IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

Thomas A. Wynn,Keke C. Fairfax,Markus Mohrs,Edward J. Pearce,Eyal Amiel,Tori C. Freitas,Irah L. King

doi:10.1371/journal.ppat.1002490

Thomas A. Wynn, Keke C. Fairfax + Show 5 more

Open Access

https://doi.org/10.1371/journal.ppat.1002490

Copy DOI

Abstract

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection.

Highlights

Schistosomiasis, a chronic neglected tropical disease caused by helminth parasites of the genus Schistosoma, affects approximately 200 million people worldwide, is associated with high morbidity, and leads to more than 300,000 deaths per year in Africa alone [1,2,3]
Immune modulation is a hallmark of chronic disease and serves to protect the host from severe pathology
We show that schistosome-specific antibody-secreting B cells accumulate in the liver as the infection progresses to the chronic state and that this accumulation is dependent on the cytokine Interleukin-10

Summary

Introduction

Schistosomiasis, a chronic neglected tropical disease caused by helminth parasites of the genus Schistosoma, affects approximately 200 million people worldwide, is associated with high morbidity, and leads to more than 300,000 deaths per year in Africa alone [1,2,3]. Hepatosplenic disease is generally thought to reflect a failure to modulate the immune response over time, with the consequence that immunopathology is severe [12,13]. Another form of severe schistosomiasis has been recognized, in which patients develop pulmonary hypertension [14,15,16]. During the course of these experiments we noted that chronic infection is associated with the striking accumulation of schistosome egg antigen (SEA)-specific IgG1secreting B cells in the liver, and that consistent with a role for IL10 in plasma cell development [21,22], this is inhibited by IL-10R

Author Summary

Findings

Materials and Methods