Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

Abstract

Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn’s disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation.

The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not antigen-experienced vaccinees

“…1D, 3B and S6 ). Despite the clear difference between both groups, IL-6 levels were relatively low for all conditions, which is in line with various previous findings showing that IgG ICs only induce pro-inflammatory cytokine production in the presence of both high afucosylation and antibody levels in the presence of viral or bacterial co-stimulus that activates receptors such as Toll-like Receptors (TLRs) ( 1, 32, 33 ).…”

The BNT162b2 mRNA SARS-CoV-2 Vaccine Induces Transient Afucosylated IgG1 in Naive But Not in Antigen-Experienced Vaccinees

“…Despite the clear difference between both groups, IL-6 levels were relatively low for all conditions, which is in line with various previous findings showing that IgG ICs only induce pro-inflammatory cytokine production in the presence of both high afucosylation and antibody levels in the presence of viral or bacterial co-stimulus that activates receptors such as TLRs. 1,48,49 In comparison, the IL-6 levels here produced by the macrophages is an order of magnitude higher than the IL-6 produced in serum of SARS-CoV-2 infected people, with a maximum of around 100 pg/mL in the serum of severely ill COVID-19 patients. 1 To further test the inflammatory capacity of anti-S IgG, we also measured IL-6 production upon TLR coerror bars (right) in the (b) absence or (c) presence of poly(I:C).…”

C-Reactive Protein Controls IL-23 Production by Human Monocytes

“…Since CRP-induced IL-23 production by monocytes was dependent on FcR activation, it was surprising that IL-23 induction was mostly independent of Syk signaling. Nearly all previously described processes induced by CRP-binding FcRs (i.e., FcγRI, IIa, III, and FcαRI) are dependent on Syk [61,62]. Recently also a Syk-independent "non-canonical" pathway has also been described in dendritic cells for FcγRIIa, which is activated in parallel with Syk-dependent signaling [63].…”