IMMEDIATE HYPERSENSITIVITY RESPONSES--CONTROL IN PARASITIC HELMINTH INFECTIONS

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Using anthelminthic treatment-induced eosinophilia (in both lymphatic filariasis and onchocerciasis) as a model for physiological activation and recruitment of eosinophils, we have clearly established that there is an inverse relationship between circulating levels of RANTES and the ability of eosinophils to migrate from the blood to the sites of inflammation. Using immunohistochemical staining of skin biopsies taken from patients with onchocerciasis after ivermectin therapy, we have shown that, once recruited, the eosinophils degranulate and stimulate eotaxin production thereby allowing further eosinophil accumulation. In a separate study in India where a flow cytometer is available, we have examined the kinetics of eosinophil activation following definitive antifilarial therapy. The data show that there is marked upregulation of the integrins (VLA-4, CD44 and alpha4beta7) as well as CD23 within the first 24 hours. IL-5 levels peaked soon thereafter and predated the universal eosinophilia that occurred following therapy.One other major approach taken to understand eosinophil activation and regulation is a genetic approach in which we have identified a large kindred with familial hypereosinophilia. This syndrome is autosomal dominant and has allowed physical linkage of the responsible gene to chromosome 5 near to marker D5S1505. There are a number of genes in the area, including that for interleukin 5, but subsequent complete sequencing of the IL-5, IL-3 and GM-CSF gene and their promotes has not identified the candidate gene or mutation. Over the past year an integrated approach to this disorder has been taken by studying close to 17 members of the kindred. Data collected on their cells and eosinophils have suggested that their eosinophils are without major activation phenotypes (based on cell surface marker expression, electron microscopy, eosinophil survival assays). Two other candidate genes have been identified but await full sequencing. Using differential representational analysis of normal and activated eosinophils close to 65 activation-specific gene products have been identified. Each is being examined for differential expression in a variety of in vitro systems.Because IgE and IgG4 levels are increased in helminth infection, the mechanisms underlying these increases have been examined, initially using a model of parasite antigen-driven in vitro production of antibody. Having identified recombinant antigens capable of inducing isotype switching to IgG4/IgE, the ability of these antigens to drive B cells in the absence of T cells was shown to occur, providing anti-CD40 and the appropriate cytokine milieu was provided. Further, these same antigens have been shown capable of priming T cells from naive hosts in such a way that they (in presence of these recombinant antigens) induce B cells to differentiate into B cells capable of producing antigen-specific IgE and IgG4. Moreover, germline expression of IgE and IgG4 in acute helminth infections has now been shown and suggests a mechanism by which parasite antigen specifically induce switching to these important isotypes. - Hypereosinophilia, allergy, immediate hypersensitivity, helminth, filarial infections, cytokines, IgE - Human Subjects