In the last several decades, we have witnessed an allergy epidemic that documented a striking global rise in the prevalence of asthma, allergic rhinitis, and eczema. More recently, the prevalence of food allergy has been rising particularly in the Western world and has been considered the second wave of the allergy epidemic. Aside from egg and cow's milk allergies that are the most prevalent food allergies in infants and young Asian children, the pattern of food allergy shows significant differences from those of Western populations.

In the Asian region, fish and peanut allergies are not common12 Instead, crustacean shellfish allergy is an important cause of food allergy. A summary of epidemiological studies of shellfish allergy are presented in Table. Population surveys show that the prevalences in teenagers are 5.12% in the Philippines and 5.23% in Singapore.1 Hospital-based studies on anaphylaxis show that crustacean shellfish is a leading cause of food-induced anaphylaxis in Singapore,34 Thailand,5 Hong Kong,6 and Taiwan.7 One unique feature in the clinical manifestation of shellfish allergy in Asia is the predominance of a milder form of allergy with reactions localized to the oral mucosa, as reported by recent studies from Singapore8 and Thailand.9

The major allergen in shrimp and shellfish allergies is tropomyosin, a pan-allergen involved in muscle contraction in invertebrates. Tropomyosins from house dust mites (HDMs) and cockroaches share a high sequence homology to shellfish tropomyosins, with an 81% amino acid sequence similarity between prawns and HDMs, and 82% similarity between prawns and cockroach.1011 Cross-reactivity between tropomyosins from HDMs and shellfish has been well demonstrated.12 House dust mites thrive in the humid tropical Asian environment, and there is a high prevalence of HDM allergy and IgE sensitization in our Asian population.13141516 In a recent report from Singapore on 39 shrimp-allergic patients, all subjects with shrimp allergy were also sensitized to HDMs.8 This review explores the hypothesis that inhalant exposure to tropomyosins from HDMs is the primary sensitizer for shellfish allergies, and IgE cross-reactivity with shellfish tropomyosins accounting for mild oral allergies upon consumption of shellfish.17 This may be similar to the oral allergy (inhalant-food) syndrome seen commonly in Europe, where birch pollen-allergic individuals react to cross-reactive allergens in fruits and nuts. The predominant clinical features are of lip itch and swelling, and are confined to the oral mucosa.18 Heat-labile pathogenesis-related (PR) proteins elicit IgE reactions from local tissue bound serum IgE in the oral mucosa, which are then rapidly denatured during digestion, halting the progression to systemic symptoms.19 Heat and proteolysis-stable Profilin and lipid transfer proteins have also been found to be involved in cross-reactivity, which likely accounts for the small subgroup of patients who do experience anaphylaxis.20 Tropomyosin is as a heat stable protein, and this may explain the spectrum of severity of reactions, although most reactions in tropical cohorts are confined to the oral mucosa. This hypothesis is supported by intriguing epidemiological, clinical, and immunochemical data that reinforces this HDM and shellfish allergy link and that tropomyosin plays a major role in these interactions.

The amino acid sequences of allergic tropomyosin are compared in Figure. Tropomyosins of shrimps, prawns, lobsters, and crabs share sequence identity between 91% and 100%. The snail tropomyosin Hel as 1 and the fish tropomyosin Ore m 4 have 63.7% and 57.4% sequence identity to the shrimp tropomyosin Pen a 1, respectively. Tropomyosins of mites and cockroaches have 78.5%-81.7% and 82.4% sequence identity to Pen a 1, respectively. The sequence identity of Pen a 1 to tropomyosins of midge (chi k 10), parasite (Ani s 3) and silverfish (Lep s 1) are 78.5%, 72.9%, and 67.9%, respectively.

