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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 35  |  Issue : 2  |  Page : 37-42

Pollen-food allergy syndrome and lipid transfer protein syndrome: Clinical relevance


1 National Allergy Centre, BLK Superspeciality Hospital, New Delhi, India
2 National Allergy Centre, New Delhi, India

Date of Submission12-Mar-2021
Date of Acceptance26-Apr-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
Dr. P C Kathuria
National Allergy Centre, 1/3 East Patel Nagar, New Delhi - 110 008
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaai.ijaai_12_21

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  Abstract 


The role of an allergist in recognizing the pollen-food allergy syndrome (PFAS) and lipid transfer protein syndrome (LTPS) is essential. LTPS differs from PFAS by having a different family of panallergens and clinical characteristics. Both are complex syndromes posing diagnostic and therapeutic challenges. Many cross-reactive allergen components are involved, such as plant panallergens profilins, PR-10 proteins (Bet v 1 homologous), and lipid transfer proteins (LTP). PFAS results from cross-reactivity between pollen-specific immunoglobulin E (IgE) and homologous proteins found in fruits and vegetables. In most cases, grass pollen is responsible for profilin hypersensitivity. But, tree and weed pollen may also act as primary sensitizers, depending on geographical differences. Nonspecific LTP (nsLTP) is ubiquitous in terrestrial plants and can induce systemic allergic severe reactions. Peach (Pru P 3) is the primary sensitizer for LTP-driven allergy, and its clinical relevance is considered the prototypic marker for LTPS. nsLTPs have been identified as a major allergen in tree and weed plants. A second critical point is the diagnosis of LTPS associated with cofactors such as exercise, alcohol, antacids, and NSAIDS, that can promote severe reactions. Skin Prick Test (SPT) with Peach extracts that have been highly enriched for Pru p 3 with very low content of other allergens for LTPS, is suggestive of LTPS. For PFAS, positive SPT with profilin-enriched date palm pollen and watermelon extract shows sensitivity and specificity that is very close to that of the recombinant grass pollen profilin. The present review address differences between the PFAS from LTP syndrome with particular attention to the clinical impact on cross-reactivity or cross-sensitization to pollens.

Keywords: Component resolved diagnosis, LTP syndrome, nonspecific LTP, oral allergy syndrome, oral food challenge, pathogenesis-related-10, pollen food allergy syndrome, profilin, subcutaneous immunotherapy, sublingual immunotherapy


How to cite this article:
Kathuria P C, Rai M. Pollen-food allergy syndrome and lipid transfer protein syndrome: Clinical relevance. Indian J Allergy Asthma Immunol 2021;35:37-42

How to cite this URL:
Kathuria P C, Rai M. Pollen-food allergy syndrome and lipid transfer protein syndrome: Clinical relevance. Indian J Allergy Asthma Immunol [serial online] 2021 [cited 2022 Aug 19];35:37-42. Available from: https://www.ijaai.in/text.asp?2021/35/2/37/350073




  Introduction Top


There are two types of food allergy: class I versus Class II food allergies. Class I food allergy is where the sensitization occurs through gastrointestinal (GIT) and Class II food allergy is caused by prior sensitization to aeroallergens and their cross-reactivity (>70% identical homologous epitopes proteins) with food allergens.[1]

Pollen-food allergy syndrome (PFAS) and LTP syndrome (LTPS) are immunoglobulin E (IgE)-mediated immediate reaction, Class II food allergies, which occur in patients already sensitized to pollens with signs and symptoms of allergic rhinitis with or without bronchial asthma. These allergic reactions may be progressive from oral allergy syndrome ([OAS] [Itching in oral mucosa and swelling of the lips] to systemic reactions (urticaria/angioedema/anaphylaxis).[2] The severity of symptoms depends on the geographical different area, concentration, nature, and duration of the allergen exposure in a susceptible individual with or without the presence of cofactors (exercise, alcohol, chemicals, and NSAIDs) [Table 1].[3],[4]
Table 1: Overview of the relationship between oral allergy syndrome, pollen-food allergy syndrome, Class 1 and Class 2 food allergens

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In-plant tissue, there are major allergenic defense-related proteins, which induce pollen-related food allergy; these include (1) members of pathogenesis-related proteins-10 family (PR-10), (2) profilins, and (3) nonspecific LTP (nsLTP) and gibberellin-regulated proteins.[1],[5] Test profile to identify those sensitized to these three groups of proteins (PR-10, profilin, and LTP) by component resolve diagnosis (CRD) should be selected according to the patterns of sensitization to their allergenic proteins in the specific country because CRD has a wide geographical variability depending on exposure to the pollen and ingested food in the particular area. Bet v 1 is regarded as a marker for a primary sensitization to the pollen of birch and other Fagales trees (e.g., alder, hazel, hornbeam, and beech). Clinically, Bet v 1 and its homologues represent important pollen allergens (after inhalant exposure) and are considered important inducers of birch pollen-associated plant food allergies.


