Immunomodulatory role of helminth-derived antigens and C-type lectin receptors on inflammatory mast cells
Vukman, Krisztina Visnovitzné
(2013)
Immunomodulatory role of helminth-derived antigens and C-type lectin receptors on inflammatory mast cells.
PhD thesis, Dublin City University.
Mast cells are normally associated with T-helper (Th)2 driven IgE mediated immune responses in helminths infection, however it was recently shown that they have an important role to play in promoting Th1 immunity during infectious and non-infectious diseases. Fasciola hepatica, a parasitic worm of humans and domestic animals, induces strong Th2/T-regulatory immune responses during infection while simultaneously suppressing Th1 immune responses that are associated with immunity. The Th1 suppressive properties of helminths can leave the host more susceptible to bystander bacterial and viral infections while protecting the host from developing Th1 mediated autoimmune diseases. It was previously shown that Fasciola tegumental antigen (FhTeg) directly targets dendritic cells impairing their ability to drive Th1 inflammatory responses. Here we show that F. hepatica infection and FhTeg enhance mast cell numbers in vivo in a STAT6 independent manner. The increased mast cell number is not the result of FhTeg induced proliferation; rather FhTeg indirectly induces mast cell migration by dendritic cell derived chemokines. FhTeg-activated mast cells do not produce Th2 cytokines, drive Th2 immune responses or inhibit IgE degranulation of mast cells. Instead FhTeg inhibits mast cells ability to drive Th1 immunity suppressing pro inflammatory cytokines and ICAM1 expression in mast cells. FhTeg suppresses the activation of transcription factors in the TLR signalling pathway through the up regulation of SOCS3 inhibitory molecule which explains its suppressive effect. This study also demonstrated for the first time that the C-type lectin receptors, mannose receptor and macrophage galactose lectin, are expressed by mast cells and that they have an important role to play in the induction of SOCS3 by FhTeg and the promotion of mast cells inflammatory responses during Bordetella pertussis infection. This study advances our knowledge on mast cell biology, in particular the identification of potential targets on pathogenic mast cells.