Specific IgE in the diagnosis of parasite induced allergy

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Lars Yman, Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden
 
Recent interest in foodborne parasites linked to allergic reactions to food have triggered new questions regarding antigens released, immunological cross-reactivities, antibody responses, clinical relevance, etc. Specific IgE antibodies against Anisakis, a marine fish parasite, have been demonstrated in patients with gastrointestinal reactions, but also in patients with urticaria, atopic dermatitis, and anaphylaxis. It is confirmed that an adverse reaction linked to fish consumption can be an IgE-mediated allergy to the parasite and not to the fish. Since the parasite is common, this obviously has diagnostic importance in reactions to seafood. However, a number of other parasites, especially helminths, cause synthesis of IgE antibodies against a wide range of proteins released by the organism during the stage of their life cycle spent in humans. Such parasite proteins show many immunological similarities to common inhaled or ingested allergens. The roles of parasites and parasite specific IgE antibodies in allergic diseases are discussed in relation to some recent investigations reviewed.
 
Fish parasites in allergic disease
Parasites infecting humans are well known triggers of IgE synthesis. Some years ago, when we were studying the relevance of a range of new food allergens in Japanese atopic dermatitis patients, Anisakis, a nematode parasitizing marine fish, was entered to the investigation (1). Although Anisakislarvae may invade the gastric or the intestinal mucosa, it does not appear to survive in humans as many other helminths do (2). The epidemiology, natural history, and public health importance of human Anisakiasis, reviewed in references 3 and 4, include allergic hypersensitivity reactions like urticaria and anaphylaxis (5). The reactions are mediated by IgE antibodies to Anisakis antigens, but were in the past often mistaken as fish allergy. In fact, mackerel-induced urticaria, a common food allergy in Japan, was shown to be caused by Anisakismore often than by the fish (6).
 
In one of our investigations of atopic dermatitis (1), we found that many patients had species-specific IgE antibodies to one or several kinds of fish, e.g. mackerel and plaice. However, we could also confirm the role of Anisakis larvae in allergy related to seafood consumption. As judged from the IgE antibody levels observed (Fig 1) Anisakis appears to be more heavily involved than the mackerel commonly associated with the symptoms.
 

 
Fig. 1. Specificity of IgE antibodies in 138 Japanese atopic dermatitis patients (1).
 
Anisakis needs marine mammals like seals or whales for its development and is spread by crustaceans to squid and fish, like mackerel or Alaska polloc (Theragra calchogramma). In our studies of allergens for immunoassay of Anisakis-specific IgE antibodies (Pharmacia CAP System™) we were able to show that larvae collected from different species of fish gave equivalent assay performance and that larvae from Japanese mackerels, also called chub mackerel (Scomber japonicus), caught in the Pacific ocean did not differ from mackerel (Scomber scombrus) landed on the Swedish west coast.
 
Anisakisis a widespread fish parasite in all seas, although the reported infection rate varies considerably (4,7). The family Anisakidae also contains other genera reported to infect humans in a similar mode as Anisakis. There are in fact two types of Anisakis, Type I and Type II, two types of Pseudoterranova, often referred to as cod worm, (3,8) and Contracaecum(3,7). The allergen used in Pharmacia CAP System is Anisakis Type I, primarily A. simplex, collected from Theragra caught in the Pacific ocean.
 

Fig. 2. Parasitic helminths.
 
Fig 2 illustrates the relations of these genera to other helminths parasitizing humans. It is obvious that the family Anisakidae is rather closely related to the family Ascaridae, which includes Ascaris and Toxocara.
 
Some degree of allergenic cross-reactivity can consequently be expected. Measuring Anisakis-specific IgE antibodies in 10 sera with very high levels of Ascaris-specific IgE, we also found low levels of Anisakisspecificity in 9 of the samples. However, other investigators (9,10) looking at more relevant patient populations showed low or no cross-reactivity to Ascaris and Toxocarawith the same assay (Pharmacia CAP System). The discrepancies between the reports are not surprising, considering the heterogeneity of the immune response observed (10). Individual sera show unique specificity patterns similar to those observed for Ascaris (11) or any inhalant or food allergen.
 
Parasite-specific IgE and development of disease
Measuring Anisakis-specific and food-specific IgE antibodies in japanese atopic dermatitis patients (1), we found a clear age dependent increase for Anisakis, while hen's egg white showed the expected decrease with increasing age (Fig 3).
 