  Prevalence Top


Although the true prevalence will be difficult to determine, given the wide geographic variability, it does affect a significant portion of the population. Often the prevalence of PFAS is reported as the percentage of another disease, such as “10% of children with allergic diseases develop OAS.” Other examples include 20% to 70% of persons with pollen allergy experience pollen-related food allergy, approximately 20% of patients who underwent skin prick testing experience PFAS, 45% of patients with seasonal allergies reported PFAS, 26% to 34% of patients with eosinophilic esophagitis have PFAS, and 47% to 70% of patients with pollen allergy experience PFAS.[1]

The prevalence of LTP sensitization is not comparable as different pollen environments with different exposure to LTP-containing pollen and food needs to be taken into consideration for prevalence.

LTP being the most prevalent sensitizer for patients with urticaria/angioedema/anaphylaxis had higher sensitization to peach, cherry, and hazelnut, 58.69% of the cases had IgE antibodies to LTP (rMal d3 or rPru p3). In the Mediterranean basin, more than 90% of fruits from the Rosaceae family are sensitized against the respective LTPs, and almost all peach allergic patients with severe systemic reactions show sensitization to Pru P 3. Cannabis allergic patients (Can s 3 positive) had a high prevalence of 92% of sensitization to other LTP such as apple (Mald-3), hazelnut (Cor a 8), walnut (Jug r 3), wheat (Tri a 14), and mugwort (Art v 3) but also (Pru P 3).[6]


  Symptoms Top


Both LTPS and PFAS have unique peculiarities: (1) onset of symptoms is within 30 min in LTPS while it is 5 min in PFAS, (2) severity of symptoms varies from oropharyngeal pruritus to urticaria, angioedema, and anaphylaxis in LTPS, whereas mild-to-moderate symptoms of oropharyngeal pruritus and swelling (OAS) in PFAS, (3) common trigger foods are raw, cooked and processed fruits, vegetables, nuts, and cereals in LTPS whereas raw fruits, vegetables, and nuts in PFAS, and (4) cofactors are commonly involved or required for allergic reaction in LTPS, while not involved in PFAS.[7]


  Diagnosis Top


The diagnosis of PFAS and LTPS starts with an in-depth medical history, skin prick test (SPT), prick-to-prick test (PPT)-specific IgE, (S IgE) extract base and molecular base are the method of choice for diagnosis. Basophil activation test is a functional test useful for the diagnosis of pollen and food allergy and can be used to evaluate the possibility of more severe allergic reactions in patients with PFAS and LTPS.

Two main patterns of sensitization to PR-10, profilins, and LTP allergen have been well described. If we do specific IgE reactivity to birch (Bet v 1-PR-10) pollen and peach allergen (Pru P 3-LTP), we can distinguish the patterns of sensitization to the PR-10-like protein (Bet v1-homologues) and profilin (Phl p12 and birch (Bet v 2) and date palm (Pho d 2). Both of these (PR-10 and profilin) are associated with OAS, whereas LTPs of mugwort and peach are also associated with the risk of systemic reactions of acute urticaria/angioedema and anaphylaxis.[8]

