van der Schoot, C. E. | bioRxiv Science

bioRxiv2021

Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination

IgG specific for members of the Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) family, which mediates receptor- and tissue-specific sequestration of infected erythrocytes (IEs), is a central component of naturally acquired malaria immunity. PfEMP1-specific IgG is thought to protect via inhibition of IE sequestration, and through IgG-Fc Receptor (Fc{gamma}R) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to Fc{gamma}RIIIa is elevated up to 40-fold compared to fucosylated IgG, resulting in enhanced antibody-dependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is likewise markedly afucosylated in a stable and exposure-dependent manner, and efficiently induces Fc{gamma}RIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a soluble subunit vaccine based on VAR2CSA-type PfEMP1 resulted in fully fucosylated specific IgG. These results have implications for understanding natural and vaccine-induced antibody-mediated protective immunity to malaria. SummaryAfucosylated IgG has enhanced Fc-receptor affinity and functionality, and is formed specifically against membrane proteins of enveloped viruses. We show that this also applies to Plasmodium falciparum erythrocyte membrane-specific IgG induced by natural infection, but not by soluble PfEMP1 vaccination.

immunology↗

bioRxiv2020

Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in COVID-19

IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc-tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated binding and killing activity through Fc receptors (Fc{gamma}RIIIa). Here, we report that afucosylated IgG which are of minor abundance in humans ([~]6% of total IgG) are specifically formed against surface epitopes of enveloped viruses after natural infections or immunization with attenuated viruses, while protein subunit immunization does not elicit this low fucose response. This can give beneficial strong responses, but can also go awry, resulting in a cytokine-storm and immune-mediated pathologies. In the case of COVID-19, the critically ill show aggravated afucosylated-IgG responses against the viral spike protein. In contrast, those clearing the infection unaided show higher fucosylation levels of the anti-spike protein IgG. Our findings indicate antibody glycosylation as a potential factor in inflammation and protection in enveloped virus infections including COVID-19.

immunology↗