Liver international : official journal of the International Association for the Study of the Liver · 2025
IgM Antibodies Targeting Malondialdehyde Promote Complement-Mediated Liver Injury in Alcohol-Related Liver Disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
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.
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.