Autoantibodies and Malaria: Where We Stand? Insights Into Pathogenesis and Protection

Abstract

Autoantibodies are frequently reported in patients with malaria, but whether they contribute to protection or to pathology is an issue of debate. A large body of evidence indicates that antibodies against host-self components are associated to malaria clinical outcomes such as cerebral malaria, renal dysfunction and anemia. Nonetheless, self-reactive immunoglobulins induced during an infection can also mediate protection. In light of these controversies, we summarize here the latest findings in our understanding of autoimmune responses in malaria, focusing on Plasmodium falciparum and Plasmodium vivax. We review the main targets of self-antibody responses in malaria as well as the current, but still limited, knowledge of their role in disease pathogenesis or protection.

Keywords: anemia; autoantibodies; cerebral malaria; malaria; renal dysfunction.

Figure 1

Schematic representation of self-reactive antibodies and their proposed role in the pathogenesis or protection against malaria. Autoantibodies that recognize host's own molecules have been reported in patients with malaria but the mechanisms by which such autoimmune response is induced are still to be completely elucidated. In infections due to P. falciparum, self-reactive immunoglobulins against voltage-gated calcium channel (VGCC), non-erythroid alpha spectrin, and beta tubulin III have been associated to cerebral malaria. In P. falciparum and P. vivax infections, anti-phosphatidylserine antibodies (IgG anti-PS) have been shown to recognize non-infected red blood cells (nRBCs) exposing phosphatidylserine, mediating their clearance and contributing to malaria-associated anemia. During P. vivax malaria, autoimmune responses to anion exchanger 1 (band 3 protein) have been implicated in the removal of nRBCs by decreasing their deformability and enhancing their uptake by THP-1 cells. On the other hand, in P. falciparum malaria, anti-band 3 self-reactive antibodies have been associated to protection through the blockage of cytoadherence. Antibodies to erythrocytic spectrin are elicited during P. vivax malaria but it remains unclear how they bind to cytoplasmic proteins. It has been hypothesized that the inflammation triggered by infection may damage brain cells, leading to the exposure of spectrin, which may activate the complement, amplifying neuronal damage. Finally, anti-DNA autoantibodies and immune complexes containing self-immunoglobulins have been suggested to play a role in renal dysfunction by depositing in renal tissues. iRBC: infected red blood cell. Ag: antigen. C3: complement component 3. Figure created with BioRender.