β-Arrestin 1 modulates functions of autoimmune T cells from primary biliary cirrhosis patients

Abstract

Objectives: Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by antimitochondrial antibodies and autoreactive T cells causing destruction of the primary bile ducts. The molecular mechanisms regulating the autoreactive T cells remain elusive. β-Arrestins (βarr) are multifunctional signaling molecules that are crucial to T cell survival. We hypothesized that βarr plays a critical regulatory function in the autoreactive T cells of PBC patients.

Methods: Patients with hepatic biliary cirrhosis (n=60) were evaluated. Cytokine expression, T cell proliferation, and transcription factors were evaluated to assess regulatory functions in autoreactive T cells from the patient.

Results: Our studies showed that expression of βarr1 was elevated significantly in T lymphocytes from patients with PBC. Moreover, the level of βarr1 mRNA positively correlated with Mayo risk score in PBC patients. Based on modulation of βarr in autoreactive T cell lines, overexpression of βarr1 increased T cell proliferation, augmented interferon production, downregulated activities of nuclear factor κB and AP-1, promoted acetylation of histone H4 in the promoter regions of CD40L, LIGHT, IL-17 and interferon-γ, while downregulating acetylation of histone H4 in the promoter regions of TRAIL, Apo2, and HDAC7A, thereby regulating expression of these genes.

Conclusions: Our findings suggest that βarr1 contributes to the pathogenesis of PBC, having significant implications for novel therapy strategy, further providing information for investigating the mechanisms of autoimmune disease.