IgM Antibodies Targeting Malondialdehyde Promote Complement-Mediated Liver Injury in Alcohol-Related Liver Disease

Autor(en)

Dragana Rajcic, Beatriz Pereira da Silva, Taras Baranovskyi, Benedikt Simbrunner, Benedikt S. Hofer, Constanze Hoebinger, Tereza Duckova, Nikolina Papac-Milicevic, Stephan Listabarth, Sabine Weber, Benjamin Vyssoki, Daniel König, Katharina Burger, Ina Bergheim, Christoph J. Binder, Mattias Mandorfer, Thomas Reiberger, Tim Hendrikx

Abstrakt

Background and Aims: Alcohol-related liver disease (ALD) is associated with elevated blood immunoglobulin-type M (IgM) levels and hepatic lipid peroxidation. Nevertheless, the functional relevance of systemic IgM targeting lipid peroxidation products during ALD is incompletely understood. Methods: Levels of IgM and IgG recognising malondialdehyde–acetaldehyde (MAA), as a hallmark epitope of lipid peroxidation, as well as complement factors were assessed in the serum of patients with ALD. The influence of alcohol abstinence on anti-MAA IgM and IgG levels was determined in AUD patients. A chronic-binge ethanol diet was given to mice deficient in sialic acid-binding immunoglobulin-like lectin G (Siglec-G

^−/−), with specifically increased systemic IgM, and mice lacking soluble IgM (sIgM

^−/−), and their corresponding littermates. Furthermore, wildtype mice were injected with MAA-binding IgM antibodies (LR04) or isotype control IgM during chronic-binge ethanol feeding. Siglec-G

^−/− bone marrow transplantation into wildtype or complement C3 deficient mice (C3

^−/−) was performed to investigate the involvement of complement activation by elevated IgM in ALD. Results: Serum levels of anti-MAA IgM positively correlated with ALD severity in humans. While mice lacking soluble IgM had less pronounced liver injury, increased circulating anti-MAA IgM titers in Siglec-G

^−/− mice associated with more hepatocellular damage after ethanol feeding than wildtypes. Similarly, mice receiving LR04 displayed elevated liver injury compared to control-injected mice. Moreover, besides less hepatic neutrophil and macrophage content, and stellate cell activation than wildtypes, ethanol-fed Siglec-G

^−/− and LR04-treated mice had increased hepatic C3b deposition. Mice deficient in C3 displayed ameliorated ethanol-induced liver injury compared with controls, despite similarly high anti-MAA IgM levels after Siglec-G

^−/− bone marrow transplantation, suggesting complement-dependent liver injury upon high anti-MAA IgM. In line, levels of MAA-binding IgM inversely correlated with C3c and C4 in serum of patients with ALD. Conclusion: Elevated systemic IgM titres that recognise MDA facilitate complement recruitment, which enhances hepatocyte injury, thereby promoting alcohol-associated liver disease.

Organisation(en)

Department für Ernährungswissenschaften

Externe Organisation(en)

Medizinische Universität Wien, Psychosoziales Zentrum ESRA

Journal

Liver international

Band

Anzahl der Seiten

ISSN

1478-3231

DOI

https://doi.org/10.1111/liv.70356

Publikationsdatum

10-2025

Peer-reviewed

ÖFOS 2012

301902 Immunologie, 302016 Gastroenterologie, 303009 Ernährungswissenschaften

Schlagwörter

ASJC Scopus Sachgebiete

Hepatology

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/53dcca23-1714-499c-a830-0f1e2c42aae7