Determination of molecular mechanisms supporting the anti-inflammatory properties of IgG4 antibodies in filarial infected individuals

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The present project aims at analysing the structural and molecular basis supporting the immunosuppressive properties attributed to IgG4 antibodies in filarial infections. Our group has extensively described the importance of this particular antibody isotype in filarial infections through both basic research and immunoepidemiological studies. Expanding on our earlier results that filarial-induced IgG4 is essential for maintaining a regulated immune response, our current preliminary data shows that IgG4 can inhibit/modulate granulocyte activity. This functional pathway applies to individuals that show no or little disease symptoms/pathology, but we could not observe this ability of IgG4 from lymphatic filariasis individuals presenting pathology, such as patients with lymphedema. This led us to investigate the biochemical patterns conferring immune suppressive properties to IgG4 antibodies and their impact on the physiopathology of filarial infections. We will investigate the structural and functional differences between IgG4 molecules from endemic normals, infected but immunologically hyporesponsive individuals without symptoms and symptomatic patients. The glycosylation profile of IgG subclasses in the different clinical groups will be analysed by combining enzymatic deglycosylation and differential mass spectrometric peptide mapping. The mechanisms underlying the suppressive activities of the characterized inhibitory IgG4 glycoforms will be then investigated using our well-established in vitro co-culture granulocyte suppression system and functional antibody-dependent cell mediated cytotoxicity (ADCC) assays. We will particularly focus on which FcR and downstream signalling pathways are involved in the IgG4-mediated suppression of granulocyte subsets. Moreover, since genetic variability may modulate granulocyte responses to IgG4 antibodies we will additionally investigate how such co-cultures impact gene expression using an expression quantitative trait locus (eQTL) approach which integrates genomic and transcriptomic information. Finally, we will investigate whether the observed glycosylation patterns and suppressive properties of IgG4 antibodies are specific for lymphatic filariasis, or also correlate with the physiopathology of another major filarial disease: onchocerciasis. The results from the project will have a profound impact on our understanding of the role of antibody isotypes in the physiopathology of filarial diseases and should have direct implications for the prevention and the treatment of infectious diseases in general.