Title

Unraveling anti-filarial immune responses: The role of macrophages

Date of Completion

January 2007

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Our laboratory studies anti-filarial immune responses in mice. Wild type mice are naturally resistant to Brugia species and generate a florid immune response against these parasites. The immune response is characterized by two phases, acute and chronic. Macrophages accumulate in the peritoneal cavity in both these phases. Using a selective labeling protocol, we demonstrate that macrophages accumulate in both these phases by recruitment from blood. CCL2 is important for the recruitment of macrophages in the acute, but not in the chronic phase. ^ Here we show by depletion strategies that macrophages are essential for the clearance of larvae. The formation of granulomas is inhibited in the absence of macrophages, demonstrating that these cells are necessary for their formation. Depletion of macrophages does not affect B or T cell responses, suggesting that the primary function of macrophages is as an effector cell. We demonstrate that macrophages adhere to larvae in vitro in the presence of antigen specific primed serum. This process of adhesion of macrophages to larva is dependent on IL-4 dependent alternate activation. We know from published results from our lab that the process of adhesion of macrophages is dependent on the presence of IgM. Following alternate activation there is an increase in cytophilic IgM on the surface of macrophages. Experiments shown in here demonstrate a close correlation between cytophilic IgM and the ability of macrophages to adhere to larvae in the presence of primed serum. ^ Macrophages are known to express the Fcα/μR for monomeric IgM. Here we demonstrate that macrophages also express the polymeric Ig receptor (pIgR) which binds J chain containing polymeric IgM. The clearance of larvae and the presence of adequate amounts of IgM on the surface of macrophages are dependent on the presence of J chain containing IgM. IgM receptors (Fcα/μR and pIgR) are upregulated in the following alternate activation and perhaps responsible for the increased cytophilic IgM. Kinetic analyses demonstrate coordinate, progressive upregulation of markers of alternate activation and IgM receptors following infection, leading to granuloma formation and worm clearance. ^