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Angiostrongylus cantonensis, the rat lungworm, is a common causative agent of human eosinophilic meningitis or eosinophilic meningoencephalitis in Taiwan. The parasitic disease is also endemic to mainland China, Japan, some Pacific islands, and Southeast Asia.
Humans contract this parasitic disease by ingesting infective third-stage larvae (L3) that are found in raw or undercooked mollusks, which are the intermediate hosts for A. cantonensis. The ingested larvae penetrate into blood vessels in the intestinal tract and are carried to the central nervous system, but are unable to migrate to the lungs, as they do in rats. Most of the larvae develop into young adults (L5) and then die shortly after reaching the subarachnoid space, and hence do not complete the developmental cycle.
When nonpermissive hosts, such as mice, are infected with A. cantonensis, the immune response is primarily of the Th2-type, including eosinophilia, increased immunoglobulin E (IgE) antibody levels in the blood and cerebrospinal fluid, and the expression of Th2-type cytokines, especially interleukin-5 (IL-5), IL-4, and IL-33.
In A. cantonensis-infected mice, eosinophils appear to release some granules that are able to kill the larvae, but some cytotoxic proteins, such as eosinophil protein X and eosinophil cationic protein, can damage the nervous tissues of the host. In addition to mechanical injuries caused by the migrating larvae, the proteins produced during eosinophil infiltration and degranulation may be important factors that contribute to the immunopathology of angiostrongylosis.
Eosinophils act as immunoregulatory erbb2 inhibitor and are able to produce many types of cytokines; however, the mechanisms that regulate the biological function of these cells are uncertain. It has been shown that several factors could enhance the survival and/or the functions of mature eosinophils, such as IL-5, IL-13, and granulocyte-macrophage colony-stimulating factor. IL-5 is an important stimulant for eosinophil, with functions that include the promotion of degranulation and superoxide production. IL-5 also synergises with various stimulating factors to increase eosinophil progenitor production and eosinophil expansion. Specific inhibitors of IL-5, such as the anti-IL-5 monoclonal antibody (mAb), were able to attenuate eosinophil-associated inflammation.
IL-33 belongs to the IL-1 family and has been shown to be a promoter of Th2-type immune response and systemic inflammation both in vivo and in vitro. In a study of patients with asthma, IL-33 induced production of Th2-type cytokines and was associated with mucus overproduction and goblet cell hypertrophy in the lungs and the gastrointestinal tract. Furthermore, the increased expression of this cytokine may be a novel inflammatory marker of asthma. In addition, blockage of IL-33 by anti-IL-33 mAb inhibits airway inflammation in an animal model. It is demonstrated that IL-33 mediated the expressions of IL-5 and IL-13 in A. cantonensis-infected mice. Blockage of IL-33 by anti-IL-33 mAb inhibits IL-5 expression in animal models. IL-33 could play an important role in the pathogenesis of angiostrongylosis and also provide a new therapeutic target for this parasitic disease.
IL-33 has a variety of effects on inflammatory cells through the ST2 receptor. The binding of IL-33 to the ST2 receptor activates inflammatory cells through the nuclear factor-κB and mitogen-activated protein kinases pathways and induces the expression of Th2-type cytokines. Blockage of IL-33 signaling by a soluble ST2 protein or anti-ST2 mAb inhibits the immune response of asthma in mice.
For elucidating the role of IL-33/ST2 pathway in the pathogenesis of angiostrongylosis, in this study, mice were experimentally infected with larvae of A. cantonensis and received injections of anti-ST2 mAb. The effects of anti-ST2 mAb were assessed by pathological examination and by measuring eosinophil percentage and the levels of IgE and cytokines in the peripheral circulation.
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