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Eur J Immunol ; 51(12): 2708-3145, 2021 12.
Article in English | MEDLINE | ID: covidwho-1568038


The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.

Autoimmune Diseases/immunology , Flow Cytometry , Infections/immunology , Neoplasms/immunology , Animals , Chronic Disease , Humans , Mice , Practice Guidelines as Topic
Immunity ; 54(6): 1186-1199.e7, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1207036


A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.

Host-Pathogen Interactions , Immunity, Cellular , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Receptor, Notch4/metabolism , Signal Transduction , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Amphiregulin/pharmacology , Animals , Biomarkers , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility , Host-Pathogen Interactions/immunology , Humans , Immunohistochemistry , Immunomodulation/drug effects , Inflammation Mediators/metabolism , Influenza A virus/physiology , Lung/immunology , Lung/metabolism , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Pneumonia, Viral/pathology , Receptor, Notch4/antagonists & inhibitors , Receptor, Notch4/genetics , Severity of Illness Index