FcγRIII stimulation breaks the tolerance of human nasal epithelial cells to bacteria through cross-talk with TLR4

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

“…For example, the recognition of IgA-ICs in the intestinal lamina propria by FcaRI drastically converts the tolerogenic phenotype of human intestinal dendritic cells into a proinflammatory phenotype, which induces protective immunity by activating antibacterial T H 17 and type 3 innate lymphoid cell responses 4 (Fig 1, B). A similar phenomenon occurs in nasal and lung epithelial cells, where activation of FcgRIII by IgG-ICs in the lumen breaks the tolerance of epithelium to commensal gramnegative bacteria 3 (Fig 1, B).…”

“…Both human IgA and IgG (and their different subclasses) are able to suppress or amplify the production of proinflammatory and anti-inflammatory cytokines and chemokines in a wide range of mucosal cell types, including immune cells and epithelial cells. [2][3][4][5] This antibody-induced control of cytokine production is predominantly mediated by the antibody receptors FcaRI (recognizing IgA) and FcgRs (recognizing IgG). Antibody control of mucosal tolerance or inflammation is dependent on intricate compartment-specific activation (schematically summarized in Fig 1, A and B).…”

“…Consequently, FcRs and TLRs engage in cross-talk that is dependent on the kinase Syk, which breaks the otherwise tolerogenic response of immune cells and epithelial cells by eliciting large amounts of proinflammatory cytokines and chemokines. 3,4 This appears to serve a physiological function by enabling the mucosal immune system to discriminate between harmless commensals and invading pathogens. Because of the high load of TLRactivating microbial structures from commensal bacteria that reach the lamina propria under steady-state conditions, mucosal immune cells are generally tolerogenic to these structures.…”

“…2 In addition, in patients with chronic rhinosinusitis with nasal polyps, the IgG/FcgRIII-induced pathway is constitutively active in polyp epithelium, leading to breaking of tolerance to commensal bacteria. 3 Interestingly, IgA subclasses have recently been identified to be associated with disease activity, with IgA 2 inducing more vigorous inflammatory responses than IgA 1 , which is related to IgA glycosylation differences that may activate additional receptors. 8 For future research, it would be valuable to assess whether these differences in inflammatory capacity also hold true for the 4 IgG subclasses, which also display extensive variability in glycosylation and FcR-binding affinity.…”

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

“…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).…”