Mucosal Defense against Gastrointestinal Nematodes: Responses of Mucosal Mast Cells and Mouse Mast Cell Protease 1 during PrimaryStrongyloides venezuelensisInfection in FcRγ-Knockout Mice

Abstract

A possible role for the ␥ subunit of immunoglobulin Fc receptors (FcR) in mucosal defenses against intestinal nematode parasites was studied using age-matched FcR␥-knockout (FcR␥ ؊/؊ ) and wild-type (FcR␥ ؉/؉ ) C57BL/6 mice. Mice were infected subcutaneously with 3,000 infective larvae of Strongyloides venezuelensis, and the degree of infection was monitored by daily fecal egg counts and adult worm recovery on days 8 and 13 postinfection. Mucosal mast cell (MMC) responses were assayed by in situ intestinal mast cell counts in stained histological sections of the jejunum and by measuring mouse mast cell protease 1 (MMCP-1) release in serum using sandwich enzyme-linked immunosorbent assay. FcR␥ ؊/؊ mice had significantly higher egg counts (P < 0.01) and numbers of adult worms (P < 0.05) than FcR␥ ؉/؉ mice, but mastocytosis and serum MMCP-1 release were comparable. It was concluded that MMCP-1 release may be spontaneous, does not depend on mast cell degranulation via the FcR␥ signaling system, and appears to play no role in the expulsion of S. venezuelensis. The delay in worm expulsion in the FcR␥ ؊/؊ mice might be related to inability of the MMC to degranulate and release effector molecules other than MMCP-1, since FcR␥ deletion abrogates mast cell degranulative responses.Fc receptors (FcR) are hetero-oligomeric complexes present on most effector cells of the immune system and, upon crosslinking by their ligand (antigen-antibody complex), mediate phagocytosis, antibody-dependent cell-mediated cytotoxicity, activation of inflammatory cells, and many other effector responses (20). However, several of the FcR require for cell surface assemblage and signal transduction into the interior of the cell an additional chain, the homodimeric ␥ subunit (20). Targeted disruption of this subunit results in pleiotropic defects in cell functions, including the loss of immunoglobulin E (IgE)-mediated mast cell degranulation (27). This is because the high-affinity FcR for IgE (FcεRI), which is also associated with host resistance to parasitic infections (12), requires the ␥ subunit to express receptor-mediated cellular functions (20). Intestinal mucosal mastocytosis is observed in certain helminth infections, and it was therefore speculated that mast cells were important in the expulsion of Strongyloides ratti in rodents (19). Subsequently, in a series of experiments in infected rodents, it was demonstrated that mucosal mast cells (MMC) induced by the mast cell growth/differentiation factor interleukin 3 (IL-3) were the effector cells in the immune expulsion of Strongyloides spp. (1,3,8,17,18). The exact mechanism of the mast cellmediated parasite expulsion is still not clear, although it has been suggested that granular contents released by activated mast cells may be the ultimate effector molecules (7, 17). Since Fc ␥ subunit deletion results in loss of mast cell function, including degranulation and granular content release (27), the aim of this study was to determine whether the MMC-mediated parasite expulsion mechanism actuall...

Differences in the Importance of Mast Cells, Basophils, IgE, and IgG versus That of CD4+T Cells and ILC2 Cells in Primary and Secondary Immunity to Strongyloides venezuelensis

“…The important role of antibodies in the primary infection with S. venezuelensis appears to depend on the binding of antibodies to FcRs that signal via the FcR common ␥-chain (8,10,14), and in our model, we found that Fcer1g-deficient mice exhibited a 19-day delay in cessation of egg excretion (Fig. 3E), a delay very similar to that seen in Igh-J-deficient mice (Fig.…”

“…We found that T and B cell-deficient Rag2 -/-mice exhibited a 20-day delay (i.e., requiring 32 days in total) in cessation of S. venezuelensis egg excretion during primary infections and a 25-day delay (i.e., requiring 37 days in total) in the secondary infection (versus no eggs detected during secondary infections in any of the wild-type mice) (Fig. 3A), underscoring the importance of an adaptive immune response for effective secondary immune responses to this nematode (8,11,13,14,41,(46)(47)(48). In addition, we confirmed that the number of adult worms in the intestines on day 8 of the primary infection was significantly higher in the Rag2 -/-mice than in the corresponding wild-type mice (Fig.…”

Strongyloides ratti: implication of mast cell-mediated expulsion through FcεRI-independent mechanisms

“…Degranulation itself is considered necessary for protection as sulfated proteoglycan, which is contained in mast cell granules, is essential for expulsion of S. venezuelensis (Metcalfe et al, 1997;Maruyama et al, 2000). Two reports showed results which conflicted with our study that S. venezuelensis expulsion was delayed in accordance with decreased release of proteoglycan into intestinal lumen using FcR-γ chain knockout mice which also had defect in IgE mediated degranulation of mast cells (Onah et al, 2000, Onah & Nawa, 2004. So further study is expected to reveal which machinery of mast cell are essential for expulsion of parasite.…”

Platelet-Activating Factor Receptor Deficiency Delays Elimination of Adult Worms but Reduces Fecundity inStrongyloides venezuelensis-Infected Mice

“…One experimental model that has been used to study the aspects of immunoprotection and immunoregulation during gastrointestinal infection is infection of rodents with Strongyloides venezuelensis (29,30,40,50), a nematode that naturally infects wild rats. In experimental infections, S. venezuelensis larvae have an obligatory migration through the lungs of the host before they become established in the duodenal mucosa (52), similar to the migration of S. stercoralis in humans, and the adult worms are spontaneously eliminated after 5 weeks in rats (55) and after 10 to 14 days of infection in mice (46).…”