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.     

In vitro and in vivo biological activities of old and fresh Cupressus arizonica pollen.

BACKGROUND: Respiratory allergy to the pollen of Cupressaceae is becoming more and more common every year in the Mediterranean area. OBJECTIVE: The purpose of this study was to see whether the allergenic potency of Cupressus arizonica pollen diminished after a 6-year period (1994-2000). MATERIALS AND METHODS: Among the Cupressaceae, we selected the pollen of C arizonica. The mode of sampling in 1994 and in 2000 was the same and the pollen was collected on the same tree and stored at room temperature. To compare its biological and allergenic activities data was collected with the following methods: cytohistology of Alexander, 2,3,5-triphenyltetrazolium chloride enzyme staining, skin testing, nasal provocation test, radioallergosorbent test (RAST), RAST inhibition, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and immunoblotting to detect protein content. Thirty-eight patients with respiratory allergy to Cupressaceae were selected. RESULTS: We found no decrease in the allergenic potency of the pollen, but did find that viability and germinating power had disappeared completely after 30 to 40 days. Moreover, the amount of protein in the old pollen was half the amount found in the fresh one. Skin prick testing showed identical results with the old and the fresh pollens. CONCLUSIONS: The allergenic in vivo and in vitro activity of cypress pollen is retained for years after its collection. This activity seems to be independent of the viability of pollen grains and of the total protein content. This may explain the presence of clinical symptoms in patients out of the pollen season.     

Are there any links between Hop Japanese pollen and other weed pollens or food allergens on skin prick tests?

Recent investigations suggest that the importance of Hop Japanese pollen, which has been known as one of the major causative weed pollens, is increasing in this country. There have been few data dealing with the allergenic relationship between Hop J pollen and other food or inhalant allergens. Among 2909 patients who visited the Allergy Clinic of Ajou University Hospital, Suwon, Korea, 471 patients sensitized to Hop J, mugwort, or ragweed pollens on skin-prick test were enrolled. Positive rates to common inhalant or food allergens and their allergenic relationships with other pollens or food allergens were analyzed based upon skin-prick test results. The positive rates to sunflower, fat hen, nettle, grass (Bermuda, Orchard) and tree (alder, birch, and poplar) pollen were significantly higher in those sensitized to Hop J pollen than in those of negative responders (p < 0.05, respectively). No significant associations were noted with ragweed or mugwort pollen (p > 0.05, respectively). In regard to food-related allergens, an association was noted between Hop (Humulus lupulus) or celery allergens in those sensitized to Hop J pollen (p < 0.05, respectively). Hop J pollen may have possible links with celery, Hop, and sunflower pollens on skin-prick test. Further in vitro investigations will be needed to evaluate the possibility of cross-reacting components between them.     

日本柳杉花粉变应原致敏蛋白组分

日本柳杉花粉变应原致敏蛋白组分目前已分离纯化并鉴定的有Cry j 1、Cry j 2、Cry j 3、CJP-6、CJP-4、CJP-8及CPA9等,其中某些致敏蛋白组分还具有多种异构体,因此日本柳杉花粉变应原的成分构成十分复杂。Cry j 1和Cry j 2是目前公认的日本柳杉花粉的主要致敏蛋白组分,二者均为糖蛋白,分子结构中均包含B细胞表位和T细胞表位,也与柏科其他植物花粉致敏蛋白组分具有很高的交叉反应性。其中Cry j 1具有果胶裂解酶活性,Cry j 2则有聚甲基半乳糖醛酸酶活性。后续发现的日本柳杉致敏蛋白组分Cry j 3、CJP-6、CJP-4、CJP-8及CPA9等也均有与花粉症患者血清IgE有较高的结合能力,这些蛋白质特点各异,但都具有与其他植物来源变应原的交叉反应性。     

