Immune response to extracellular matrix collagen in chronic hepatitis C-induced liver fibrosis

Abstract

Hepatitis C virus (HCV) infection and its recurrence after orthotopic liver transplantation (OLT) are associated with the remodeling of extracellular matrix (ECM) components [particularly collagen (Col)], which leads to fibrosis. Our aim was to determine whether the development of antibodies (Abs) to self-antigen Col in HCV-infected patients correlates with the fibrosis stage and the peripheral cytokine response. Patients with chronic HCV infection, patients with HCV recurrence after OLT who had undergone a biopsy procedure, and healthy control subjects were enrolled. The HCV subjects (n = 70) were stratified as follows: (1) a non-OLT group without fibrosis (Scheuer stages 0-2), (2) a non-OLT group with fibrosis (Scheuer stages 3-4), (3) a post-OLT group without fibrosis (Scheuer stages 0-2), and (4) a post-OLT group with fibrosis (Scheuer stages 3-4). Serum samples were analyzed for Abs against Col1, Col2, Col4, Col5, and vimentin with enzyme-linked immunosorbent assays. Serum levels of cytokines were measured with multiplex bead immunoassays. The levels of Abs to Col1 were higher in the fibrosis groups versus the no-fibrosis groups and the controls for both non-OLT patients (P < 0.001) and post-OLT patients (P = 0.01). There were increased levels of Abs to Col2, Col4, Col5, and vimentin in the non-OLT fibrosis group (Col2, P = 0.0001; Col4, P = 0.122; Col5, P < 0.0001; vimentin, P = 0.36) and in the post-OLT fibrosis group (Col2, P = 0.006; Col4, P = 0.19; Col5, P < 0.0001; vimentin, P = 0.24) in comparison with the no-fibrosis groups. The non-OLT and post-OLT fibrosis groups demonstrated significantly higher T helper 2 (T(h) 2) and T helper 17 (T(h) 17) cytokine levels and lower T helper 1 cytokine levels in comparison with the no-fibrosis groups. Our results demonstrate that in HCV-infected patients, the levels of Abs to ECM Col1, Col2, and Col5 positively correlate with liver fibrosis, which is associated with a predominantly T(h) 2 and T(h) 17 cytokine profile.

Figure 1. Increased Ab levels to ECM Col-1, 2 and 5 in Non OLT Patients with Advanced Fibrosis

25 HCV+ non OLT subjects with no fibrosis (Scheuer 0–2), 25 HCV+ non OLT with fibrosis (Scheuer 3–4), and 25 healthy controls were compared. Col 1 Ab levels in the Fibrosis group (27(4.1)) were significantly higher than in the no fibrosis group (18.8(1.6)) and healthy controls (12.2(0.5)) (p<0.0001). A similar trend was seen for Col 2: fibrosis group (8(1.8)), no fibrosis group (2.4(0.3)) and controls (1.6(0.2)) (p=0.0001) and Col 5: fibrosis group (474.9(48.4)), no fibrosis (302.8(37.4)) and controls (124.5(20)) (p<0.0001). There was no difference in the antibodies to Col 4 and vimentin among the three groups (Values expressed as mean (SEM) in ng/mL)

Figure 2. Increased Ab levels to ECM Col-1, 2 and 5 in Post OLT Patients with Advanced Fibrosis

10 HCV+ Post OLT subjects with no fibrosis (Scheuer 0–2), 10 HCV+ Post OLT with fibrosis (Scheuer 3–4), and compared with 25 healthy controls Col 1 Ab levels in the Fibrosis group (17.3(1.8)) were significantly higher than in the no fibrosis group (13.8(1.8)) and healthy controls (10.2(5)) (p=0.01). A similar trend was seen Col 2 Ab: fibrosis group (4.6(1.5)), no fibrosis group (1.3(0.5)) and controls (1.6(.2)) (p=0.006). Col 5 Ab: fibrosis group (573.5(56.3)) no fibrosis (169.9(44.5)) and controls (124.5(20)) (p<0.0001). There were no difference in the antibodies to Col4 and vimentin among the three groups. (Values expressed as mean(SEM) in ng/mL)