TNFRSF13B Common Variants Enhance Antibody-Dependent Complement Activation and Susceptibility to Acute Respiratory Distress Syndrome Following Respiratory Viral Infection
Naing, L.; de Mattos Barbosa, M. G.; Connell, I. P.; Chicca, J.; Zhao, Z.; Reister, N. A.; Bruchez, A.; Greenspan, N.; McComsey, G.; Platt, J. L.; Cascalho, M.
Show abstract
Acute respiratory distress syndrome (ARDS) is a devastating complication of respiratory infections; however, the biological mechanisms that initiate its onset are poorly defined. Here we show that TNFRSF13B polymorphisms increase the risk of ARDS following SARS-CoV-2 infection up to 7.4-fold compared to the WT genotype. The increased risk was not due to immune-deficiency or impaired virus neutralization. On the contrary, TNFRSF13B mutant subjects mounted better antibody neutralization compared to subjects with WT TNFRSF13B. However, IgG from subjects expressing TNFRSF13B variants had less sialic acid, terminal galactose, and fucose than IgG from subjects with a WT genotype. Moreover, IgG from TNFRSF13B mutant subjects exhibited increased recruitment of complement factors. Thus, besides well-known actions governing plasma cell differentiation, TNFRSF13B impacts both affinity maturation and effector functions of IgG in ways that independently govern complement activation controlling inflammatory responses known to trigger ARDS.
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