PMO-136 Defective inhibitory molecules expression may contribute to breakdown of tolerance characteristic of autoimmune liver disease. (28th May 2012)

• Record Type: Journal Article
• Authors: Liberal, R; Grant, C; Grant, C; Mieli-Vergani, G; Vergani, D; Longhi, M
• Is Part Of: Gut. Volume 61(2012)Supplement 2
• Page Start: A128
• Page End: A128
• Publication Date: 2012-05-28
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2012-302514b.136
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Introduction: Autoimmune hepatitis (AIH) is a severe hepatopathy often progressing to end-stage liver disease. Evidence implicates the involvement of both CD4 and CD8 T cell responses in its pathogenesis. There are a number of different inhibitory molecules expressed by T cells that can attenuate T cell receptor signalling. These include cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and the recently described T cell immunoglobulin and mucin domain-3 (Tim-3). Whether a disturbed expression of these inhibitory molecules can result in an increased susceptibility to autoimmune liver disease is unknown. Aims: to evaluate the expression of CTLA-4, PD-1, and Tim-3 by CD4 and CD8 T cells in patients with autoimmune hepatitis. Methods: 12 ANA/SMA+ AIH patients (6 females, median age: 14 years) and 6 healthy subjects (HS, four females, median age: 26.4 years) were studied. Phenotype of CD4 and CD8 T cells was determined by flow cytometry using monoclonal antibodies against CD4, CD8, PD-1 and Tim-3. Expression of CTLA-4 was determined by intracellular staining. Results: The frequency of Tim-3 pos and PD-1 pos cells within CD4 and CD8 T cells was lower in AIH (CD4 pos Tim-3 pos : 1.6±0.3; CD4 pos PD-1 pos : 4.8±0.5; CD8 pos Tim-3 pos : 9.6±1.6; CD8 pos PD-1 pos : 6.7±0.7) than in HS (CD4 pos Tim-3 pos : 6.2±0.8, PposPD-1 pos : 8.1±1.9, P=0.04; CD8 pos Tim-3 pos : 15.8±1.8, P=0.04; CD8 pos PD-1 pos : 12.6±1.4 6.7±0.7, Ppos cells between the two groups of subjects. While in health dually Tim-3 and PD-1 positive populations are recognisable (CD4 pos Tim-3 pos PD-1 pos : 0.7±0.1; CD8 pos Tim-3 pos PD-1 pos : 1.7±0.4), they are reduced in AIH (CD4 pos Tim-3 pos PD-1 pos : 0.4±0.1, p=0.007; CD8 pos Tim-3 pos PD-1 pos : 0.9±0.3, p=0.03). Conclusion: AIH patients have fewer PD-1 and Tim3 positive cells within both CD4 and CD8 T cells. Defective expression of these negative immune-regulatory molecules may contribute to breakdown of tolerance, possibly accounting for the initiation and/or perpetuation of the autoimmune liver attack. Competing interests: None declared.