 
Fig. 3. Specific IgE antibodies to Anisakis and common food allergens in Japanese atopic dermatitis patients (1).
 
Searching the literature for further links between parasitosis and allergy symptoms, we found several examples of disease development involving parasite-specific IgE antibodies.
 
In an investigation of whether infection by helminths can be associated with a state of bronchoconstriction, the response to inhaled bronchodilator as a function of the degree of infection was studied in children in Caracas (12). Measuring the response before and after long term antihelminthic therapy and in untreated controls, a direct relation was detected between the degree of helminthic infection and an increase in peak expiratory flow by the bronchodilator. The results indicate contribution of helminthic infection to the development of asthmatic conditions.
 
IgE and IgG antibodies to excretory-secretory antigens of Paragonimus Westermaniwere measured in serum and pleural effusion in a group of patients with paragonomiasis (13). The results indicated local production of antibodies in the lung. Parasite-specific IgE antibodies were also found in bronchoalveolar lavage of patients with tropical pulmonary eosinophilia caused by the human filarial parasite Brugia malayi (14), suggesting a role in the pathogenesis of the syndrom.
The development of the IgE antibody response and its dependence on exposure, i.e. antigen dose, was demonstrated by several investigators over the last few years. In a study of antibody response, including IgE, to Plasmodiumin paired maternal-cord sera it was shown that the IgE antibodies could be found in the cord in higher frequencies than in the mothers (15). Positivity rates for IgG, IgM, and IgE antibodies were 54, 28, and 8 % in maternal sera, respectively, and 37, 0, and 17 % in the cord sera.The specificity patterns in immunoblotting were also heterogeneous and even within the pairs mothers and children showed different antibody patterns to the malarial antigens. The data suggest that prenatal sensitization can occur.
 
A study of an outbreak of human trichinosis in Thailand showed a rather rapid sensitization with measurable IgE antibodies in 100 % of the population studied by day 85 after infection (16). The immune response persisted in many individuals for the entire study period, 2 years and 7 months, probably due to a continued antigen exposure.
 
Investigating the development of the IgE response to Schistosoma mansoniadult-worm antigen, a positive correlation with age and infection rate was found in school children (17). All the children were treated and the mean concentration of IgE antibody to adult worm 6 months later correlated negatively with the cumulated reinfection rate over the following 30 months. The data support a protective role of worm-antigen specific IgE antibodies.
 
A very clear influence of antigen dose on the concentration of circulating IgE antibody was shown in a study of a case of anaphylaxis after rupture of a hepatic hydatid cyst (18). Echinococcus-specific IgE antibodies measured with Pharmacia CAP System decreased dramatically over a few days. IgE antibody decrease or disappearance was also strongly associated with successful mebendazole therapy (19). Although IgG, IgM, and IgE antibodies were all measured, only IgE antibodies were strongly associated with successful mebendazole therapy, showing decreasing levels or negative results. Similar changes were seen as a result of diethylcarbamazine treatment of Toxocariasis (20), suggesting usefulness of Toxocara canis-IgE antibody measurement for monitoring of therapy.
 
In summary
IgE antibodies to parasites:
  • are induced by protozoa and helminths
  • are as heterogeneous as antibodies to common allergens
  • are species specific and cross-reactive between related species
  • can be locally produced
  • can contribute to asthma
  • can cause urticaria and atopic dermatitis
  • can cause anaphylactic shock
  • are correlated to age
  • are correlated to degree of infection
  • decrease or disappear after successful therapy

Measurements of IgE antibodies to parasites:

  • aid in diagnosis
  • are superior tools for therapy monitoring

It is logical, and supported by data, to state that the parasite-specific IgE antibody is part of the defense system against foreign invaders, and as such protective. At the same time, though, due to the high concentrations of antigens and antibodies, it also participates in the pathological mechanisms behind a range of inflammatory reactions related to parasite infection or, as in the case of Anisakis, a temporary attack.

Measurement of IgE antibodies can thus aid in the diagnosis of parasitosis, in some situations with high sensitivity and specificity. Hydatid cyst in the liver, as an example, can be diagnosed with 88 % sensitivity and 93 % specificity (19). However, potentially even more important, IgE antibody measurements can contribute essential information to the investigation of several allergic conditions, and, finally, measurement of changes in the concentration of specific IgE antibodies in serum or other fluids has an important potential for monitoring of the efficacy of treatment, surgical interventions and pharmacotherapy.

References:

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1998