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Basic science (liver)
PMO-136 Defective inhibitory molecules expression may contribute to breakdown of tolerance characteristic of autoimmune liver disease
  1. R Liberal1,2,
  2. C Grant2,
  3. C Grant2,
  4. G Mieli-Vergani2,
  5. D Vergani2,
  6. M Longhi2
  1. 1Faculdade de Medicina da Universidade do Porto, Porto, Portugal
  2. 2King's College London, London, UK

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-3pos and PD-1pos cells within CD4 and CD8 T cells was lower in AIH (CD4posTim-3pos: 1.6±0.3; CD4posPD-1pos: 4.8±0.5; CD8posTim-3pos: 9.6±1.6; CD8posPD-1pos: 6.7±0.7) than in HS (CD4posTim-3pos: 6.2±0.8, PposPD-1pos: 8.1±1.9, P=0.04; CD8posTim-3pos: 15.8±1.8, P=0.04; CD8posPD-1pos: 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 (CD4posTim-3posPD-1pos: 0.7±0.1; CD8posTim-3posPD-1pos: 1.7±0.4), they are reduced in AIH (CD4posTim-3posPD-1pos: 0.4±0.1, p=0.007; CD8posTim-3posPD-1pos: 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.

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