Anti-Self Phosphatidylserine Antibodies Recognize Uninfected Erythrocytes Promoting Malarial Anemia

Abstract

Summary Plasmodium species, the parasitic agents of malaria, invade erythrocytes to reproduce resulting in erythrocyte loss. However, a greater loss is caused by the elimination of uninfected erythrocytes, sometimes long after infection has been cleared. Using a mouse model, we found that Plasmodium infection induces the generation of anti-self antibodies that bind to the surface of uninfected erythrocytes from infected, but not uninfected, mice. These antibodies recognize phosphatidylserine, which is exposed on the surface of a fraction of uninfected erythrocytes during malaria. We find that phosphatidylserine-exposing erythrocytes are reticulocytes expressing high levels of CD47, a ‘do-not-eat-me’ signal, but the binding of anti-phosphatidylserine antibodies mediates their phagocytosis, contributing to anemia. In human patients with late post-malarial anemia, we found a strong inverse correlation between the levels of anti-phosphatidylserine antibodies and plasma hemoglobin, suggesting a similar role in humans. Inhibition of this pathway may be exploited for treating malarial anemia.

Effects of IgG and IgM autoantibodies on non-infected erythrocytes is related to ABO blood group in Plasmodium vivax malaria and is associated with anemia

“…Our defocusing microscopy and erythrophagocytosis results indicate that IgG antibodies purified from anemic patients with vivax malaria can decrease nRBCs membrane dynamics fluctuations and increase their in vitro phagocytic uptake, mainly of those from O phenotype. This clearance of non-infected erythrocytes is an important component of malaria-associated anemia as previously demonstrated [5, 17] and suggests that O individuals may be more prone to develop anemia during P. vivax infections. These data add new insights about the possible association between ABO blood groups and P. vivax -associated anemia.…”

“…Another result that is worth mentioning is the detection of high levels of IgM antibodies against nRBCs in P. vivax -infected patients. It is possible that those antibodies may recognize phosphatidylserine, which is exposed in the surface of both infected and non-infected RBCs during malaria [17], as it has been demonstrated by Barber et al [18]. Further studies are necessary to elucidate this hypothesis.…”

Breaking down defenses: quantitative analysis of malaria infection dynamics reveals distinct immune defense strategies

“…We expect that, in general, multiple cell types and signaling molecules will mediate the responses we describe. For example, there are several mechanisms that might be responsible for the increased removal of uninfected cells during malaria infections (Salmon et al, 1997;Safeukui et al, 2015;Fernandez-Arias et al, 2016). Experimental manipulation of infection dynamics, in combination with measurement of a panel of putative mediators (as per the procedures used in systems immunology (Davis et al, 2017)), has the potential to tease apart which of the array of cell types are the most sensitive predictors of each of these functional components of the host response.…”

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

“…Recently, additional evidence for the contribution of PS to malarial anemia was reported in a study of mice infected with the nonlethal (17XNL) P. yoelii (Fernandez-Arias et al, 2016). In this model, as observed by our group with the lethal (17XL) strain P. yoelii (Totino et al, 2010), there was a significant increase in the levels of PS-exposing nRBCs.…”

“…This connection between CD47, nRBC and anemia was also confirmed in a study with wild type mice infected by P. yoelii 17XNL that found a decline in the number of nRBCs expressing high levels CD47 when RBC counts were falling. An increase in newly formed RBCs (reticulocytes) that express high levels of CD47 was detected later at the recovery stage (Fernandez-Arias et al, 2016), implicating CD47 in the pathogenesis of malarial anemia through elimination of nRBCs.…”