Abstract
Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4Rα-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4Rα-deficient (mb1creIL-4Rα−/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4Rα-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (μMT) mice, succumbing to infection at the acute stage whereas μMT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4Rα expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis—which mimics the course of clinical chronic disease—demonstrated that depleting IL-4Rα-expressing B cells in mb1creIL-4Rα−/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4Rα-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.
Highlights
The ability of B cells to drive host protective defense mechanisms during parasitic infections has received a lot of attention of late
We examined the role of IL-4Rα expressing B cells in driving immunoregulation of inflammatory granulomatous tissue pathology during schistosomiasis
We demonstrated that mice lacking IL-4Rα expressing B cells have enlarged liver and gut granulomas, and display a mixed cytokine profile indicated by augmented secretion of Th1, Th2, and Th17 cytokines at 24 weeks post-infection
Summary
The ability of B cells to drive host protective defense mechanisms during parasitic infections has received a lot of attention of late. A pioneering study by Harris et al classified B cells into two effector subsets: B effector 1 (Be1) cells that secrete IFN-γ, IL-12p40, and TNF-α under the control of the transcription factor T-bet [5, 6] and B effector 2 (Be2) cells that produce low IL-4, IL-13, and IL-2 after receiving instruction from IL-4, IL-4Rα, and Th2 cells [5, 7, 8] The latter subset was identified in vitro and in vivo after infection with H. polygyrus. B cell-derived IL-2, and TNF-α are crucial for clearance of Heligmosomoides polygyrus (H. polygyrus) worms, development of CD4+ T cells secreting IL-4 and generation of type 2 antibody responses [10] Another key molecule derived from B cells that is crucial for the development of robust host defense mechanisms is the MHCII molecule, and mice carrying a specific deletion of MHCII on B cells failed to clear H. polygyrus infection and exhibited impaired humoral and cellular immunity [10]
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