Autoantibody levels are associated with acute kidney injury, anemia and post-discharge morbidity and mortality in Ugandan children with severe malaria

Abstract

Autoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission.

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].…”

“…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].…”

“…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.…”

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

“…Acute renal failure is most reported in P. falciparum infections (Frutakul et al, 1974;Burchard et al, 2003;von Seidlein et al, 2012;Conroy et al, 2016;Sypniewska et al, 2017;Rivera-Correa et al, 2019b), but this complication can occasionally occurs in infection due to P. malariae (Neri et al, 2008;Badiane et al, 2016). Renal failure is considered a clinical manifestation with high prognostic value to severe malaria (von Seidlein et al, 2012;Sypniewska et al, 2017).…”

“…Self-reactive antibodies recognize different self-antigens such as erythrocyte proteins (Rosenberg et al, 1973;Fontaine et al, 2010;Mourão et al, 2016Mourão et al, , 2018Ventura et al, 2018), brain molecules (Bansal et al, 2009;Gitau et al, 2013), phospholipids (Adebajo et al, 1993;Jakobsen et al, 1993;Facer and Agiostratidou, 1994;Fernandez-Arias et al, 2016;Barber et al, 2019;Rivera-Correa et al, 2019a,b), and nucleic acids (Adu et al, 1982;Adebajo et al, 1993;Rivera-Correa et al, 2019b). Although the literature reporting the detection of autoantibodies in plasmodial infections is vast, the role of such molecules in malaria is still a controversial issue.…”