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

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 immunoglobulin G (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 proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. 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 Fc gamma receptor (Fc gamma R) Ila and FeyRIII 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. Last, 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.Proteomic

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Specific induction of TSLP by the viral RNA analogue poly(I:C) in primary epithelial cells derived from nasal polyps

<p>Database with files used for generating the result in this manuscript.</p

Plasticity of innate lymphoid cell subsets

Innate lymphoid cells (ILCs) are important for tissue homeostasis and for the initiation of immune responses. Based on their transcriptional regulation and cytokine profiles, ILCs can be categorized into five subsets with defined phenotypes and functional profiles, but they also have the ability to adapt to local environmental cues by changing these profiles. This plasticity raises the question of the extent to which the cytokine production profiles of ILCs are pre-programmed or are a reflection of the tissue microenvironment. Here, we review recent advances in research on ILCs, with a focus on the plasticity of these cells. We highlight the ability of ILCs to communicate with the surrounding microenvironment and discuss the possible consequences of ILC plasticity for our understanding of the biological roles of these cells. Finally, we discuss how we might use this knowledge of ILC plasticity to develop or improve options for the treatment of inflammatory diseases

The effect of coronaviruses on olfaction: systematic review

Background: Unlike other respiratory viruses, SARS-CoV-2 causes anosmia without sinonasal inflammation. Here we systematically review the effects of the 7 known human coronaviruses on olfaction to determine if SARS-CoV-2 distinctly affects the olfactory system. Method: PubMed, EMBASE, Web of Science, bioRxiv, medRxiv and DOAJ were searched for studies describing pathophysiological, immunohistochemical, cytological and clinical data. Results: 49 studies were included. Common cold coronaviruses lead to sinonasal inflammation which can cause transient and chronic loss of smell. MERS-CoV entry receptors were not found in the nasal mucosa and it did not impair olfaction. SARS-CoV-1 had low affinity for its receptor ACE2, limiting olfactory effects. Anosmia is frequent in SARS-CoV-2 infections. SARS-CoV-2’s entry factors ACE2 and TMPRSS2 are expressed in the nasal respiratory epithelium and olfactory supporting cells. SARS-CoV-2 appeared to target the olfactory cleft while diffuse nasal inflammation was not observed. Damage of the olfactory epithelium was observed in animal models. Alternative receptors such as furin and neuropilin-1 and the similarity of viral proteins to odourant receptors could amplify olfactory impairment in SARS-CoV-2 infection. Conclusions: The pathophysiology of anosmia in SARS-CoV-2 infection is distinct from other coronaviruses due to preferentially targeting olfactory supporting cells. However, SARS-CoV-2 does not cause sinonasal inflammation in spite of preferred entry factor expression in the nasal respiratory epithelium. This raises doubts about the attention given to ACE2. Alternative receptors, odourant receptor mimicry and other as yet unknown mechanisms may be crucial in the pathogenesis of anosmia in SARS-CoV-2 infection. Further studies are warranted to investigate infection mechanisms beyond ACE2

The multi-faceted role of allergen exposure to the local airway mucosa

Airway epithelial cells are the first to encounter aeroallergens and therefore have recently become an interesting target of many studies investigating their involvement in the modulation of allergic inflammatory responses. Disruption of a passive structural barrier composed of epithelial cells by intrinsic proteolytic activity of allergens may facilitate allergen penetration into local tissues and additionally affect chronic and ongoing inflammatory processes in respiratory tissues. Furthermore, the ability of rhinoviruses to disrupt and interfere with epithelial tight junctions may alter the barrier integrity and enable a passive passage of inhaled allergens through the airway epithelium. On the other hand, epithelial cells are no longer considered to act only as a physical barrier toward inhaled allergens, but also to actively contribute to airway inflammation by detecting and responding to environmental factors. Epithelial cells can produce mediators, which may affect the recruitment and activation of more specialized immune cells to the local tissue and also create a microenvironment in which these activated immune cells may function and propagate the inflammatory processes. This review presents the dual role of epithelium acting as a passive and active barrier when encountering an inhaled allergen and how this double role contributes to the start of local immune responses

Histone deacetylase inhibitors up-regulate LL-37 expression independent of toll-like receptor mediated signalling in airway epithelial cells

HDAC inhibitors have been proposed as anticancer agents. However, their roles in innate genes expression remain not well known. Cathelicidin LL-37 is one of the few human bactericidal peptides, but the regulation of histone acetylation on LL-37 expression in airway epithelium remains largely unknown. Therefore, we investigated the effects of two non-selective HDACi, trichostatin A (TSA) and sodium butyrate (SB), on the expression of the cathelicidin LL-37 in human airway epithelial cells. LL37 in human NCI-H292 airway epithelial cells and the primary cultures of normal nasal epithelial cells(PNEC) in response to HDAC inhibitors with or without poly (I:C) stimulation was assessed using real-time PCR and western blot. In parallel, IL-6 expression was evaluated by ELISA. Our results showed that HDAC inhibitors up-regulated LL-37 gene expression independent of poly (I:C) stimulation in PNEC as well as in NCI-H292 cells. HDAC inhibitors increased LL37 protein expression in N CI-H292 cells but not in PNEC. In addition, HDAC inhibitors significantly inhibited poly (I:C)-induced IL-6 production in both of the epithelial cells. In conclusion, HDAC inhibitors directly up-regulated LL-37 gene expression in human airway epithelial cells