Schutzmechanismen des angeborenen Immunsystems gegen Helicobacter-induzierte Erkrankungen [12.03.20]
Helicobacter-Bakterien sind für die meisten Menschen harmlos. Eine zufällig entdeckte Infektion mit Helicobacter pylori ohne Symptome muss daher nicht zwingend behandelt werden. Nistet sich das Bakterium jedoch in der Magenschleimhaut ein, kommt es zu Reizungen und in schweren Fällen auch zu einer chronischen Entzündung. In der Folge können weitere Erkrankungen, zum Beispiel Magen-Darm-Geschwüre auftreten. Ein internationales Forscher-Team unter Beteiligung von Prof. Kufers Arbeitsgruppe zeigt in einem Mausmodell, dass das Protein NLRC5 entzündungshemmend wirkt und damit H. pylori- induzierten Erkrankungen positiv entgegenwirkt.
Foto: Helicobacter pylori (Elektronenmikroskopische Aufnahme von Dan O'Brien)
Mehr Informationen zu den Forschungsprojekten und Publikationen der Arbeitsgruppe Kufer finden Sie hier.
Originalartikel, online 10 March 2020, In Press, Journal Pre-proof
Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue
doi.org/10.1053/j.gastro.2020.03.009
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia
- Department of Molecular and Translational Science, Monash University, Victoria, Australia
- School of Medicine and Public Health, Faculty of Health and Medicine, The University of Newcastle, N. S. W., Australia
- Department of Pathology, University of Melbourne, Victoria, Australia
- Department of Medicine, Monash University, Monash Medical Centre, Victoria, Australia
- Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
- Department of Immunology, University of Toronto, Ontario, Canada
- University of Hohenheim, Institute of Nutritional Medicine, Department of Immunology, Stuttgart, Germany
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Victoria, Australia
Abstract
Background & Aims
Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, NLR family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection.
Methods
We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5møKO) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative PCR. THP-1 cells (human macrophages, controls) and NLRC5¬–/– THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed.
Results
Levels of NLRC5 mRNA were significantly increased in gastric tissues from patients with H pylori infection, compared to patients without infection (P<.01), and correlated with gastritis severity (P<.05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5-/- THP-1 macrophages than by control THP-1 cells (P<.05). After 3 months infection with H felis, Nlrc5mø-KO mice developed gastric hyperplasia (P<.0001), splenomegaly (P<.0001) and increased serum antibody titers (P<.01), whereas control mice did not. Nlrc5mø-KO mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P<.0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5mø-KO mice.
Conclusions
NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.