Recombinant cypress allergens

Cedar/cypress/juniper pollen allergy is probably one of the most common worldwide pollen allergy. Purification, identification and characterization of allergens increased the knowledge about the IgE reactivity of allergic subjects toward defined allergenic components. Molecular biology give the opportunity to produce the allergens in virtually unlimited reproducible amount, to further characterize the IgE reactivity of the allergenic molecule, and finally how this reactivity can be modified for therapeutic purposes. The DNA recombinant technique has been applied to the study of cedar/cypress/juniper pollen allergens and several molecules have been cloned. These molecules can be divided in four groups depending on their biologic activity: he Pectate lyases (rCry j 1, rCha o 1, rJun a 1); the Polygalacturonase (rCry j 2, rCha o 2); the Thaumatin-like pathogenesis-related protein (rJun a 3); the Calcium-binding protein (rJun o 2). Main immunobiologic features of these cedar/cypress/juniper recombinant allergens will be summarized.     

Conifer pollen sensitivity in western New York: cedar pollens.

Cedar pollens might be significant allergens in areas where they have not been so considered but are prevalent. Eastern red cedar (Juniperus virginiana) and white cedar (Thuja occidentalis, American arbor vitae) are common plants in western New York. We analyzed skin test results from 158 patients with asthma, rhinitis, or both; 102 had positive skin tests to at least one pollen. Among those, 52 patients (51%) had positive skin tests to at least one of the cedar pollens. Patients sensitive on skin testing to cedar pollen were strongly likely (p < 0.0001) to be sensitive to deciduous tree, grass, or ragweed pollen. Sensitivity on skin testing to indigenous cedar pollens is common in our area of western New York and therefore could be clinically significant.     

Recognition of T Cell Epitopes Unique to Cha o 2, the Major Allergen in Japanese Cypress Pollen,in Allergic Patients Cross-Reactive to Japanese Cedar and Japanese Cypress Pollen

BackgroundPollens from species of the Cupressaceae family are one of the most important causes of respiratory allergies worldwide. Many patients with pollinosis have specific IgE to both allergens from Japanese cedar and Japanese cypress pollen. We set out to identify T cell epitopes in Cha o 2, the second major allergen of Japanese cypress pollen.MethodsT cell lines (TCL) and T cell clones (TCC) specific to Cha o 2 were generated from allergic patients cross-reactive to Japanese cedar and Japanese cypress pollen. T cell epitopes in Cha o 2 were identified by responses of TCL stimulated with overlapping peptides. Abilities of IL-4/IFN-γ production by TCC were evaluated using enzyme immunoassay.ResultsUsing TCL, 11 dominant and subdominant T cell epitopes were identified in Cha o 2. The subsets of TCC were predominantly of T helper 2-type. A T cell epitope p141-160 in Cha o 2 and corresponding peptide in Cry j 2 showed high homology. Although TCC PC.205.159 responded to stimulation with p141-160 in Cha o 2, it did not respond with corresponding peptide in Cry j 2, therefore, the T cell epitope was unique to Cha o 2.ConclusionsEleven T cell epitopes that were identified are unique to Cha o 2. Cha o 2 is a putative aeroallergen that can potentially sensitize human T cells. We concluded that generation of T cells specific to Cha o 2 in allergic patients acts as one of the causes of continuous allergic symptoms in April.     

Present Situation of Cedar Pollinosis in Japan and its Immune Responses

Recent observations have suggested significant worldwide increase in the prevalence of allergic rhinitis and cedar pollinosis. In Japan, Japanese cedar (Cryptometria japonica) and Japanese cypress (Chamaecyparis obtusa) pollens are considered to be the major unique allergens and their extent of dispersal is quite large, travelling more than 100 km and thus causing serious pollinosis. Cedar pollinosis is a typical type 1 allergic disease by an adaptive immune response that occurs through the induction of allergen-specific effector T cells from naive T cells. We examined the number of Japanese cedar pollen specific memory Th cells in the peripheral blood of the patients and found that the cedar pollen specific IL-4-producing Th2 memory cells increased during the pollen season and decreased during the off-season. However, more than 60% of the cedar-specific memory Th2 cells survived up to 8 months after the pollen season. Natural killer T(NKT) cells represent a unique lymphocyte subpopulation and their activity is not restricted to MHC antigens. NKT cells play an important role in innate immunity, however, the participation in development of allergic rhinitis could not be clarified.     

