Active control of mucosal tolerance and inflammation by human IgA and IgG antibodies

Hoepel, Willianne; Golebski, Korneliusz; Drunen, Cornelis M. van; Dunnen, Jeroen den

doi:10.1016/j.jaci.2020.04.032

Cited by 8 publications

(11 citation statements)

References 10 publications

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“…While we show that FcγRIII was partially responsible for anti-Spike-induced inflammation, FcγRII contributed most, indicating that collaboration between multiple FcγRs is required for the hyper-inflammatory responses induced by the aberrant glycosylation of anti-Spike IgG. In addition to human alveolar macrophages, these FcγRs are expressed by various other myeloid immune cells (15), but also by airway epithelial cells (37), which are one of the main target cells of infection by SARS-CoV-2 and closely interact with activated macrophages (38).…”

Section: Main Textmentioning

confidence: 65%

“…While different protocols are available for generating human M2 macrophages, our previous transcriptional analyses demonstrated that an M-CSF and IL-10-induced monocyte differentiation protocol generates cells that most closely resemble primary human lung macrophages (14). Since activation of immune cells by IgG antibodies is known to require immune complex formation by binding of IgG to its ligand (15,16), we generated Spike-IgG immune complexes by incubating SARS-CoV-2 Spike-coated wells with diluted serum from severely ill COVID-19 patients (i.e. patients from the intensive care unit at the Amsterdam UMC) that tested positive for anti-SARS-CoV-2 IgG.…”

Section: Main Textmentioning

confidence: 99%

“…In addition to fostamatinib, also other drugs that target key molecules in FcγR signaling could be efficacious to counteract anti-Spike IgG-induced inflammation in COVID-19 patients. For example, the Sykdependent FcγR signaling pathway critically depends on the transcription factor IRF5 (15,28), which can be targeted using cell penetrating peptides (40). Furthermore, FcγR stimulation is known to induce metabolic reprogramming of human macrophages (28), which is also observed in COVID-19 patients (41), and therefore may provide additional targets for therapy.…”

Section: Main Textmentioning

confidence: 99%

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Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Hoepel

Chen

Allahverdiyeva

et al. 2020

Preprint

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For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.One sentence summaryAnti-Spike IgG promotes hyper-inflammation.

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Section: Main Textmentioning

confidence: 65%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Hoepel

Chen

Allahverdiyeva

et al. 2020

Preprint

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“…Our previous transcriptional analysis revealed that macrophage colony-stimulating factor (M-CSF) plus interleukin (IL)-10 induces M2 monocyte differentiation that generates macrophages that most closely resemble primary human lung macrophages (16). Since activation of immune cells by IgG antibodies requires immune complex formation by binding of IgG to its cognate antigen (17,18), we generated spike-IgG immune complexes by incubating SARS-CoV-2 spike-coated wells with diluted serum from patients with severe COVID-19 treated in the intensive care unit at the Amsterdam University Medical Centers (UMC) that tested positive for anti-SARS-CoV-2 IgG (fig. S1A).…”

Section: High Titers Of Anti-spike Igg Promote Inflammation By Alveolar Macrophagesmentioning

confidence: 99%

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

et al. 2021

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Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.

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“…Under homeostatic conditions, epithelial cells are unresponsive to Gram-negative bacteria, but in IgG immune complexes break this epithelial tolerance, leading to the production of pro-inflammatory cytokines and chemokines ( Figure 2 E) [ 28 ]. Simultaneously, IgA immune complexes, which under homeostatic conditions are only present in the lumen, will translocate to the lamina propria upon barrier damage, generating a strong pro-inflammatory immune response by immune cells ( Figure 2 E) [ 40 ] (reviewed in more detail in Hoepel et al [ 77 ]).…”

Section: Physiological Immune Activation: Host Defense Against Pathogensmentioning

confidence: 99%

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

Geyer

Mes

Newling

et al. 2021

Cells

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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.

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Active control of mucosal tolerance and inflammation by human IgA and IgG antibodies

Cited by 8 publications

References 10 publications

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

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

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

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