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

Simone Haeberlein,Mathilde A M Chayé,Arifa Ozir-Fazalalikhan,Hermelijn H Smits,Ruud H P Wilbers,Joke M M Den Haan,Lotte B Westerhof,Astrid Voskamp,Gabriele Schramm,Louis Boon,Luciën E P M Van Der Vlugt,Arjen Schots,Henrike Veninga,Katja Obieglo,Cornelis H Hokke,Edward Mitre

doi:10.1371/journal.ppat.1006539

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.

Highlights

Helminths can persist for up to decades in the human host
While Schistosoma (S.) mansoni has been described to exert its downmodulatory effects on inflammation by inducing a network of regulatory immune cells such as regulatory B (Breg), the mechanisms of Breg cell induction remain unclear
We use in vivo and in vitro approaches to show that antigens from S. mansoni eggs, among which the major glycoprotein IPSE/alpha-1, directly interact with splenic marginal zone B cells of mice which triggers them to produce the anti-inflammatory cytokine IL-10 and their capacity to induce regulatory T (Treg) cells

Summary

Introduction

Helminths can persist for up to decades in the human host. This is hypothesized to be, at least in part, because of their evolutionarily adapted relationship with the host [1]. Helminths can suppress immune responses to other antigens, such as allergens and auto-antigens, and other pathogens. This bystander effect seems to be so pronounced that it may prevent the development of inflammatory diseases. Both epidemiological studies and mouse models show a clear protective role of helminths against various forms of auto-immunity, allergic airway inflammation, colitis etc. In particular infection with schistosomes such as Schistosoma (S.) mansoni are well-known to induce regulatory B (Breg) cells [8,9,10,11,12,13,14,15], a relatively new member in the network of regulatory immune cells. Regulatory B cells suppress pro-inflammatory immune responses via several mechanisms, of which the ones best described are the expression of the regulatory cytokine interleukin-10 (IL-10) and induction of regulatory T (Treg) cells [24]

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