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

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.

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.

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.

Elevated systemic IgM titres that recognise MDA facilitate complement recruitment, which enhances hepatocyte injury, thereby promoting alcohol-associated liver disease.