To investigate this homology, IgE-binding epitopes have been evaluated. The IgE epitopes of shrimp tropomyosin was first studied using the approach of peptide epitope mapping.2122 Eight IgE-binding epitopes were identified in Pen a 1 from Penaeus aztecus.21 Further investigations showed that the 2 sequences 145-164 and 263-280 inhibited IgE-binding reactivity to tropomyosin of Penaeus monodon (Pen m 1) in all the shrimp-allergic sera tested, and these were proposed to be the major IgE epitopes.23

The multiple sequence alignment of tropomyosin from shrimp (Pen a 1, Pen m1), crab (Por p 1), lobster (Hom a 1), and HDM (Der p 10 and Blo t 10) revealed that the shrimp tropomysin Pen m 1 and the lobster tropomyocin Pro p 1 and Hom a 1 have almost identical sequences at all the 8 identified Pen a 1 IgE epitopes. The sequence identity of the HDM tropomyosins Der p 10 and Blo t 10 to Pen a 1 at these 8 IgE epitopes was also high (>80%), with the exception of the first epitope 43-55 for which the sequence identity is 58% (Figure). Pen a 1 epitopes and their homologous sequences in Hom a 1 (lobster tropomyosin) have similar IgE-binding reactivity to sera from shrimp-allergic subjects. In contrast, these sera showed similar IgE-binding reactivity to only 4 homologous sequences in Der p 10 (187-197, 249-259, 266-273, and 273-281) and had less or no IgE reactivity to the other 4 homologous sequences.24

An earlier study using Blomia tropicalis-allergic sera revealed that the IgE epitopes of Blo t 10 were mainly located at N- and C-terminal of the molecule.25 Only one-third of subjects had IgE reactivity to the middle region 125-214, indicating that the middle region of Blo t 10 is less allergenic. This may explain the reduced IgE cross-reactivity of shrimp-allergic sera to 2 IgE epitopes of Pen a 1 homologous sequences (137-141, 144-151) in Der p 10.

This data indicates the presence of IgE cross-reactivity between tropomyosins of shellfish and HDMs; however, the cross reactivity is stronger within shellfish (shrimp and lobster) than between shellfish and HDMs.

Tropomyosin remains the most thoroughly investigated and most prevalent allergen in shellfish allergy, with considerable evidence of cross-reactivity with HDMs, snails, and other molluscs. Sensitization to shellfish tropomyosins has been investigated through specific serum IgE measurement and has higher sensitivity and specificity in prediction of shellfish allergy than skin prick tests for the whole shrimp extract.40 Arginine kinase, a new class of invertebrate pan-allergens, has been shown to be cross-reactive in a Malaysian study of patients allergic to both red crab and blue crab.41 Myosin light chain kinase (Lit v 3)42 and sarcoplasmic calcium-binding protein (Lit v 4)43 have recently been identified as allergens in the Pacific white shrimp. In addition, α-actinin, β-actin, fructose biphosphate aldolase, and ubiquitin have been identified as allergens in the Solenocera melantho (red shrimp) species.38 A recent review of 40 shrimp-allergic patients from Italy showed that 10%-15% were sensitized to arginine kinase and Lit v4, suggesting that tropomyosin remains the primary allergen.44 However, only 1 case of co-sensitization with tropomyosin was recorded, suggesting that these minor allergens remained clinically relevant. Low rates of sensitization to other shrimp allergens, such as Lit v2, Lit v3, and Lit v4, have also been documented in a cohort of 39 shrimp-allergic patients from Singapore,8 indicating that in some populations, these non-tropomyosin allergens may be of less clinical importance.

We have reviewed the evidence to support the hypothesis that inhaled tropomyosins from HDMs are the primary sensitizer for shellfish allergy in warm and humid tropical climates. These findings open the possibility of novel therapeutic approaches with allergen immunotherapy for shellfish allergy.

The unique epidemiology of shellfish allergy in Asia raises intriguing questions: Is the high prevalence of shellfish allergy merely related to repeated exposure to inhaled HDM tropomyosins? Further studies on the temporal relationship between shellfish and HDM sensitization and the effect of genetic background on the development of shellfish allergy would provide insights into the mite-shellfish link.