Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections.

Juan Rivera-Correa,Ana Rodriguez,Julian Sherman,Joseph Verdi,Jayne Raper,Jeremy M Sternberg,Alvaro Acosta-Serrano

doi:10.1371/journal.pntd.0009814

Abstract

Anemia caused by trypanosome infection is poorly understood. Autoimmunity during Trypanosoma brucei infection was proposed to have a role during anemia, but the mechanisms involved during this pathology have not been elucidated. In mouse models and human patients infected with malaria parasites, atypical B-cells promote anemia through the secretion of autoimmune anti-phosphatidylserine (anti-PS) antibodies that bind to uninfected erythrocytes and facilitate their clearance. Using mouse models of two trypanosome infections, Trypanosoma brucei and Trypanosoma cruzi, we assessed levels of autoantibodies and anemia. Our results indicate that acute T. brucei infection, but not T. cruzi, leads to early increased levels of plasma autoantibodies against different auto antigens tested (PS, DNA and erythrocyte lysate) and expansion of atypical B cells (ABCs) that secrete these autoantibodies. In vitro studies confirmed that a lysate of T. brucei, but not T. cruzi, could directly promote the expansion of these ABCs. PS exposure on erythrocyte plasma membrane seems to be an important contributor to anemia by delaying erythrocyte recovery since treatment with an agent that prevents binding to it (Annexin V) ameliorated anemia in T. brucei-infected mice. Analysis of the plasma of patients with human African trypanosomiasis (HAT) revealed high levels of anti-PS antibodies that correlated with anemia. Altogether these results suggest a relation between autoimmunity against PS and anemia in both mice and patients infected with T. brucei.

Highlights

Anemia is a very common, but poorly understood, complication in many infectious diseases, including protozoan parasitic infections, such as trypanosomiasis and malaria
T. brucei-induced anemia is associated with autoimmunity decision to publish, or preparation of the manuscript
After gating out non-B cells (CD19−) in splenic lymphocytes (S1 Fig), we identified an atypical B cells (ABCs) population, as defined by high expression of CD11c and T-bet [17,18], which expanded in T. b. brucei-infected mice (Fig 1)

Summary

Introduction

Anemia is a very common, but poorly understood, complication in many infectious diseases, including protozoan parasitic infections, such as trypanosomiasis and malaria. The most relevant human trypanosome pathogens are Trypanosoma brucei and Trypanosoma cruzi, that cause sleeping sickness in Africa, and Chagas disease in the Americas, respectively [1,2] Both infections, but Trypanosoma brucei, lead to some degree of anemia [3,4]. Autoimmune antibodies targeting the membrane lipid phosphatidylserine (PS) exposed in the membrane of uninfected erythrocytes promote their lysis and premature clearance in both mice and humans, aggravating anemia [6,7,8,9,10,11]. A role for autoimmunity in promoting anemia during trypanosomiasis has been suggested [3] but remains poorly understood

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Conclusion