The immunology of hepatitis A is important for two reasons. First, specific diagnostic tests for the confirmation of HAV as the etiologic agent are dependent on the production of antibody by the humoral immune response (see below). The humoral immune response also leads to the development of circulating immune complexes 160, 248 with associated symptoms and signs in some patients 122, 123. Second, clearance of viral infection and the disease manifestations associated with this process is almost certainly produced by the cellular immune response.
Humoral Immune Response
Immunoglobulin M (IgM), IgG, and IgA antibodies directed against conformational epitopes on the HAV particle are induced and can usually be detected by the onset of clinical illness 228. In addition, total IgM levels are often elevated in acute hepatitis A infection (28 of 33 cases [85%]) but not in acute hepatitis B infection (3 of 24 cases [13%]) 175. The hepatitis A-specific IgM response is limited to the initial infection except in rare instances and thus becomes a useful marker of acute disease. IgA is also produced for a limited period of time. Its role in immunity is uncertain. Theoretically, if antibodies such as secretory IgA were transported into the intestinal tract, then enterohepatic circulation of viral particles could be interrupted by neutralizing the virus. In experimental and naturally acquired hepatitis A, however, neutralizing antibodies are uncommonly found in fecal extracts 229. In contrast, another picornavirus, the poliovirus, elicits effective intestinal and salivary neutralizing antibody 229. The IgG response to HAV is delayed compared with IgM and IgA responses but is long-lived and accounts for resistance to reinfection. In an isolated Amerindian tribe, anti-HAV antibody was present in everyone over the age of 50 years but in no one younger 31. This observation suggests that the tribe members had not been exposed to HAV for 50 years and that anti-HAV IgG persisted for that length of time without need for additional exposure. Loss of detectable antibody following immunosuppression for organ transplantation may occur 19. Whether this represents risk for repeat infection has not been documented.
The antibodies are usually directed against surface proteins. The capsid proteins VP1 and VP3 and the precursor protein VP0 may be recognized 256. Almost all patients expressed both IgG and IgM antibodies to VP1. The IgG response to VP3 was detectable for years after disease resolution 256. Antibodies to nonstructural proteins are also induced. Although they are less abundant and lack neutralizing activity, they are produced in most individuals early in the infection 210. Detection of antibodies recognizing P2 permits differentiation between infection (antibody present) and vaccination (no antibody) as sources of antigenic determinants 210.
Cellular Immune Response
The pathologic changes described above were initially considered to be secondary to viral infection alone. However, large quantities of infectious virus are produced in the liver and excreted in stool before the onset of any recognizable hepatic disease 51, 139, 245. Furthermore, HAV is not directly cytopathic in cell culture but rather is associated with persistent infection without cell injury 115, 201. Taken together, these observations led to the recognition of immune-mediated injury as the most plausible explanation for hepatic inflammation. Consistent with this hypothesis is the observation that cytotoxic lymphocytes isolated from patients with acute hepatitis A infection lyse autologous, HAV-infected target cells 83, 249. Other cytotoxic cells, such as natural killer cells, may also be involved 83, 142. Their role may be limited, since they lack antigen specificity. Overall, therefore, hepatitis A and hepatitis B are similar not only in their clinical manifestations but also in the mechanism underlying their production, that of cytotoxic T-cell recognition and destruction of virus-infected cells.