Artikel
Inhibition of histone deacetylase class I change CD4+ T cell lineage genes and might supported the differentiation to CD4+CD8+ T cells in rheumatoid arthritis
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Autoren
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Laurin Braune
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Hannah R. Spatzier
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Anne-Marie Glimm
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Kathleen Friedrich
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Lina E. Werner
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Phoung Nguyen
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Ulf Wagner
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
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Kathrin Rothe
- University of Leipzig Medical Center, Rheumatology Unit, Department of Endocrinology, Nephrology, Rheumatology, Leipzig
| Veröffentlicht: | 18. September 2024 |
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Gliederung
Text
Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disorder specified by chronic inflammation mainly affecting the synovial membrane of the joints [1], [2]. Pivotal contributors to the pro-inflammatory milieu in RA are autoantigen-specific CD4+ T cells [3]. We have previously shown that CD4+ T cells which upregulate CD8a on their surface, contribute to increased disease activity and joint erosions [4]. Epigenetic changes can induce the expression of CD8 lineage genes in CD4+ T cells [5]. We suggest that in particular the modulation of histone deacetylase (HDAC) class I leads to the phenotype of RA CD4+ T cells.
Methods: Peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors (HD) were isolated by density gradient centrifugation. Surface and intracellular T cell markers were analyzed by flow cytometry. Using an in-vitro assay, naïve CD4+ T cells from peripheral blood of HD (n=5) were cultured for 3d under Th0 polarizing conditions and HDAC class I were inhibited for 24 h. Afterwards, functional and phenotypic changes of CD4+ T cells were investigated by flow cytometry. The expression of the HDAC class I was analyzed with RT-qPCR and western blot.
Results: The first results showed an increased frequency of CD4+CD8aalow T cells in peripheral blood of RA patients (n=24; 2.55%) in comparison to CD8ab+CD4low T cells (0.77%). These CD4+CD8aalow T cells exhibit an effector-memory phenotype with a significantly increased granzyme A/B, and perforin expression. Furthermore, the expression of RunX3 and ThPOK in CD4+CD8aalow T cells were divergent in HD.
The inhibition of HDAC class I increases the expression of CD8a (+1.67%) on the surface of CD4+ T cells. In contrast, ThPOK (MFI=-70), CD27 (MFI=-3444.7), and CD40L (-17.74%) were downregulated. To clarify the pivotal role of the class I HDAC enzymes, we analyzed the mRNA and protein expression and identified a correlation between HDAC2 and SDAI.
Conclusion: In summary, HDAC inhibition in HD resulted in an increased expression of cytotoxic markers on CD4+ T cells and concomitant inhibition of CD4 lineage markers, which is comparable to RA CD4+CD8aalow T cells. This suggest that a dysregulation of class I HDAC expression/activity in RA might be responsible for pro-inflammatory peripheral CD4+ T cells.
References
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