Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses

Mari Kaarbø; Mingyi Yang; Johannes R Hov; Kristian Holm; Mirta Mittelstedt Leal de Sousa; Magnhild E Macpherson; Henrik M Reims; Anne-Marte Bakken Kran; Bente Halvorsen; Tom H Karlsen; Pål Aukrust; Knut E A Lundin; Børre Fevang; Magnar Bjørås; Silje Fjellgård Jørgensen

doi:10.1016/j.jaci.2022.09.029

Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses

J Allergy Clin Immunol. 2023 Mar;151(3):767-777. doi: 10.1016/j.jaci.2022.09.029. Epub 2022 Oct 8.

Authors

Affiliations

¹ Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
² Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.
³ Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
⁴ Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.
⁵ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Proteomics and Modomics Experimental Core Facility (PROMEC) at Norwegian University of Science and Technology, Trondheim, Norway.
⁶ Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, Ullevål, Oslo, Norway.
⁷ Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.
⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹⁰ Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K. G. Jebsen Celiac Disease Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹ Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹² Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
¹³ Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway. Electronic address: s.f.jorgensen@ous-research.no.

PMID: 36220400
DOI: 10.1016/j.jaci.2022.09.029

Abstract

Background: A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism.

Objective: We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID.

Methods: DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry-based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed.

Results: CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls-DBNL, TRMT11, GCHFR, and IGHA2-independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls.

Conclusion: Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID.

Keywords: CVID; IgA; Primary immunodeficiency; RNA sequencing; celiac disease; duodenum; gastrointestinal tract; gut microbiota; microbiome; microbiota; proteomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bacteria
Celiac Disease* / genetics
Common Variable Immunodeficiency*
Humans
Inflammation
Lipopolysaccharides
Proteomics
RNA
Viruses* / genetics

Substances

Lipopolysaccharides
RNA