An epidemiological survey on the allergological importance of some emerging pollens in Italy.

Epidemiological studies on the pollens responsible for allergic diseases throughout Italy are lacking. Routine diagnostic panels consist prevalently of grass, Parietaria, weeds, birch, olive and mugwort. Considering the great variety of Italian geographical areas and the observation of the growing allergological importance of new botanical species (e.g., ambrosia), a survey on pollen species considered "minor" was necessary. A panel of "emerging" pollens (birch, hazelnut, alder, hornbeam, cypress, ragweed) and a routine panel were used to skin prick test 2,934 consecutive outpatients with respiratory pathology of suspected allergic origin, in 21 centers across Italy. A specific questionnaire was compiled. It was found that 20.1% of patients did not react to allergens tested, 28.2% were positive for at least one emerging pollen and 51.7% did not react to emerging pollens but tested positive for at least one allergen from the routine panel. The prevalence of single pollen species was related to geographical areas. Ragweed pollen was shown to provoke asthma much more frequently than other pollens. Hitherto scarcely considered pollens play a considerable role in causing allergic diseases in Italy. In the great majority of patients, positivity for these pollens was associated with positivity to the better recognized group of pollen allergens, although in some cases they were the primary pathogenic agent. We suggest that these more recently considered allergens be included in routine diagnostic panels.     

Pollen proteolytic enzymes degrade tight junctions

BACKGROUND AND OBJECTIVE: Asthma and allergic rhinitis are significant, increasing causes of morbidity worldwide. Pollen, a major cause of seasonal rhinitis/conjunctivitis, carries proteolytic enzymes on its surface. We showed previously that peptidase allergens from house dust mites compromise epithelial barrier function by degrading the extracellular domains of the tight junction proteins, occludin and claudin, thus facilitating allergen delivery across epithelial layers. In this study, we aimed to determine whether peptidases from allergenic pollens should similarly be considered to have a role in disrupting tight junctions. METHODS: Diffusates from stored pollen of Giant Ragweed, White Birch and Kentucky Blue Grass, and fresh pollen from Easter Lily were applied to confluent monolayers of Madin-Darby canine kidney (MDCK) and Calu-3 cells in serum-free medium. Immunofluorescence was performed for the tight junction proteins, occludin, claudin-1 and ZO-1. The effect of pollen diffusate on occludin was studied by Western blotting, and enzymatic activity in the diffusates was demonstrated by zymography. The ability of protease inhibitors to block the action of the diffusate on tight junctions was investigated. RESULTS: Diffusates from all four allergenic pollens caused loss of immunofluorescence labelling for tight junction proteins on MDCK and Calu-3 cells. The effect was blocked by inhibitors of serine and cysteine proteases. Degradation of occludin was demonstrated by Western blotting and zymography indicated that diffusates contain proteolytic activity. CONCLUSIONS: Pollen peptidases directly or indirectly disrupt epithelial tight junctions, and this activity should be considered as a possible mechanism for facilitating allergen delivery across epithelia.     

Identification of Cha o 3 homolog Cry j 4 from Cryptomeria japonica (Japanese cedar) pollen: Limitation of the present Japanese cedar–specific ASIT

Background

About one-third of the Japanese population suffers from Japanese cedar pollinosis, which is frequently accompanied by Japanese cypress pollinosis. Recently, a novel major Japanese cypress pollen allergen, Cha o 3, was discovered. However, whether a Cha o 3 homolog is present in Japanese cedar pollen remains to be determined.

