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

Abstract

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.

Keywords: IgM; alcohol‐associated liver disease; complement; malondialdehyde.