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Review
, 21 (2), 360-79, table of contents

Anisakis Simplex: From Obscure Infectious Worm to Inducer of Immune Hypersensitivity

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Review

Anisakis Simplex: From Obscure Infectious Worm to Inducer of Immune Hypersensitivity

M Teresa Audicana et al. Clin Microbiol Rev.

Abstract

Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites ("gastroallergic anisakiasis"), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive.

Figures

FIG. 1.
FIG. 1.
High-level parasitism by Anisakis simplex L3 in the flesh of a hake (Merluccius merluccius). Larvae persist in an arrested development stage (hypobiosis) prior to ingestion by the final host. Embedded larvae are dark in color due to a protective cuticle and different from the pinkish-white color typical of free and motile L3 (see Fig. 4).
FIG. 2.
FIG. 2.
Life cycle of Anisakis simplex including accidental human hosts. Adult parasites live in the stomach of marine mammals and, following copulation, fertilized but unembryonated eggs are expelled with the feces. The eggs develop and then hatch, releasing free-living Anisakis simplex L3. These L3 are ingested by euphausiid oceanic krill and copepods (intermediate hosts). Sea fish and cephalopods (paratenic hosts) ingest planktonic crustaceans or other fish and cephalopods infected with L3, contributing to the dissemination of the parasite. The infective L3 (embedded in the viscera and muscle or free in the body cavity) are transferred to the final hosts (marine mammals) by ingestion of sea fish and cephalopods (in the case of dolphins, porpoises, seals, sea lions, and walruses) or via oceanic krill (in the case of whales). In the final host, two molts occur (from L3 to adult) before sexual maturity to produce eggs, and a further life cycle is initiated. If L3-infected raw fish or cephalopods are eaten by humans, larvae present in the flesh produce a zoonotic infection, and humans act then as accidental hosts, since L3 usually do not develop any further and the cycle cannot be completed.
FIG. 3.
FIG. 3.
Attributions of anaphylaxis before and after screening for anti-Anisakis simplex responses. Adult patients studied in the Allergy Department of the Santiago Apóstol Hospital (Vitoria-Gasteiz, Basque Country, northern Spain). Cases of anaphylaxis (n = 625) were reviewed during six consecutive years (1994 to 1999). Allergic diagnoses of those cases were as follows: drug (n = 389), hymenoptera venom (n = 88), food (n = 67), parasites (n = 62), idiopathic (n = 32), and latex (n = 12). Note that the incidence of A. simplex allergy is similar to that of all food allergies combined (10%) and idiopathic causes are reduced from 14% (before A. simplex screening) to 4% when this parasite is considered. (Based on data from reference .)
FIG. 4.
FIG. 4.
Schematic representation of Anisakis simplex pathogenicity in the alimentary tract. The human patient can be exposed to A. simplex antigens from several sources: ES antigens from living larvae and somatic and cuticular antigens from dead and disintegrating larvae present in food. Epithelial cells might secrete cytotoxic molecules such as NO (1) and also chemokines and cytokines (2), which attract polymorphonuclear leukocytes (PMN), tissue macrophages (MΦ), naïve dendritic cells (NDC), basophils (Bas), and eosinophils (Eos) (3). Innate responses may also involve TLRs (4) from epithelial cells and activated dendritic cells (ADC). In the adaptive response, antigen presentation by mature dendritic cells (MDC) stimulates a double response of Th1 (5) and Th2 (6). Other T cells can be recruited as T-regulatory cells and Th3. Th1 cytokines (IFN-γ, tumor necrosis factor beta, IL-2, and IL-3) (5) induce IgG2a, opsonizing and complement-fixing antibodies, macrophage activation, antibody-dependent cell-mediated cytotoxicity, and delayed-type hypersensitivity. Th2 cytokines (IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13) promote IgG1 and IgA production (6), and by T-lymphocyte (T) stimulation, antigen-specific IgE and total/polyclonal IgE are produced. Mastocytosis and eosinophilia are induced by a Th2 response and chemoattractive cytokines and may be responsible for parasite expulsion (7). Basophils are crucial for the initiation of a Th2 response. Eosinophilia may be due to the release of numerous chemotactic factors by epithelial cells, T lymphocytes, mast cells, basophils, and factors derived directly from the parasites.
FIG. 5.
FIG. 5.
Human BAT in allergic and normal control subjects. Activation of basophils was detected by flow cytometry using a fluorophore-tagged (phycoerythrin [PE]) MAb against the CD63 cell activation marker. The expression of CD63 (horizontal axis) is plotted against levels of anti-IgE fluorescein isothiocyanate (FITC) (vertical axis) in response to A. simplex crude extract. The left-hand plot shows results from the first patient described 11 years before (25), although the test was carried out 11 years later (2006), and the right-hand panel corresponds to a female subject exhibiting no allergy to A. simplex used as a control. The results are expressed as the percentage of CD63+ basophils. Note that activated basophils from the allergic patient appear in the upper right window encompassing 98% of marked cells. In contrast, the control (right-hand plot) shows that a mere 3% of basophils were activated upon exposure to parasite antigen/allergens. (M. T. Audicana and N. Longo, unpublished data.)

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