中山市气传花粉调查

目的探讨中山市气传花粉飘散的种类、数量及规律,以指导本地区对花粉症的预防、诊断及免疫治疗。方法采用重力沉降法自制取样器,于2007年在中山市城区进行1年每日花粉曝片调查。结果全年共收集曝片315张,花粉总计数13222粒/1000mm2,花粉种类48种,其中禾本科花粉含量最高,占花粉总计数的27.61%;其次是松属,占26.55%。花粉计数月高峰分布在3月,该月花粉量占全年花粉总计数的31.73%,花粉种类主要为松属、杉柏科、构属和木麻黄科花粉。其次分别为11月及2月,花粉量分别占14.45%及14.37%。11月主要气传花粉为禾本科,2月主要花粉种类与3月相同。结论中山市空气中花粉飘散的数量、种类多,且常年均有飘散;花粉高峰以春季为主;禾本科及松属为该地区优势气传花粉。     

Juniperus ashei: the gold standard of the Cuppressaceae

The non-standardized Cupressus sempervirens allergen extract currently available for the diagnosis of cypress allergy has a low level of activity. The search for an active material consisted of in vitro and in vivo comparison of three Cupressaceae pollen extracts: Cupressus sempervirens (Cs), Cupressus arizonica (Ca) and Juniperus ashei (Ja) (synonyms: Juniperus sabinoides and Mountain Cedar). These 3 trees belong to the same botanical family of Cupressaceae. While Cs and Ca are commonly encountered in Mediterranean regions, Ja is only present in Europe in the Balkans, but is a major cause of allergy in the USA. In vitro, with a similar protein content, the allergenic properties of Ja extract are 20-Fold higher than those of Cs and 11-fold higher than those of Ca. IgE immunoblotting revealed 14, 42 and 70 kDa allergens common to all 3 extracts. The inhibition curves of the 3 extracts were more than 88% parallel. A significant correlation was observed between serum specific IgE titres for Ja and Cs in 23 patients (r = 0.916; p < 0.001). In vivo, in 23 patients with cypress allergy, the mean diameter of the prick test papule at 1/20 W/V of Ja (8.3 mm) was greater than that of the Cs papule (6.3 mm) (p = 0.001) and the Ca papule (6.7 mm) (p < 0.001). Correlations between cutaneous responses to Cs and Ja (r = 0.629; p = 0.002), and to Cs and Ca (r = 0.75; p = 0.001) were significant. These results demonstrate the intense cross-reactivity between Cs, Ca and Ja. The allergenic potency of the Ja extract is superior to that of Cs and Ca extracts, both in vitro and in vivo. This superiority is correlated with a high concentration of the major allergen, Jun a 1. The non-standardized The now standardized extract of in vitro ashei pollen therefore represents an effective and documented solution for identification, and probably for treatment, of Cupressaceae pollen allergy.     

四川省成都市城区气传花粉监测

目的探索四川省成都市城区气传花粉的种类、数量及飘散规律。方法应用重力沉降法于2018年3月1日至2019年2月28日在四川省成都市城区进行为期1年的连续每日气传花粉曝片。结果共收集到花粉139520粒/1000 mm 2,能鉴定的花粉总计隶属36科、31属、2个种。其中构属花粉含量最高,达81754粒/1000 mm 2,占全年花粉总量的58.60%,其播粉期为3~4月,高峰期为3月下半月至4月上半月;其次是柏科花粉,达27518粒/1000 mm 2,占全年花粉总量的19.72%,其播粉期为1~3月,高峰期为1月下旬至3月上旬;大麻/葎草属占第三位,花粉含量5112粒/1000 mm 2,占全年花粉总量的3.66%,其播粉期为8~10月,高峰期为8月下旬至10月下旬。上述3种花粉为本地区优势气传花粉,合计占全年花粉总量的81.98%。含量超过1%的花粉还依次包括银杏、桦木属、松属、悬铃木属、枫杨属及蒿属花粉。全年花粉含量月分布呈现2个高峰,第一高峰为1~5月,主要气传花粉为构属、柏科、银杏、桦木属、松属、悬铃木属、枫杨属等树木花粉,占全年花粉总量的89.38%。第二高峰为8~10月,主要气传花粉为大麻/葎草属、蒿属等莠草花粉,占全年花粉总量的5.04%。结论本地区花粉季节有两个:春季为主要花粉季节,主要气传花粉为构属、柏科等树木花粉;夏秋季为次要花粉季节,主要花粉气传为大麻/葎草属、蒿属等莠草花粉。构属、柏科、大麻/葎草属花粉为本地区优势气传花粉,构属花粉为本地区绝对优势气传花粉。     

