RESUMEN
Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of "piecemeal necrosis". In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation.
RESUMEN
Over 240 million people worldwide are chronically infected with Hepatitis B Virus (HBV), a hepatotropic DNA virus with an evolutionary root of over 400 million years. Persistent HBV infection exhibits distinct and diverse phases of disease, from minimal liver pathology to fulminant Hepatitis, that vary in duration and severity among individuals. Although huge progress has been made in HBV research which has yielded an effective prophylactic vaccine and potent antiviral therapy, our understanding of its virology and immunobiology is still far from complete. For example, the recent re-discovery of serum HBV RNA in chronic Hepatitis B (CHB) patients has led to the proposal of noncanonical viral particles such as RNA virion and capsid-derived immune complex (Capsid-Antibody-Complexes, CACs) that contradict long-established basic theory. Furthermore, the existence of capsid-derived immune complex may hint at novel mechanism of HBV-induced liver disease. Here, we summarize the past and recent literature on HBV-induced immune complex. We propose that the release of capsid-derived particles by HBV has its deep evolutionary origin, and the associated complement activation serves as an indispensable trigger for intrahepatic damage and a catalyst for further cell-mediated immunopathology.