key: cord-0728593-6eglp0xo
authors: McKenzie, Steven E.
title: Sugar and spike: not so nice
date: 2021-10-21
journal: Blood
DOI: 10.1182/blood.2021013359
sha: 2ee61b9b5f61c19e81b556ad8ce10e4d7d15b8bb
doc_id: 728593
cord_uid: 6eglp0xo

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Over the past 2 decades, the interplay among immunity, inflammation, hemostasis, and thrombosis has been more clearly appreciated. Advances in fundamental immunology have translated into improved understanding of the relationship of human thrombotic disorders and immune stimuli. This work by Bye and colleagues fits nicely into that tradition. Thrombosis related to COVID-19 is important and incompletely understood. It is clearly multifactorial, with alterations of endothelial cells and activation of leukocytes, platelets, and coagulation. Since the beginning of the pandemic, clinicians have recognized that critical pulmonary (acute respiratory distress syndrome with pulmonary vascular thrombosis) and systemic (deep vein thrombosis) manifestations of COVID-19 infection are often pronounced when adaptive immunity has begun. IgG is an important component of the adaptive response. Immunoglobulin (IgG) undergoes N-glycosylation of the heavy chain in the Fc region during biosynthesis (see figure) . The nature of these sugars in circulating IgG has been well studied, consistent with fucose and galactose residues being regulated in a narrow range. New fundamental studies have identified reduced fucosylation and increased galactosylation status of the IgG in response to certain viral infections, including HIV and dengue, and indicate that it may be a generalizable feature of the early IgG response to enveloped viruses that bud from cells. [2] [3] [4] Enter the human IgG response to the COVID-19 spike protein. Bye anti-SARS-CoV-2 IgG immune complex with FcgRIIa, the sole Fcg receptor on human platelets that is capable of mediating immunity and thrombosis. 6 Additional evidence includes blockade of FcgRIIA with the anti-FcgRIIA ligand-blocking antibody IV.3 and reduction in activation with inhibitors to known platelet-signaling components downstream of FcgRIIA (Syk, Btk, and P2Y12).

Together with a related study of anti-SARS-CoV-2 IgG stimulation of alveolar macrophages, 4 Bye et al show that both FcgRIIA and FcgRIIIA have increased avidity for the IgG Fc end that presents low-fuc/high-gal modifications. The result is increased effector functions, which in this case are prothrombotic. This paradigm is a new one for antibodydependent inflammation contributing to prothrombotic effects (see figure) . The new appreciation of the interactions of underfucosylated/overgalactosylated IgG with Fcg receptors could advance the understanding and management of COVID-19, coagulopathies from other enveloped viruses, and other immune thrombotic thrombocytopenic disorders.

Conflict-of-interest disclosure: The author declares no competing financial interests.

In this issue of Blood, Yanatori et al 1 demonstrate that the vesicular protein CD63 is regulated by iron and facilitates the secretion of iron-laden ferritin into extracellular vesicles, suggesting that CD63 may enable the transfer of iron-rich ferritin among cells.

Ferritin is a 24-subunit protein nanocage best known for its ability to store intracellular iron in a nontoxic but bioavailable form. A typical ferritin nanocage contains 1000 to 1500 atoms of iron and has the capacity to store .4000 atoms of iron, making it the principal intracellular iron reservoir and a critical contributor to the maintenance of intracellular iron homeostasis. However, ferritin is also found in extracellular compartments, notably human plasma. Levels of ferritin in plasma correlate with body iron stores and are also elevated in inflammation. Clinically, serum ferritin levels are used to assess iron status. The presence of ferritin in extracellular compartments has led to the suspicion that ferritin may play a role in extracellular as well as intracellular spaces, although the nature of that role and the mechanism by which ferritin reaches external environments have remained obscure for decades and are still incompletely understood. Yanatori et al now demonstrate that increased iron levels increase expression of CD63, a tetraspanin protein and important constituent of extracellular vesicles. Mechanistically, CD63 induction is accomplished through an iron responsive element (IRE) in the 59 untranslated region of CD63 messenger RNA (mRNA) that is controlled by the same iron regulatory network that controls levels of ferritin itself. This network consists of iron regulatory proteins, which bind to IREs in the untranslated regions of selected mRNAs to posttranscriptionally control their activity or stability (see figure) . Targets of the posttranscriptional iron regulatory network include not only ferritin but also proteins that regulate iron uptake and iron efflux, such as transferrin receptor 1 and ferroportin. Thus, the identification of a functional IRE in the 59 untranslated region of CD63 directly connects CD63 to pathways of iron metabolism.

The authors further show that the induction of CD63 by iron has a functional impact on iron metabolism by increasing the secretion of CD63 1 extracellular vesicles containing iron-loaded ferritin. Mechanistically, iron loading stimulates

Aberrant glycosylation of anti-SARS-CoV-2 IgG is a prothrombotic stimulus for platelets

Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity

Proinflammatory IgG Fc structures in patients with severe COVID-19

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages

Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability