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Liver-derived apolipoprotein B-100 (ApoB100) is an autoantigen that is recognized by atherogenic CD4+ T cells in cardiovascular disease (CVD). CVD is a major mortality risk for patients with chronic inflammatory liver diseases. However, the impact of liver damage for ApoB100-specific T-cell responses is unknown. We identified ApoB100-specific T cells in blood from healthy controls, nonalcoholic fatty liver disease (NAFLD) patients, and CVD patients by activation-induced marker expression and analyzed their differentiation pattern in correlation to the lipid profile and liver damage parameters in a cross-sectional study. To assess the induction of extrahepatic ApoB100-specific T cells upon transient liver damage in vivo, we performed hydrodynamic tail vein injections with diphtheria toxin A (DTA)-encoding plasmid in human ApoB100-transgenic mice. Utilizing immunodominant ApoB100-derived peptides, we found increased ApoB100-specific T-cell populations in NAFLD and CVD patients compared to healthy controls. In a peptide-specific manner, ApoB100 reactivity in healthy controls was accompanied by expression of the regulatory T (Treg)-cell transcription factor FOXP3. In contrast, FOXP3 expression decreased, whereas expression of pro-inflammatory cytokine interleukin (IL)-17A increased in ApoB100-specific T cells from NAFLD and CVD patients. Dyslipidemia and liver damage parameters in blood correlated with reduced FOXP3 expression and elevated IL-17A production in ApoB100-specific T-cell populations, respectively. Moreover, DTA-mediated transient liver damage in human ApoB100-transgenic mice accumulated IL-17a-expressing ApoB100-specific T cells in the periphery. Our results show that liver damage promotes pro-inflammatory ApoB100-specific T-cell populations, thereby providing a cellular mechanism for the increased CVD risk in liver disease patients. © 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.


Bastian F J Plochg, Hanna Englert, Chandini Rangaswamy, Sandra Konrath, Mandy Malle, Sibylle Lampalzer, Claudia Beisel, Salma Wollin, Maike Frye, Jens Aberle, Johannes Kluwe, Thomas Renné, Reiner K Mailer. Liver damage promotes pro-inflammatory T-cell responses against apolipoprotein B-100. Journal of internal medicine. 2022 May;291(5):648-664

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PMID: 34914849

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