One can distinguish their pattern of sensitization of PR-10 and profilin from LTP by skin prick test (SPT) with commercial extracts and PPT of allergen extract. In PFAS, skin prick test (SPT) with date palm (Pho d 2) and melon (Cuc m 2) extract enriched with profilins shows sensitivity and specificity which is very close to that of recombinant grass profilin (Phl P 12) and tree pollen (Bet v 2) and PR-10 (Bet v 1) panallergen. In LTPS, CRD by skin prick test (SPT) is possible using peach extracts, and most of the patients with nsLTP-mediated food allergic reaction will be positive to peach extract (Pru P 3). Different studies described the strong association between peach (Pru P 3) positivity by skin prick test (SPT) and the severity of systemic reaction of urticaria, angioedema, and anaphylaxis. While skin testing by PPT of peach peel and peach extract which contains enriched unique LTP Pru P 3, reagents have also proven vital in confirming the diagnosis of ns LTP syndrome. Peach ns-LTP (Pru P 3) has a very limited homology with pollen ns-LTPs such as Par j 1 (Parietaria judaica) or Ole e 7 (Olive), which means ns-LTP foods have a complete lack of cross-reactivity between weed and tree pollens. There are three nuts – nsLTP (peanut – Ara h 9, hazelnut – Cor a 8, and walnut – Jug r 3), one cereal flour – nsLTP wheat (Triticum aestivum – Tri a 14), two citrus foods nsLTP – lemon –Cit I 3 and orange – Cit s 3, and four pollen – nsLTP [mugwort (Artemisia vulgaris) – Art v 3, olive (Olea europaea) – Ole e 7, plane (Planatus acerifolia) – Pla a 3, Parietaria Judaica – Par j 1].[Table 2],[Table 3],[Table 4].[4],[9],[10]
Table 2: Bet v 1-homologous allergens from plant foods

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Table 3: Representative members of the nonspecific lipid transfer protein family and cross-reactivity between them

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Table 4: Profilins from different pollen and plant sources

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CRD is a reliable parameter in the diagnosis of cross-reactive proteins of panallergens (profilin, pathogenesis-related protein Type-10 [PR-10], and nsLTP). Profilin is a ubiquitous family of proteins of about 12–16 kDa present in eukaryotic cells and is involved in the control of actin polymerization. It is a marker of disease evolution, an early marker of symptom severity in those suffering from allergic rhinitis with or without bronchial asthma and food allergy with sensitization to pollen and plant foods. A positive skin prick test (SPT) with profilin-enriched date palm pollen extract shows sensitivity and specificity that is very close to that of the recombinant grass pollen profilin.[2] CRD can allow for the discrimination between genuine sensitization from sensitization due to cross-reactivity. The principal allergens involved in LTPS are family of stable allergens (resistant to heat and acid) of nsLTP which are abundant, soluble, cysteine (cys) rich, with molecular size usually belonging to 10 kDa, with a rigid tertiary structure formed by four disulfide bridges. Their function is to carry lipids through the cell walls. These allergens are mainly represented in surface tissue (peel) and are present in apples, peaches, apricots, cherries, plums, pears, raspberries, strawberries, blackberries, and weed and tree pollens, while in PFAS, the allergens belong to Bet v 1 family (PR-10) and profilins are labile allergens present in fruits, vegetables, and pollens (tree, grass, and weed) which are denatured by high temperatures and gastric enzymes.[11]


  Cross-Reactivity between Pollen Aeroallergens and Food Allergens Top


Wheat is a grass pollen from Poaceae family, wheat contains albumin and globulin that may be responsible for its allergy, while molecular characterization of wheat allergen has shown many cross-reactive allergens, who are sensitized to grass pollens. The wheat allergens containing alpha purothionin, Tri a 37 and Tria 12 profilin epitope, alpha amylase inhibitor (Tri a 15) and LTP (Tri a 14), cross-react with grass pollen. Tria a 37 is a plant defense protein, highly stable, and resistant to heat and digestion; patients who have IgE antibodies against Tri a 37 have a four-fold increased risk of severe allergic symptoms upon wheat ingestion. The author has published seven cases of PFAS between Cynodon dactylon and Pennisetum typhoides related with foods (seeds, wheat, maize, watermelon, and citrus fruits), clinical and immunological diagnosis was based on history, skin prick test (SPT), serum-specific IgE (ImmunoCap, Thermofisher), and oral food challenge (OFC).[12]

Mugwort (Latin: Artemisia vulgaris) is an important representative of the Asteraceae family. In India, mugwort pollen flowers appear in late summer and autumn. It is a coarse perennial herb, often reddish, angled stems, having dark green above, and white woolly beneath.[11] The main allergen in mugwort is 80% glycoprotein with a defensive-like domain (Art v 1) and has 60% (nsLTP-Art v 3). This nsLTP has cross-reactivity with peanut, soybean, wheat, and sunflower seeds. In mugwort-mustard allergy syndrome (MMAS), individuals sensitized to mugwort may develop an allergic reaction (urticaria, angioedema, and anaphylaxis) to mustard.[11] Mugwort pollen may represent the primary allergen source for nsLTP sensitization. The pathogenesis of LTPS is linked to cross-reactivity between pollens (A. vulgaris, etc.) and homologous epitopes contained in food protein (wheat, peanut, etc.). In one study, it was found that 20% of patients allergic to grass and mugwort pollen are suffering from PFAS with symptoms of urticaria, nasal symptoms, angioedema, abdominal symptoms, and even anaphylaxis.[3] Mugwort-related PFAS and LTPS are classified as celery-mugwort-spice syndrome (CMSS), mugwort-peach association (MPA), mugwort-mustard allergy syndrome (MMAS), and mugwort-chamomile association (MCA). In India, sensitization has been reported to A. vulgaris (mugwort) in Aligarh (28%), Bhopal (23%), Kanpur (22%), Delhi (19%), Mumbai (8%), and Bangalore (5–7%).[11]

