Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency-Associated Villous Atrophy and Norovirus Infection
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Journal of clinical immunology - 43(2023), 2 vom: 18. Feb., Seite 371-390 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Strohmeier, Valentina [VerfasserIn] |
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| Links: |
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| Themen: |
9008-11-1 |
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| Anmerkungen: |
Date Completed 06.02.2023 Date Revised 22.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s10875-022-01379-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Strohmeier, Valentina |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency-Associated Villous Atrophy and Norovirus Infection |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CVID | |
| 650 | 4 | |a Cytotoxic T cell response | |
| 650 | 4 | |a Duodenum | |
| 650 | 4 | |a Interferon response genes | |
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| 650 | 4 | |a Villous atrophy | |
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| 700 | 1 | |a Klocperk, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Seidl, Maximilian |e verfasserin |4 aut | |
| 700 | 1 | |a Marques, Otavio Cabral |e verfasserin |4 aut | |
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| 700 | 1 | |a Shabani, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a von Spee-Mayer, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Friedmann, David |e verfasserin |4 aut | |
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| 700 | 1 | |a Gutenberger, Sylvia |e verfasserin |4 aut | |
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| 700 | 1 | |a Provaznik, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Benes, Vladimir |e verfasserin |4 aut | |
| 700 | 1 | |a Goldacker, Sigune |e verfasserin |4 aut | |
| 700 | 1 | |a Schell, Christoph |e verfasserin |4 aut | |
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