Liver damage promotes pro-inflammatory T-cell responses against apolipoprotein B-100
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Published on: November 27, 2019
Bastian F J Plochg1, Hanna Englert1, Chandini Rangaswamy1
1Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Insights
Liver damage increases pro-inflammatory T-cells targeting apolipoprotein B-100 (ApoB100), explaining higher cardiovascular disease (CVD) risk in liver patients. This study reveals a cellular mechanism linking liver disease to CVD.
Area of Science:
- Immunology
- Cardiovascular Disease Research
- Hepatology
Background:
- Apolipoprotein B-100 (ApoB100) is recognized by T-cells in cardiovascular disease (CVD).
- CVD poses a significant mortality risk for patients with chronic inflammatory liver diseases.
- The effect of liver damage on ApoB100-specific T-cell responses remains unclear.
Purpose of the Study:
- To investigate the impact of liver damage on ApoB100-specific T-cell responses.
- To analyze the differentiation patterns of ApoB100-specific T-cells in relation to lipid profiles and liver damage.
- To assess the induction of extrahepatic ApoB100-specific T-cells following transient liver damage.
Main Methods:
- Identified ApoB100-specific T-cells in healthy controls, nonalcoholic fatty liver disease (NAFLD), and CVD patients using activation-induced marker expression.
- Analyzed T-cell differentiation patterns correlating with lipid profiles and liver damage parameters in a cross-sectional study.
- Induced transient liver damage in human ApoB100-transgenic mice via hydrodynamic tail vein injection with diphtheria toxin A (DTA)-encoding plasmid.
Main Results:
- ApoB100-specific T-cell populations were elevated in NAFLD and CVD patients compared to controls.
- Healthy controls showed regulatory T (Treg)-cell marker FOXP3 expression in ApoB100-reactive T-cells; NAFLD/CVD patients exhibited decreased FOXP3 and increased pro-inflammatory IL-17A.
- Liver damage correlated with reduced FOXP3 and elevated IL-17A in ApoB100-specific T-cells, and transient liver damage in mice increased peripheral IL-17A-expressing ApoB100-specific T-cells.
Conclusions:
- Liver damage promotes pro-inflammatory ApoB100-specific T-cell populations.
- This provides a cellular mechanism linking liver disease to increased CVD risk.
- Findings highlight the immunological connection between liver health and cardiovascular outcomes.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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