New clinical data and therapeutic prospects in Cupressaceae pollen allergy

The authors emphasize, thanks to their clinical data over the last 20 years: The steady increase of allergy to C. sempervirens pollen compared to other pollinosis and to atopy. The frequency of cross-reactivity between C. sempervirens and other pollens belonging to Cupressaceae and Taxodiaceae families, in order, in the absence of a very good standardization and of a purification of this pollen, to try to undertake a sound specific immunotherapy using the most cross-reactive pollen mixed with C. sempervirens extracts. As a matter of fact the partially purified extracts of C. japonica gave the higher incidence (91%) of cross-reactivity. Consequently, a mixture of C. sempervirens and C. japonica extracts was used since 1993 with good results in a double blind study.     

Diagnostic biologique de l'allergie respiratoire : évaluation du réactif Vidas Stallergy genévrier dans l'allergie au cyprès

Cypress allergy is an important health issue in Mediterranean areas but its diagnosis is still difficult in some cases. The fact that cypress and juniper tree pollens share a number of allergens, together with the higher allergenic protein contents of the latter have recently led allergologists to use juniper pollen extracts while testing for cypress allergy. In the present study we have evaluated a new Vidas bioMérieux reagent, Stallergy ST6, designed for the detection and quantification of anti-juniper serum IgE, when applied to cypress allergy diagnosis. In thirty-one Respiratory Diseases Department outpatients clinically suspected of cypress pollen allergy, Stallergy ST6 results were compared to those of prick tests and of serum IgE quantification using the CAP System (Phadia). There is a good class concordance between IgE results yielded by the two methods. We conclude that Stallergy ST6 provides a sensitive and specific reagent for cypress allergy diagnosis.     

Airborne pollens and prevalence of pollenosis in western Liguria: a 10-year study.

During the last 15 years aerobiology has become a relevant branch of allergy, making possible the partial clarification of the relationships between clinical diseases and environment. We performed a 10-year survey of pollen counts and pollen sensitization in a confined area on the western Ligurian coast of Italy in order to evaluate possible changes in aerobiological pattern and to correlate them with the prevalence of sensitization. Pollen counts for the area surrounding Bordighera in the period from 1988-1997 were analyzed; the occurrence of skin sensitization in outpatients were also studied during the same period. We considered the following allergens: Parietaria, grasses, Compositae, Cupressaceae, olive and birch. We also examined the possible differences between patients living on the seaside and those living inland. Over the 10-year period a significant increase in the pollen counts was seen for birch and Compositae (p = 0.001); this was accompanied by a parallel significant increase in the rate of sensitization (p = 0.004 and p = 0.01, respectively). Conversely, an increase in sensitization to Cupressaceae (p = 0.001) and olive (p = 0.03) was also seen, although no change in the pollen counts was detectable. Finally, the prevalence of sensitization to Cupressaceae and Compositae was higher in the patients living in the coastal region than those residing inland. These data suggest that a positive correlation between the pollen counts and the rate of sensitization exists for certain pollens. Nevertheless, for other species such a correlation was not apparent, and additional environmental factors maybe involved in the increased prevalence of sensitization.     

Analysis of new respiratory allergies in patients monosensitized to airborne allergens in the area north of Milan.

