Ana c 2
Summary
Ana c 2, commonly known as bromelain, is a mixture of cysteine protease enzymes present in pineapple (Ananas comosus) stem and fruit. The bromelain allergen extracted from the stem has a molecular weight of 22.8 kDa. Consumption of pineapple has been associated with systemic immunoglobulin E (IgE)-mediated hypersensitivity reactions (both delayed and immediate phase reactions) along with respiratory and gastrointestinal symptoms and can even result into anaphylaxis. This may be attributed to the presence of bromelain in pineapple. Positive-IgE reactivity to bromelain may be found widespread due to its glycosylated epitopes, which could be detected by many allergenic extracts, however the clinical allergy due to bromelain may rarely be reported, except in a few case reports. Thus, it is currently suggested that a positive-IgE response to bromelain may be investigated with care to relate it as a possible bromelain allergy. The route of exposure for limited clinical allergy to bromelain may be inhalation. Additionally, it could lead to sensitization to several other glycoprotein allergens through ingestion. In addition, Ana c 2 or bromelain is widely used as a marker for determining cross-reactive carbohydrate determinants (CCD) in the allergenic extracts. It is found to cross-react with several other glycoprotein allergens due to its N-glycan structure. Thus, the specific IgE towards CCD of bromelain is widely used in the diagnosis to differentiate true clinical allergy from that of mere cross-reactivity. Besides, cross-reactivity between plant-protease enzyme, such as papain and bromelain has also been identified in literature.
Epidemiology
Worldwide distribution
Consumption of pineapple has been associated with allergic reactions, such as oral allergy syndrome (OAS), that may be related to pollens (pollen-food-syndrome) and systemic immunoglobulin E (IgE)-mediated hypersensitivity reactions that may even result into anaphylaxis. Further, pineapple allergy is found to be related to pollen allergy in several regions, such as Latin America, Europe, Korea, Japan and Australia.
Ana c 2, commonly known as bromelain, belongs to the family of cysteine proteases and is widely used as a marker for determining cross-reactive carbohydrate determinants (CCD) in the allergenic extracts. (pg 80). Positive-IgE reactivity may be found widespread due to its glycosylated epitopes, which could be detected by many allergenic extracts, however the clinical allergy due to bromelain may rarely be reported.
A large cross-sectional cohort study was conducted on 16,408 allergic patients in Italy, that evaluated the prevalence of IgE to several allergens by multiplex microarray. The results reported positive IgE to Ana c 2 in 2.45% of patients. Similarly, another study was conducted in Sweden among 371 patients without asthma and 96 patients with asthma, that evaluated the IgE prevalence of 103 allergens through multiplex microarray. The study reported positive IgE to bromelain in only one asthmatic patient, while in none of the non-asthmatic patients.
Furthermore, a study conducted in Spain among 130 individuals sensitized to cannabis found positive sensitization to CCD (Ana c 2) in 33.8% of individuals. While another study conducted among 1025 respiratory-allergic patients reported the prevalence of IgE to bromelain and/or MUXF (glycan part of bromelain) to be about 18%. Furthermore, the prevalence of IgE reactivity to Ana c 2 was reported to be 5% among 140 children with atopic dermatitis in a German study. In another study performed in Denmark among 105 pollen-allergic patients, positive IgE to bromelain was found to be in 20% of the subjects.
Besides Europe, other regions have also reported similar postive-IgE reactivity to bromelain due to its carbohydrate epitopes. In a study conducted in Brazil among 51 patients allergic to Hymenoptera, postive-IgE reactivity to bromelain was observed in 43% of patients, wherein it was used as a CCD marker. Further, in a study conducted in Turkey among 27 latex-allergic patients and 17 atopic patients with positive-latex IgE, bromelain CCD-specific IgE was found in 2 and 12 patients, respectively, suggesting significantly higher levels (p<0.0001) observed in atopic individuals. A Japanese study utilizing bromelain as a CCD marker, found positive IgE in 16.7% of orchard grass-pollen sensitive (n=30), 54.5% of ragweed-pollen sensitive (n=11) and 8.9% of Japanese cedar-pollen sensitive (n=79) patients.
Clinical Relevance
Disease Severity
Ana c 2 or bromelain is a glycoprotein widely used clinically as a CCD marker. This protein is also reported to induce IgE-mediated sensitization to CCDs. However, in a study that evaluated correlation of positive IgE with the presence of clinical allergy through skin prick test (SPT), presence of bromelain-IgE was reported in multiple allergenic extracts. Despite this, they were not able to initiate an allergenic reaction on SPT, suggesting poor correlation of bromelain in triggering a true clinical allergy. Also, a study conducted in Spain among 1025 subjects with respiratory allergy (allergic rhinitis and/or asthma) reported the sensitization of bromelain, with significantly more prevalence observed in atopic individuals than the non-atopics (p<0.001). Similarly, the sensitization was noted to be higher in patients with pollen sensitization than the ones with sensitization to mites (p<0.01).
Bromelain has reported to induce IgE-mediated allergic reactions (both delayed and immediate phase reactions) along with respiratory and gastrointestinal symptoms. This evidence is supported by a case study reported in a worker who worked in a pharmaceutical plant and developed respiratory allergic reactions, such as allergic rhinitis, difficulty in breathing and wheezing due to prolonged, inhalational exposure to bromelain at irregular intervals. On further evaluation, oral challenge with pineapple resulted in gastrointestinal symptoms, such as abdominal pain and bloating.
Although, there are some earlier case reports of allergenic asthmatic reactions due to bromelain inhalation as part of occupational exposure, none of the recent case reports suggest such inhalational allergic response towards bromelain. Further, a rare case of allergic contact cheilitis has been identified in a 56-year-old woman as a result of continued use of mouthwash containing bromelain. However, it is currently suggested that a positive-IgE response to bromelain may be investigated with caution to relate it as a possible bromelain allergy.
Cross-reactive molecules
Cross-reactivity has been observed between bromelain and water-soluble fraction of wheat in a study conducted in Japan. Similarly, cross-reactivity between plant-protease enzyme, such as papain and bromelain has also been identified in literature.
Diagnostics
Disease Severity
The specific IgE towards CCD of bromelain is widely used in the diagnosis to differentiate true clinical allergy from that of mere cross-reactivity.
Exposure
The route of exposure for limited clinical allergy to bromelain may be inhalation. Additionally, it could lead to sensitization to several other glycoprotein allergens through ingestion.
Cross-Reactivity
Bromelain based on its amino acid sequence is a member of papain family. Due to its glycoprotein structure (the N-glycans), it is found to cross-react with several other glycoprotein allergens that resemble each other. These allergens include a wide range of allergens from pollens, food, venoms or latex.
References
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