DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

Abstract

Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/or outcome-specific biomarkers, and as arthritis can precede skin manifestations, diagnostic and therapeutic delays are common and contribute to disease burden and damage accrual.Objective: Altered epigenetic marks, including DNA methylation, contribute to effector T cell phenotypes and altered cytokine expression in autoimmune/inflammatory diseases. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to healthy controls.Method: Peripheral blood CD8+ T cells from nine healthy controls, 10 psoriasis, and seven PsA patients were collected to analyze DNA methylation marks using Illumina Human Methylation EPIC BeadChips (>850,000 CpGs per sample). Bioinformatic analysis was performed using R (minfi, limma, ChAMP, and DMRcate packages).Results: DNA methylation profiles in CD8+ T cells differentiate healthy controls from psoriasis patients [397 Differentially Methylated Positions (DMPs); 9 Differentially Methylated Regions (DMRs) when ≥CpGs per DMR were considered; 2 DMRs for ≥10 CpGs]. Furthermore, patients with skin psoriasis can be discriminated from PsA patients [1,861 DMPs, 20 DMRs (≥5 CpGs per region), 4 DMRs (≥10 CpGs per region)]. Gene ontology (GO) analyses considering genes with ≥1 DMP in their promoter delivered methylation defects in skin psoriasis and PsA primarily affecting the BMP signaling pathway and endopeptidase regulator activity, respectively. GO analysis of genes associated with DMRs between skin psoriasis and PsA demonstrated an enrichment of GABAergic neuron and cortex neuron development pathways. Treatment with cytokine blockers associated with DNA methylation changes [2,372 DMPs; 1,907 DMPs within promoters, 7 DMRs (≥5 CpG per regions)] affecting transforming growth factor beta receptor and transmembrane receptor protein serine/threonine kinase signaling pathways. Lastly, a methylation score including TNF and IL-17 pathway associated DMPs inverse correlates with skin disease activity scores (PASI).Conclusion: Patients with skin psoriasis exhibit DNA methylation patterns in CD8+ T cells that allow differentiation from PsA patients and healthy individuals, and reflect clinical activity of skin disease. Thus, DNA methylation profiling promises potential as diagnostic and prognostic tool to be used for molecular patient stratification toward individualized treatment.

Prediction of Psoriatic Arthritis in Patients With Psoriasis Using DNA Methylation Profiles

“…As a limitation of this study, because of the nature of the cohort, we are unable to separate specific cell populations and measure the extent to which the methylation changes identified might be affected by different cellular compositions between patients. However, a recent study (25) found no significant differences in the proportions of CD8+ T cell subpopulations (naïve, effector memory, central memory, and effector memory cells re‐expressing CD45RA) between cutaneous psoriasis and PsA, suggesting that the effect of these cell subpopulations is not as marked in PsA as in other diseases.…”

cAMP responsive element modulator α promotes effector T cells in systemic autoimmune diseases

“…It is characterized by increased keratinocyte proliferation and immune cell infiltration of the skin, including T lymphocytes. Effector CD4 + and CD8 + T cells centrally contribute to skin inflammation and tissue damage in psoriasis [12,13]. As in SLE, the molecular pathophysiology of psoriasis is incompletely understood.…”

“…Increased methylation of the PDCD1 gene results in reduced expression of the regulatory co‐receptor PD‐1 on CD4 + T cells [18]. Reduced methylation of the IFNG promoter in DN T cells allows for IFN‐γ expression [48], and distinct DNA methylation patterns in CD8 + T cells allow distinguishing between patients with skin psoriasis, psoriatic arthritis and healthy individuals [13].…”

How does age determine the development of human immune-mediated arthritis?

“…However, leakage of immune deregulation from the skin to the joint is suspected 73 , potentially involving lymphocyte subsets such as CD8 + T effector memory CD45RA cells 74 and CD8 + CCR10 + T cells 75 . DNA methylation patterns of CD8 + T cells can differentiate patients with psoriasis from those with PsA, suggesting the potential for early patient stratification for therapy 76 . Another comorbidity in adult chronic arthritis is an increased cardiovascular risk.…”