Atypical memory B-cells are associated with Plasmodium falciparum anemia through anti-phosphatidylserine antibodies

Abstract

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+ B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5+T-bet+ B-cells is observed, revealing high specificity in this response. We also identify FcRL5+T-bet+ B-cells as producers of anti-PS antibodies in ex vivo cultures of naïve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum-infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia.

Atypical memory B-cells and autoantibodies correlate with anemia during Plasmodium vivax complicated infections

“…Binding of anti-PS antibodies to uninfected erythrocytes probably explains, at least in part, the correlation we observed between anti-RBC and hemoglobin, since PS is highly abundant in erythrocyte lysates, along with other reported protein auto antigens (spectrin and band 3) [12,35]. Antibodies against DNA also correlate with anemia in Ugandan children who suffered P. falciparum malaria [15], but not in first-time infected European travelers [16]. The mechanism by which anti-DNA antibodies are related to anemia is not established but could be mediated by the recently reported ability of erythrocytes to bind cell-free DNA on their surface [10,36].…”

“…AtMBCs are a highly reported B-cell subset known to expand in P. falciparum-exposed individuals in endemic areas [18][19][20][21]39] and in P. vivax patients [22,[40][41][42]. Importantly, we have reported how P. falciparum-induced AtMBCs, characterized by double positivity of FcRL5 and T-bet, are able to secrete anti-PS antibodies in vitro and how they correlate with anemia in first-time infected P. falciparum patients [16]. This led us to explore whether AtMBCs also correlated with anemia and autoantibodies in Colombian P. vivax and P. falciparum malaria patients.…”

“…The mechanism by which anti-DNA antibodies are related to anemia is not established but could be mediated by the recently reported ability of erythrocytes to bind cell-free DNA on their surface [10,36]. Similarly as for other P. falciparum cohorts [15] [16], no correlation was observed between anti-parasite antibodies (P. vivax MSP1) and hemoglobin. However, a correlation between hemoglobin levels and different P. vivax antigens, including MSP-1, has been described in other cohorts with larger numbers of patients [37,38].…”

“…Previous reports show increased levels of atypical memory B-cells (AtMBCs) in populations chronically exposed to P. falciparum [17][18][19][20][21] or P. vivax infections [22]. In P. falciparum acute infections, a strong correlation was observed between the levels of AtMBCs, the levels of anti-PS antibodies and the levels of plasma hemoglobin [16], suggesting that atMBCs may be the main B-cell type secreting anti-PS antibodies that contribute to human malarial anemia, as was previously observed in mice models of infection [23]. However, the relationship between AtMBCs, autoimmunity and the role they might play during anemia and other complications has not been explored during P. vivax infections.…”

“…In malaria patients, the levels of anti-PS antibodies correlate inversely with hemoglobin levels in different cohorts infected with P. falciparum, including children with severe infections in Uganda [15], European travelers with post-malarial anemia [14] or first-time malaria infections [16] and uncomplicated P. vivax infections in Malaysia [17]. The relationship betweenanti-PS antibodies and other autoantibodies with anemia has not been explored longitudinally or during complicated P. vivax infections.…”