BACKGROUND: A recent study carried out in North of Milan, an area that was recently colonized both by birch and ragweed pollen, showed that subjects developing allergies to these "new" allergens were much older than those becoming allergic to "traditional" airborne allergens, which suggests that predisposition to develop respiratory allergies is probably allergen-specific, persists throughout life, and does not occur until the patient encounters the appropriate allergen for a sufficiently long period. OBJECTIVE: The present study aimed to test this hypothesis by following-up a large cohort of patients monosensitized to airborne allergens. METHODS: The prevalence and characteristics of new sensitizations to airborne allergens after >2 years of follow-up were retrospectively assessed in 726 patients monosensitized to grass, pellitory, mite, birch, ragweed, Alternaria, mugwort, or plantain living North of Milan. RESULTS: The overall prevalence of new sensitizations was 35% (256/726), with marked differences between the subgroups ranging from 11% in Alternaria-allergic subjects to 46% in grass-allergic subjects. Patients allergic to grass, birch, or pellitory pollen showed a significantly higher propensity to become sensitized to a second airborne allergen than subjects allergic to ragweed, Alternaria, and mite. Overall, the "new" allergens (birch and ragweed) caused 228/256 (89%) new sensitizations detected in the whole study group. Ragweed pollen induced 90% (38/42) of new sensitizations in birch pollen allergic patients, and birch pollen induced 80% (8/10) of new sensitizations in ragweed allergic patients. No difference in age at the first visit or in duration of the follow-up between patients developing and not developing new respiratory allergies was observed. CONCLUSION: This study shows that: 1) predisposition to develop respiratory allergies is allergen-specific and persists throughout life; 2) proneness to become allergic to certain airborne allergens might be associated with primary sensitization to specific airborne allergens; 3) in monosensitized adults, sensitization to another airborne allergen that has been always present in that particular geographical area is unlikely.     

Biology of weed pollen allergens

Weeds represent a heterogeneous group of plants, usually defined by no commercial or aesthetic value. Important allergenic weeds belong to the plant families Asteraceae, Amaranthaceae, Urticaceae, Euphorbiaceae, and Plantaginaceae. Major allergens from ragweed, mugwort, feverfew, pellitory, goosefoot, Russian thistle, plantain, and Mercurialis pollen have been characterized to varying degrees. Four major families of proteins seem to be the major cause of allergic reactions to weed pollen: the ragweed Amb a 1 family of pectate lyases; the defensin-like Art v 1 family from mugwort, feverfew, and probably also from sunflower; the Ole e 1-like allergens Pla l 1 from plantain and Che a 1 from goosefoot; and the nonspecific lipid transfer proteins Par j 1 and Par j 2 from pellitory. As described for other pollens, weed pollen also contains the panallergens profilin and calcium-binding proteins, which are responsible for extensive cross-reactivity among pollensensitized patients.     

Prevalence of cypress pollen sensitization and its clinical importance in Izmir, Turkey, with cypress allergy assessed by nasal provocation.

BACKGROUND AND OBJECTIVE: Pollens from the Cupressaceae family are considered important allergens in the Mediterranean area, though reports of the prevalence of allergic symptoms have ranged from 1.04% to 35.4%. Our aim was to detect the prevalence of cypress pollen sensitization and determine its clinical importance in patients with seasonal respiratory allergy. METHODS: We used skin prick tests (SPT) and serum specific IgE assays to reveal sensitization to cypress pollen. In patients who showed positive results to cypress pollen, a nasal provocation test (NPT) with pollen extract was used to assess the target organ response. RESULTS: Sixty-five (14.3%) of 455 patients showed positive SPT responses to Cupressus sempervirens extract. Only 1 patient was monosensitized while 64 patients were polysensitized. Among those, 2 pollen cosensitizations were found to be significant (86% were cosensitized to grasses and 72% were cosensitized to olive (P < .001). Serum specific IgE to cypress pollen was measured in 50 of the 65 patients; findings were positive for 37. When these 37 patients underwent NPT with C sempervirens allergen extract, only the single monosensitized patient had a positive NPT. CONCLUSION: A positive SPT to cypress pollen may not reflect the true prevalence of sensitization. We assume that in the absence of a positive NPT, positive SPT results might be related to the presence of cross-reactivity between pollen species.