CRD of Art v 1, Art v 6, and Art v 3 would be the diagnostic marker for PFAS and LTPS which is not yet available in India for routine diagnosis. nsLTP-specific IgE antibody is an important marker of true food allergy with a high risk of severe systemic reaction and is found in the peel of the fruit more than the pulp and has been recognized in tree and weed pollens and in vegetable food allergen sources. Sensitivity to nsLTP is expressed in variable ways: (a) Patients can tolerate certain food even when SPT or specific IgE is positive, indicating sensitization, (b) Some patients will react only in the presence of associated cofactors (exercise, nonsteroidal anti-inflammatory drugs, or alcohol), and (c) Patients can get severe allergic reaction despite low or negative specific IgE.

The clinical reactivity of the individual associated with sensitivity to pollen (A. vulgaris, etc.) and food (wheat/peanut, etc.) depends on the amount of the allergen ingested, the affinity of IgE antibodies in the blood, co-exposure to other allergens, and the degree of processing and storage of foodstuff.[9],[10] The author has reported four cases of suspected LTPS, diagnosis was based on SPT and specific IgE and OFC against mugwort, peanut, and wheat. Whether Art v 3 (nsLTP) in Artemisia may have cross-reactivity to peanut (Arh 9) and wheat (Tria 14) food or independent nsLTP syndrome needs further studies in India.[13]

In India, Prosopis juliflora flowers twice a year in February–March and August–September, pollination is by both insects and wind and is a potent allergenic source of nasobronchial allergy. In one study, it was found that 34.7% of patients of nasobronchial allergy being sensitized to Prosopis juliflora allergen.[14] Holoptelea integrifolia is also an important tree pollen allergen of India and sensitizes almost 10% of the atopic population in Delhi as shown by an epidemiological survey carried out on the adult population of India. These flowers, for a short period of 2–3 weeks in February–March in various parts of India, have four allergenic components with a molecular weight of 50, 60, 66, and 70 kDa.[15]

Dhyani et al. have documented the cross-reactivity among Prosopis juliflora, Ailanthus excelsa, and Senna siamea pollen components with Holoptelea integrifolea, Putranjiva roxburghii, and Salvadora persica tree pollen allergens. Extensive cross-reactivity has been observed between Prosopis juliflora with legumes (lima beans and broad beans) with proteins of molecular weight of 20, 26, 35, 66, and 72 kDa.[16] Assarehzadegan et al. found using SD-PAGE that there were several IgE binding proteins in Prosopis juliflora pollen extract with a molecular weight of 10–85 kDa, among which molecular weight of approximately 20 and 60 kDa was the most frequent IgE reactive bands among patients.[17],[18]

In India, there is a geographic diversity of different exposure of airborne allergens and food allergens in climate zones of different populations. None of the identified specific IgE cutoffs have shown a specificity and sensitivity profile as accurate as oral food challenge (OFC) which is still the gold standard to diagnose food allergy up till now.[2]


  Treatment Top


The 2014 update to food allergy practice parameters states that patients with a history of laryngeal swelling or respiratory compromise should strictly avoid raw foods and must be prescribed an epinephrine auto-injector. Although avoidance measures of Class I allergens are commonly recommended, food avoidance does not seem to have any lasting treatment benefit in Class II allergens because of continuous exposure to the original sensitizing agent.[19]

