Hepatitis C Virus (HCV) infection and recurrence post-transplant (OLT) is associated with extracellular matrix (ECM) components remodeling particularly collagen (Col) leading to fibrosis. measured using Multiplex Bead immunoassays. Levels of Abs to Col 1 were SLIT1 higher in fibrosis groups compared with no fibrosis groups and control both Non OLT (p<0.0001) and Post OLT (P=0.01). There were increased levels of Abs to Col 2 4 5 and vimentin in fibrotic groups Non OLT (Col 2: p=0.0001 Col 4: p =0.09 Col 5: p<0.0001 vimentin: p=0.36) and Post OLT (Col 2: p=0.006 Col 4: p = 0.1 Col 5: p<0.0001 vimentin: p=0.24) compared with non fibrotic groups. Fibrotic groups non-OLT and post OLT demonstrated significantly higher Th2 Th17 cytokines and lower Th1 cytokines compared to non fibrotic groups. Our results demonstrate that in HCV infection Abs to ECM Collagen 1 2 5 positively correlate with liver fibrosis which is associated with a predominant Th2 and Th17 cytokine profile. Keywords: Autoantibodies IL-17 Fibrosis HCV Recurrence Chronic hepatitis C (HCV) is the leading indication for orthotopic liver transplantation (OLT) in the United States accounting for up to 40-45% of all transplants (1). HCV recurrence in the allograft is universal (2). The natural history of HCV in the native liver is characterized by a slow progression to cirrhosis end-stage liver disease and in some cases hepatocellular carcinoma (3). Many factors including but not limited to: age ethnicity concurrent alcohol use duration of infection inflammatory activity index (HAI) and steatosis (4 5 account for the variability of progression. HCV following OLT has an accelerated course with the development of cirrhosis in 20-30% of patients within 5 years (6 7 In this setting factors impacting progression of fibrosis include liver donor quality recipient factors (older age non-Caucasian race higher Child-Pugh score prior to transplantation) and systemic immunosuppression (8-10). Liver KB130015 fibrosis due to different etiologies has been associated with an increased deposition of collagens (Col) and other connective tissue components (11 12 In particular HCV infection in the native liver and its recurrence post-transplant has been shown to significantly impact deposition and remodeling of extracellular matrix (ECM) components particularly Col leading to enhanced fibrosis (13). Further chronic rejection in the allograft is initiated by a host-anti-graft-immune response with both antigen-dependent and non-immune (antigen-independent) factors leading to fibroproliferative changes affecting graft function. Inflammation and tissue remodeling promoted by alloimmune mechanisms facilitate the induction of autoimmune responses against self-antigens. KB130015 Studies in the arena of heart lung and kidney transplantation have identified putative mechanisms that contribute to the development of chronic rejection (14 15 In these instances an emerging paradigm is that inflammation and associated tissue remodeling attendant to KB130015 the post-transplant state exposes cryptic self-antigens or their determinants that along with a favorable cytokine milieu allows for loss of peripheral tolerance and activation of cell-mediated immunity towards development of de novo immune responses to self antigens (16). Previous studies have shown a higher prevalence of auto-Abs to nuclear smooth muscle and anti-mitochondrial antigens in patients with chronic HCV infection (17 18 In addition the presence of circulating Abs to ECM collagen has been well established in liver disease (19). However the clinical implications of their occurrence in particular their relation to HCV induced fibrosis of the native and allograft liver and their functional significance in the induction of fibrosis needs better characterization. In this investigation we postulated that chronic HCV infection resulting in liver parenchymal damage and progressive ECM remodeling may lead to the induction of an immune response to ECM proteins. This was assessed by determining Abs to ECM collagen (subtypes 1 2 4 and 5) and vimentin at various stages of HCV infection KB130015 in the native liver and in the allograft post OLT. The study group was also examined for the presence of classic autoimmune markers such as anti-nuclear anti-smooth muscle anti-mitochondrial Abs rheumatoid factor and cryoglobulins. In addition we measured serum levels of pro-inflammatory cytokines (IL-17 IL-6.