Schistosome egg antigens, including the glycoprotein IPSE/alpha-1, trigger the development of regulatory B cells

Abstract

Infection with the helminth Schistosoma (S.) mansoni drives the development of interleukin (IL)-10-producing regulatory B (Breg) cells in mice and man, which have the capacity to reduce experimental allergic airway inflammation and are thus of high therapeutic interest. However, both the involved antigen and cellular mechanisms that drive Breg cell development remain to be elucidated. Therefore, we investigated whether S. mansoni soluble egg antigens (SEA) directly interact with B cells to enhance their regulatory potential, or act indirectly on B cells via SEA-modulated macrophage subsets. Intraperitoneal injections of S. mansoni eggs or SEA significantly upregulated IL-10 and CD86 expression by marginal zone B cells. Both B cells as well as macrophages of the splenic marginal zone efficiently bound SEA in vivo, but macrophages were dispensable for Breg cell induction as shown by macrophage depletion with clodronate liposomes. SEA was internalized into acidic cell compartments of B cells and induced a 3-fold increase of IL-10, which was dependent on endosomal acidification and was further enhanced by CD40 ligation. IPSE/alpha-1, one of the major antigens in SEA, was also capable of inducing IL-10 in naïve B cells, which was reproduced by tobacco plant-derived recombinant IPSE. Other major schistosomal antigens, omega-1 and kappa-5, had no effect. SEA depleted of IPSE/alpha-1 was still able to induce Breg cells indicating that SEA contains more Breg cell-inducing components. Importantly, SEA- and IPSE-induced Breg cells triggered regulatory T cell development in vitro. SEA and recombinant IPSE/alpha-1 also induced IL-10 production in human CD1d+ B cells. In conclusion, the mechanism of S. mansoni-induced Breg cell development involves a direct targeting of B cells by SEA components such as the secretory glycoprotein IPSE/alpha-1.

Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs

“…To assess whether IFN‐I signaling provides important signals for Breg development and IL‐10 production in response to S. mansoni egg products not only in vitro but also in vivo, we induced Breg development by two doses of i.p. administered S. mansoni eggs (5000) in WT control or IFNAR1 −/− mice, a model we previously showed to be very suitable to demonstrate schistosome‐induced splenic Breg development . The absence of IFNAR1 did not affect the concentration of IL‐10 in B cells and total splenocyte culture supernatants in response to restimulation with SEA and anti‐CD40 (Fig.…”

“…Adding blocking antibody against CD40L to the cultures, and thereby preventing the ligation of CD40 expressed on B cells by accessory cells present in whole splenocyte cultures, had only negligible effects. This might indicate that although CD40 ligation has previously been shown to enhance B‐cell IL‐10 expression , it does not provide additional signals for B‐cell IL‐10 production in this restimulation setting. This might point at a difference in the contribution of CD40 signaling to Breg induction upon concurrent priming of B cells with an antigen and agonistic anti‐CD40 and upon ex vivo restimulation as performed in this study.…”

“…We and others have previously shown that chronic S. mansoni infection induces Bregs , and that this Breg‐inducing effect can be replicated by isolated eggs, SEA, and even the single, egg‐derived molecule IPSE/alpha‐1 in the absence of adult worms and a natural infection . Components of SEA directly bind to splenic B cells , but the receptors ligated and signaling pathways activated by these antigens remain to be identified. Moreover, SEA immunization is less potent than chronic infection at Breg induction in vivo, and the induction of Bregs by IPSE/alpha‐1 has only been demonstrated in vitro .…”

Isolated Schistosoma mansoni eggs prevent allergic airway inflammation

“…Despite the difference in OVA‐specific Th2 responses, egg treatment equally protects from AAI both in WT and μMT mice, indicating that mature B cells are not crucial for protection. While this does not formally exclude a role for all Breg cell subsets, which can be present in both the B1 and B2 B‐cell compartment, we believe they are unlikely to play a major role as we have previously studied the induction of Breg cells by S. mansoni infection, SEA and the single egg molecule IPSE/alpha‐1 and predominantly identified Breg cells within the splenic marginal zone (MZ) B‐cell compartment as well as the pulmonary B‐cell compartment . Both MZ B cells, which belong to the B2 B‐cell lineage, and pulmonary B cells are absent in μMT mice and thus unlikely crucial for protection.…”

Worms: Pernicious parasites or allies against allergies?

“…Adoptive transfer of TLR‐7 stimulated splenic CD1d hi B cells reduced allergic airway inflammation through the recruitment of regulatory T cells. Further mechanistic insight was recently supplied by the finding that the S. mansoni ‐derived molecule IPSE/alpha‐1 could drive Breg differentiation in vitro . In addition, and separately to “conventional” IL‐10‐producing Bregs, S. mansoni ‐infected mouse lungs also contain a nonclassical regulatory B‐cell population that could also inhibit AAI by reducing allergen‐specific Th2 responses, in an IL‐10 and Treg‐independent manner…”