports on results of a study of glycoform analysis of Japanese cypress or Chamaecyparis obtusa pollen allergen, Cha o 1. A description of the experimental set-up and measurement methods is presented. The study showed that the major N-glycan structure of allergen is GlcNAc2Man3Xyl1-Fuc1GlcNAc2 and that high-mannose type structures occur as minor components.

Background To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. Methods Japanese patients aged 5–65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). Results Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. Conclusions Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU. [ABSTRACT FROM AUTHOR]

• Japanese HDM Allergic rhinitis patients without asthma showed a high prevalence of allergic sensitization to the HDM major allergens Der p 1 (94.2%), Der p 2 (97.5%) and Der p 23 (71.7%). The prevalence of Der p 23 specific-IgE was significantly higher in the younger group. • No significant correlation was found between AR symptom scores and concentration of s-IgE towards Der p extract and HDM major allergens (Der p 1, 2 and 23). Der p 23 has recently been recognized as a new house dust mite (HDM) major allergen that may be linked to the development of asthma in HDM allergic patients. This study aimed to investigate the frequency of sensitization to HDM major allergen components including Der p 23 and to examine the correlation between HDM-sensitization and AR symptom score in Japanese HDM allergic rhinitis (AR) patients without allergic asthma. Serum samples (n = 120) collected from Japanese HDM AR patients (12 to 64 years) without asthma were assessed for allergen-specific IgE (s-IgE) by ImmunoCAP (Dermatophagoides pteronyssinus (D. pteronyssinus; Der p) extract, Der p 23) or immunosolid-phase allergen chip (Der p 1, Der p 2). Japanese HDM AR patients without asthma showed a high prevalence of allergic sensitization to the HDM major allergens Der p 1 (94.2%), Der p 2 (97.5%) and Der p 23 (71.7%). No difference in the prevalence was detected for Der p 1 and Der p 2 s-IgE among three age groups. However, the prevalence of Der p 23 s-IgE was significantly higher in the younger group compared to the elderly group. No significant correlation was found between AR symptom scores and concentration of s-IgE towards Der p extract and any of the three HDM major allergens. Although the prevalence of sensitization towards D. pteronyssinus major allergens is high in Japanese AR patients without asthma, there was no correlation between allergen specific IgE including IgE towards Der p 23 and AR symptom in this population. [ABSTRACT FROM AUTHOR]