Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I

Abstract

Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow–derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI–driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.

The effect of ovine peripheral blood mononuclear cells on Haemonchus contortus larval morbidity in vitro

“…Parasite-resistant sheep develop a stronger acquired immune response and have increased circulating antibody. 3,5 In vitro studies involving multiple species of helminth larvae and innate immune cells demonstrated that larvae coated with antibody enhanced leucocyte adherence to the larval cuticle, 19 and antibody was able to effectively immobilize H. polygyrus larvae independent of CD11b, the key complement receptor mediating macrophage attachment to larvae. 20 Mackenzie et al demonstrated that antibodies directed against surface antigens were highly specific towards different N. brasiliensis life stages and altered worm survival in vitro.…”

IgG-Mediated Immune Suppression to Erythrocytes by Polyclonal Antibodies Can Occur in the Absence of Activating or Inhibitory Fcγ Receptors in a Full Mouse Model

“…The polyclonal anti-HEL used in this study was produced in C57BL/6 mice, which are known to express IgG2c instead of IgG2a (39). The binding of IgG2c to FcgRI has been previously demonstrated (40), but to the best of our knowledge, interactions with other FcgRs are not yet known.…”

Macrophages treated with antigen from the tapeworm Hymenolepis diminuta condition CD25 + T cells to suppress colitis

“…If translated, this would indicate a unique functional program for M (HdAg) characterized by, for example, CCL5, CCL12, CD40, ICAM1 (all confirmed by qPCR (Supplemental Fig. S4), CCL7, CDD6, CLEC4e [belonging to a lectin family characteristic of tolerogenic Kupffer cells (33)], and Fcγ receptor 1 [antibody and worm antigen have been shown to have synergistic effects on macrophage function (34)].…”