IgG autoantibody to brain beta tubulin III associated with cytokine cluster-II discriminate cerebral malaria in central India.

Devendra Bansal,Ilaria De Maria,Rajendra Jain,Jean Claude Rousselle,Gyan Chandra Mishra,Pierre-André Cazenave,Christophe Bécavin,Arndt Benecke,Vincent Guiyedi,Fabien Herbert,Constantin Fesel,Pharath Lim,Sylviane Pied,Prakash Deshpande,Cristiano Ferlini,Abdelkader Namane,Mauricio Martins Rodrigues

doi:10.1371/journal.pone.0008245

Abstract

BackgroundThe main processes in the pathogenesis of cerebral malaria caused by Plasmodium falciparum involved sequestration of parasitized red blood cells and immunopathological responses. Among immune factors, IgG autoantibodies to brain antigens are increased in P. falciparum infected patients and correlate with disease severity in African children. Nevertheless, their role in the pathophysiology of cerebral malaria (CM) is not fully defined. We extended our analysis to an Indian population with genetic backgrounds and endemic and environmental status different from Africa to determine if these autoantibodies could be either a biomarker or a risk factor of developing CM.Methods/Principal FindingsWe investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. A two-fold complete-linkage hierarchical clustering allows classifying the different patient groups and to distinguish the CM from the others on the basis of their profile of IgG reactivity to brain proteins defined by PANAMA Blot. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine (IFNγ, IL1β, TNFα, TGFβ) previously demonstrated to be a predictor of CM in the same population.Conclusions/SignificanceCollectively, these findings validate the relationship between antibody response to brain induced by P. falciparum infection and plasma cytokine patterns with clinical outcome of malaria. They also provide significant insight into the immune mechanisms associated to CM by the identification of TBB3 as a new disease-specific marker and potential therapeutic target.

Highlights

Malaria remains a major cause of morbidity and mortality in humans, resulting 350–500 million clinical cases and over one million deaths annually [1]
We extended our analysis to an Indian population with genetic backgrounds, endemic and environmental status different from the Gabonese population to determine if autoreactive antibodies specific to brain antigens are present in cerebral malaria (CM) patients and could play a role in malaria pathogenesis
Group 1 consisted of subjects, who had CM within the past 6 months and recovered, healthy malaria endemic controls (EC) were patient’s relatives who accompanied the patient to the hospital and not had malaria for at least the preceding 2 years, nor were they clinical asymptomatic carriers; and malaria non-endemic controls (NEC) were the subjects residing in the Pune city with no history of malarial disease for $5 years

Summary

Introduction

Malaria remains a major cause of morbidity and mortality in humans, resulting 350–500 million clinical cases and over one million deaths annually [1]. Plasmodium falciparum infection generates pleiomorphic clinical outcomes, from asymptomatic to severe syndromes depending on transmission intensity, age of the individuals and on the immunity and the genetic background of the populations [2,3,4]. The main processes in the pathogenesis of cerebral malaria caused by Plasmodium falciparum involved sequestration of parasitized red blood cells and immunopathological responses. IgG autoantibodies to brain antigens are increased in P. falciparum infected patients and correlate with disease severity in African children. Their role in the pathophysiology of cerebral malaria (CM) is not fully defined.

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