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

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.

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.

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.

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.