Rajcic Dragana, da Silva Beatriz Pereira, Baranovskyi Taras, Simbrunner Benedikt, Hofer Benedikt S, Hoebinger Constanze, Duckova Tereza, Papac-Milicevic Nikolina, Listabarth Stephan, Weber Sabine, Vyssoki Benjamin, König Daniel, Burger Katharina, Bergheim Ina, Binder Christoph J, Mandorfer Mattias, Reiberger Thomas, Hendrikx Tim
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Liver Int. 2025 Oct;45(10):e70356. doi: 10.1111/liv.70356.
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.
酒精性肝病（ALD）与血液中免疫球蛋白M（IgM）水平升高及肝脏脂质过氧化有关。然而，在ALD期间系统性IgM靶向脂质过氧化产物的功能相关性尚未完全明确。
评估ALD患者血清中识别丙二醛 - 乙醛（MAA，脂质过氧化的标志性表位）的IgM和IgG水平以及补体因子水平。在酒精使用障碍（AUD）患者中确定戒酒对抗MAA IgM和IgG水平的影响。给缺乏唾液酸结合免疫球蛋白样凝集素G（Siglec - G，系统性IgM特异性增加）的小鼠、缺乏可溶性IgM（sIgM）的小鼠及其相应的同窝小鼠喂食慢性暴饮乙醇饮食。此外，在慢性暴饮乙醇喂养期间，给野生型小鼠注射与MAA结合的IgM抗体（LR04）或同型对照IgM。将Siglec - G骨髓移植到野生型或补体C3缺陷小鼠（C3）中，以研究IgM升高引起的补体激活在ALD中的作用。
人类血清中抗MAA IgM水平与ALD严重程度呈正相关。虽然缺乏可溶性IgM的小鼠肝损伤不太明显，但与野生型相比，Siglec - G小鼠中循环抗MAA IgM滴度升高与乙醇喂养后更多的肝细胞损伤相关。同样，与注射对照的小鼠相比，接受LR04的小鼠肝损伤加重。此外，与野生型相比，除了肝中性粒细胞和巨噬细胞含量以及星状细胞激活较少外，乙醇喂养的Siglec - G和LR04处理的小鼠肝C3b沉积增加。尽管Siglec - G骨髓移植后抗MAA IgM水平同样高，但C3缺陷小鼠与对照相比，乙醇诱导的肝损伤有所改善，提示高抗MAA IgM时补体依赖性肝损伤。同样，ALD患者血清中与MAA结合的IgM水平与C3c和C4呈负相关。
识别丙二醛的系统性IgM滴度升高促进补体募集，增强肝细胞损伤，从而促进酒精性肝病。
