The COVID-19 antibody responses, isotypes and glycosylation: Why SARS-CoV-2 Spike protein complex binding of IgG3 is potentiated in some and immuno-pathologies manifest

Abstract

AbstractCOVID-19 syndrome does not occur in all who are infected with SARS-CoV-2, and symptoms vary. The anti-SARS CoV-2 Spike immune responses is confounded by the Spike proteins ability to bind Igγ3 heavy chains. This appears to be via sialic acid glycans found on the O-Linked glycosylation moieties of this heavy chain extended neck domain. Furthermore glycosylation of light chains, particularly Kappa (κ), is an associated feature of antibodies binding to SARS-CoV-2 antigens nucleocapsid and Spike protein. COVID-19 recovered patients had increased IgG1 and IgM levels and un-glycosylated κ light chains; possibly In order to counter this immune system subjugation of IgG3. These molecular finding, together with our previous finding that Spike protein binds glycated human serum albumin (HSA), may explain the micro-vascular inflammatory clots that are a causative feature of COVID-19 acute respiratory syndrome (ARDS).The postulated molecular sequelae are that SARS-CoV-2 virion, entering the blood circulation, being coated with IgG3 and glycated HSA forms a colloid and deposits into micro-focal clots which are also inflammatory. It is not that all IgG3 and albumin is being bound by the virus; this depends on the affinity the SARS-CoV2 virion has for binding an individual’s IgG3 and albumin due to glycosylation and glycation status. The degree of glycosylation and terminal sialyation of an individual’s antibodies is both a genetic and age-maturity dependant feature of the immune system. The degree of HSA glycation is also age related feature particularly related to type 2 diabetes. Thereby establishing the molecular basis of the association of severe COVID-19 disease syndrome and deaths with diabetes, metabolic disorders, and old age. Furthermore, already having cardiovascular disease, with hardened arteries, SARS-CoV2-glycated HSA-IgG3 deposition is going to exacerbate an already compromised circulatory physiology. The binding of IgG3 might also drives a shift in the immune repertoire response to SAR-CoV-2 anti-spike antibodies of increased IgG1 and prolonged IgM levels. This may be associated with Long Covid.In summary, SARS-CoV-2 Spike protein binding of IgG3, via sialic acid glycan residues, along with increased glycosylated κ-light chains and glycated-HSA may form a focal amyloid-like precipitate within blood vessels which in turn leads to the inflammatory micro-thrombosis characteristic of COVID-19 immuno-pathology.