Autoantibodies against red blood cells in malaria- good or bad?

Abstract

Malaria is a life-threatening disease today occuring mostly in tropical regions and it is transmitted through the bite of female Anopheles mosquitoes. Many species of Plasmodium infect humans where P. falciparum is the most fatal. Red blood cells (RBCs) are the main target where the parasite replicates. A better understanding of how naturally immune individuals control infections could facilitate future vaccine studies. This thesis investigates the ambiguous role of autoantibodies against RBCs in malaria development. We have investigated healthy adults living in a malaria endemic area in Uganda and found that more than half had antibodies against RBCs. Specific antibodies directed against RBC surface antigens, incriminated in merozoite invasion such as glycophorins A, B and C, as well as JMH (SEMA7A), were detected, and potentially these antibodies could be beneficial. Other antibodies had partial specificity against the blood group antigens Rh, Diego, and Cromer. 15% were DAT-positive and 28% were parasite positive (by PCR), and these had higher anti-parasite extract IgG levels and more inhibition in growth/invasion assays, however there was no correlation with presence of antibodies against RBCs. We also measured different inflammatory markers and found some Ugandans to have low haptoglobin levels and more than half had low orosomucoid levels. There was no correlation with PCR-positivity or anti-RBCs or anti-parasite antibodies, and in general there were very few signs of inflammation in spite of presence of parasites. In contrast to the above possibly beneficial autoantibodies, anti-Phosphatidylserine (PS) antibodies have been linked to anemia, a common complication in pregnancy. The levels of anti-PS IgG antibodies were investigated in pregnant Ugandan women. Anti-PS inversely correlated with packed cell volume (PCV) but not with anti-VAR2CSA IgG or parasitemia, indicating a multifactorial modulation. Anti-PS levels were lowest in multigravidae which may explain the better control of anaemia in these individuals. During the first year of life, levels of anti-PS gradually increase and show several correlations with atypical P. falciparum-specific B-cells, implicating that further investigations are needed to conclude the functional aspects of these antibodies and which part they play in development of immunity against malaria. In conclusion, our results showed that specific autoantibodies against RBCs are very common in malaria endemic areas. A clear presence of antibodies against RBCs in parallel with high levels of IgG and almost no signs of inflammation was observed in healthy adults living in such areas, even though many were carrying parasites, indicating that these Ugandan adults have reached a state of immunity where they can harbor parasites without the need for any major inflammatory response. We speculate that antibodies against different RBC surface antigens which are also receptors for merozoite invasion might be beneficial for long term protection, while other antibodies such as those against PS could be more harmful.