Chemokines in the immunopathogenesis of hepatitis C infection

Abstract

Hepatitis C Virus (HCV) ImmunopathologyHCV is a hepatotropic virus consisting of a polyprotein processed into structural proteins (core and envelope proteins 1 and 2), nonstructural proteins (NS2 to NS5), and a protein of unknown function (p7). 1,2 The viral polymerase lacks proof-reading capability, and this results in the generation of sequence diversity and quasispecies that contribute to evasion of the host immune response and chronic infection. [2][3][4] Although hepatocytes are the primary target of HCV, the virus can interact with monocyte, lymphocyte, and endothelial cells. 5,6 The recent description of in vitro models of HCV replication is elucidating HCV biology, 7 but the lack of small-animal models hinders studies of disease course and outcome. 3 The liver is a unique immunological environment with a dual blood supply and distinct rheological requirements for leukocyte recruitment. Although hepatic immune tolerance prevents exuberant responses to food antigen, 8 the liver can generate strong immune responses to infections, including hepatitis A and E viruses. 9 In general, a vigorous intrahepatic immune response requires activation of T cells by activated dendritic cells (DCs) within secondary lymphoid tissues, whereas activation within the liver by hepatocytes or endothelial cells results in tolerance. 10 This allows the liver to tolerate food antigens captured by endothelial cells and self-antigens on hepatocytes while responding appropriately to infections that cause inflammation and activation of DCs. The ability of HCV to infect hepatocytes without causing marked inflammatory damage may prevent the activation of a full immune response. 2,11 Whether HCV infection is acute and self-limiting or persistent is determined early. 3,4 The first line of defense is provided by infected hepatocytes that secrete interferon (IFN) and down-regulate RNA translation in response to infection before innate immune cells, including macrophages, DCs, natural killer (NK) cells, and natural killer T (NKT) cells, are activated to amplify secretion of type I IFNs and IFN-response genes. Activation of pattern recognition receptors, particularly Toll-like receptors, trig-

In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C

“…Indeed, the lack of gene induction may be related to the fact that only hepatocytes in small clusters were 'ER-stressed' and surrounded by numerous cells that did not experience ER stress (see above). Instead, processes such as proliferation, inflammation, and apoptosis are known to be diffuse in livers with CHC [11,26,[38][39][40]. Inflammation is a diffuse feature in CHC driven by the persistent expression of chemokines [26,38,40].…”

Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis

“…S2A), and IP10 (CXCL10) (Fig. 2B), three chemokines associated with inflammatory reactions (23)(24)(25)(26), became significantly higher (P < 0.05) in rapid progressors in the period between the ALT peak and 6 mo post the onset of infection, reflecting a prolonged inflammatory state following the onset of liver injury.…”

The Lifelong Effects of Early Childhood Adversity and Toxic Stress

“…[61][62][63][64][65][66][67] Beyond its strong association with later risk-taking and generally unhealthy lifestyles, it is critically important to underscore the extent to which toxic stress in early childhood has also been shown to cause physiologic disruptions that persist into adulthood and lead to frank disease, even in the absence of later healththreatening behaviors. For example, the biological manifestations of toxic stress can include alterations in immune function 68 and measurable increases in inflammatory markers, [69][70][71][72] which are known to be associated with poor health outcomes as diverse as cardiovascular disease, 69,70,73 viral hepatitis, 74 liver cancer, 75 asthma, 76 chronic obstructive pulmonary disease, 77 autoimmune diseases, 78 poor dental health, 72 and depression. [79][80][81] Thus, toxic stress in early childhood not only is a risk factor for later risky behavior but also can be a direct source of biological injury or disruption that may have lifelong consequences independent of whatever circumstances might follow later in life.…”