Background/Purpose: Autoreactive T cells drive the inflammatory process, which leads to an irreversible destruction of the joints. Gene transcription and regulation of proinflammatory cytokine production in T cells is regulated by epigenetic mechanisms. Among them histone deacetylases (HDACs) modify the epigenetic landscape by removing acetyl groups of lysine residues of histones, resulting in chromatin condensation and repression of transcription. The application of pan-HDAC inhibitors has been shown to be a potential therapeutic strategy. However, major side effects limited the clinical use and underline the need of more specific HDAC inhibitors. Therefore we addressed the effects of selective HDACs on the development of autoimmune diseases.

Methods: Mice with a T cell specific deletion of HDAC1 (HDAC1cKO) were generated by using the CD4Cre/LoxP system. The clinical and the histological phenotype were assessed in the collagen-induced arthritis (CIA) and the experimental autoimmune encephalitis (EAE) model. Anti-collagen antibody levels were determined by ELISA. Qualitative and quantitative analysis of T cell subsets of the spleen and draining LN were assessed using flow cytometry. Additionally comparative RNA-sequencing of CD4⁺ T cells from wild type (WT) and HDAC1cKO mice was performed.

Results: To address whether HDAC1 is involved in the pathogenesis of autoimmune diseases we induced the CIA and the EAE in WT and HDAC1cKO mice. Surprisingly, despite the presence of serum anti-CII antibodies, HDAC1cKO mice did not develop any clinical or histological signs of inflammation in the CIA model. These data were confirmed in an additional T cell dependent model, the EAE model. HDAC1cKO mice were completely protected against the development of EAE. The total number of cells isolated from the CNS, consisting predominately of CD4⁺ T cells, was significantly reduced in the absence of HDAC1. Molecular analysis of HDAC1cKO CD4⁺ T cells revealed diminished expression of CCR6, which is an essential chemokine receptor for the development of arthritis and EAE. This was accompanied with an increased production of IFNγ and with an enhancement of STAT1 phosphorylation in activated HDAC1cKO CD4⁺ T cells in comparison to WT cells. In line with this finding we observed increased expression of CCR6 in STAT1^-/- CD4⁺ T cells. This indicates a negative role of STAT1 in the regulation of CCR6 expression in HDAC1cKO CD4⁺ T cells, suggesting an impairment to migrate to the site of inflammation to initiate arthritis and EAE.

Conclusion: Our data show the importance of HDAC1 as a key immune regulator in the pathogenesis of the CIA and EAE model. Therefore it might be considered as an interesting novel therapeutic target in autoimmune diseases, in particular patients with RA.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/histone-deacetylase-1-hdac1-a-novel-therapeutic-target-for-patients-with-rheumatoid-arthritis/