The primary sensitizer in Class II allergens is typically pollen. Considering the association between birch-related allergens and PFAS, it was expected that AIT with birch extracts would be efficacious for PFS. Numerous clinical trials by both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been studied to see whether tolerance to provocative foods can be increased. One study enrolled 74 birch-allergic patients in a double-blinded placebo-controlled trial in a comparison between SLIT and SCIT. In that study, no significant difference was noted between SLIT, SCIT, or placebo when comparing pretreatment OFCs. Another study by Asero looked prospectively at 49 birch-sensitive patients with positive PFAS to apple who had received SCIT for 1–3 years. In that study, 80% of patients reported subjective improvement in their symptoms to apples; of those, 54% showed complete resolution of their symptoms.[20] Biologics represent a new avenue for the development of therapies that inhibit specific mechanisms of food allergy and perhaps prevent sensitization to the food allergen in the first place. Newer biologics (omalizumab and dupilumab) are now available that have been shown to help in many atopic conditions such as PFAS and LTPS.[21]


  Conclusion Top


PFAS and LTPS are caused primarily by Class II allergens. These allergenic sources, while containing homologous proteins, are not always recognized by every allergic patient. The knowledge of PFAS and LTPS and their impact to relevant cross-reactivities between aeroallergens and food allergens are of great importance for the allergy specialist. The clinician can have a tailored discussion with the patients, which can include risks of reaction, the severity of reaction of potentially cross-reactive foods and can be treated as individual precision medicine. Whether allergen immunotherapy by pollen or food combined with biological, will modify the natural course of disease, needs further evidence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Carlson G, Coop C. Pollen food allergy syndrome (PFAS): A review of current available literature. Ann Allergy Asthma Immunol 2019;123:359-65.  Back to cited text no. 1
    
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Alessandri C, Ferrara R, Bernardi ML, Zennaro D, Tuppo L, Giangrieco I, et al. Molecular approach to a patient's tailored diagnosis of the oral allergy syndrome. Clin Transl Allergy 2020;10:22.  Back to cited text no. 4
    
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Jeon YH. Pollen-food allergy syndrome in children. Clin Exp Pediatr 2020;63:463-8.  Back to cited text no. 8
    
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Figueroa J, Blanco C, Dumpiérrez AG, Almeida L, Ortega N, Castillo R, et al. Mustard allergy confirmed by double-blind placebo-controlled food challenges: Clinical features and cross-reactivity with mugwort pollen and plant-derived foods. Allergy 2005;60:48-55.  Back to cited text no. 9
    
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Gao ZS, Yang ZW, Wu SD, Wang HY, Liu ML, Mao WL, et al. Peach allergy in China: A dominant role for mugwort pollen lipid transfer protein as a primary sensitizer. J Allergy Clin Immunol 2013;131:224-6.e1-3.  Back to cited text no. 10
    
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Singh AB, Kumar P. Common environmental allergens causing respiratory allergy in India. Indian J Pediatr 2002;69:245-50.  Back to cited text no. 11
    
12.
Kathuria PC, Rai M. Sensitization profiles of seven (7) cases of pollen-food allergy syndrome (PFAS)- Grass pollen (Cynodon dactylon and Pennisetum typhoides) related foods: Seeds (chia, sunflowers, mustard), wheat, maize, watermelon and citrus fruits. JSM Allergy Asthma 2020;4:1023.  Back to cited text no. 12
    
13.
Kathuria PC, Rai M. Wheat and peanut food allergy in mugwort (Artemesia vulgaris) sensitized patients: A case series of four cases. Indian J Case Rep 2020;6:292-5.  Back to cited text no. 13
    
14.
Sharma S, Kathuria PC, Gupta CK, Nordling K, Ghosh B, Singh AB. Total serum immunoglobulin E levels in a case-control study in asthmatic/allergic patients, their family members, and healthy subjects from India. Clin Exp Allergy 2006;36:1019-27.  Back to cited text no. 14
    
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Malik P, Singh AB, Gangal SV, Babu CR. Comparison of antigenic and allergenic components of Holoptelea integrifolia pollen collected from different source materials. Allergy 1991;46:284-91.  Back to cited text no. 15
    
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17.
Assarehzadegan MA, Khodadadi A, Amini A, Shakurnia AH, Marashi SS, Ali-Sadeghi H, et al. Immunochemical characterization of Prosopis juliflora pollen allergens and evaluation of cross-reactivity pattern with the most allergenic pollens in tropical areas. Iran J Allergy Asthma Immunol 2015;14:74-82.  Back to cited text no. 17
    
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20.
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21.
Bauer RN, Manohar M, Singh AM, Jay DC, Nadeau KC. The future of biologics: Applications for food allergy. J Allergy Clin Immunol 2015;135:312-23.  Back to cited text no. 21
    



 
 
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