PURPOSE: About 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, which resembles celiac disease with regard to histopathology but evolves from a distinct, poorly defined pathogenesis that has been linked in some cases to chronic norovirus (NV) infection. Interferon-driven inflammation is a prominent feature of CVID enteropathy, but it remains unknown how NV infection may contribute. METHODS: Duodenal biopsies of CVID patients, stratified according to the presence of villous atrophy (VA), IgA plasma cells (PCs), and chronic NV infection, were investigated by flow cytometry, multi-epitope-ligand cartography, bulk RNA-sequencing, and RT-qPCR of genes of interest. RESULTS: VA development was connected to the lack of intestinal (IgA+) PC, a T helper 1/T helper 17 cell imbalance, and increased recruitment of granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. A mixed interferon type I/III and II signature occurred already in the absence of histopathological changes and increased with the severity of the disease and in the absence of (IgA+) PCs. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples. CONCLUSIONS: Our study suggests that increased IFN signaling and T-cell cytotoxicity are present already in mild and are aggravated in severe stages (VA) of CVID enteropathy. NV infection preempts local high IFN-driven inflammation, usually only seen in VA, at milder disease stages. Thus, revealing the impact of different drivers of the pathological mixed IFN type I/III and II signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

CIBSS Centre for Integrative Biological Signalling Studies Albert Ludwigs University Freiburg Germany

Department of Clinical and Toxicological Analyses School of Pharmaceutical Sciences University of São Paulo São Paulo SP Brazil

Department of Immunology 2Nd Faculty of Medicine Charles University and University Hospital in Motol Prague Czech Republic

Department of Immunology Institute of Biomedical Sciences University of São Paulo São Paulo SP Brazil

Department of Medicine 2 Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Pharmacy and Postgraduate Program of Health and Science Federal University of Rio Grande do Norte Natal Brazil

Department of Rheumatology and Clinical Immunology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin Charitéplatz 1 10117 Berlin Germany

Department of Rheumatology and Clinical Immunology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

DZIF German Center for Infection Research Satellite Center Freiburg Freiburg Germany

European Molecular Biology Laboratory Genomics Core Facility Heidelberg Germany

Faculty of Biology University of Freiburg Freiburg Germany

German Cancer Consortium Partner Site Freiburg 79110 Freiburg Germany

Immune Dynamics Deutsches Rheuma Forschungszentrum a Leibniz Institute Charitéplatz 1 10117 Berlin Germany

Institute for Surgical Pathology University Medical Center Freiburg Freiburg Germany

Institute of Medical Bioinformatics and Systems Medicine Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Pathology Heinrich Heine University and University Hospital of Dusseldorf Dusseldorf Germany

Network of Immunity in Infection Malignancy and Autoimmunity São Paulo SP Brazil

RESIST Cluster of Excellence 2155 to Hanover Medical School Satellite Center Freiburg Freiburg Germany

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