ABSTRACT
Like other hepatotropic viruses, hepatitis C virus (HCV) shares the property of inducing
hepatocellular damage, possibly through induction of immune mechanisms that lead to
hepatocellular necrosis. After infection of hepatocytes, and possibly other cells,
humoral and cellular responses occur aimed at prevention of virus dissemination and
elimination of infected cells. The early activated mechanisms include production of
nonspecific and specific antibodies that represent the first-line of defense against
invading foreign pathogens. As a consequence, circulating immune complexes are promptly
formed, and antigen uptake and processing by specialized cells are enhanced. A major
fraction of circulating immunoglobulins (Igs) are part of the spectrum of the so-called
natural antibodies, which include anti-idiotypic antibodies and molecules with rheumatoid
factor (RF) activity. They mainly belong to the IgM class, are polyclonal, and have
no intrinsic pathogenetic potential. In 20-30% of HCV-infected patients, RFs share
characteristics of high affinity molecules, are monoclonal in nature, and result in
the production of cold-precipitating immune complexes and mixed cryoglobulinemia.
It has been shown that anti-idiotypic antibodies and polyclonal and monoclonal RF
molecules have the same cross-reactive idiotype, called WA, suggesting that their
production is highly restricted. This strongly indicates that they arise from stimulation
with the same antigen, likely HCV. It has also been speculated that B-1 (CD5+ ) and B-2 (CD5- ) B-cell subsets, which use a limited number of VH germline genes, underlie the production of low-affinity polyclonal and high-affinity
monoclonal antibodies, respectively. The persistent production of monoclonal RF molecules
implies the existence of a further mechanism capable of restricting the reactivity
and reflects a distinct selection of a cell population that can be maintained throughout
life because they are continuously exposed to antigen pressure. Either polyclonal
or monoclonal profiles of B-cell expansion are demonstrable in the liver of most HCV-infected
patients. The occurrence of B-cell clonal expansion is strictly related to intrahepatic
production of RF molecules, and this suggests that liver is a microenvironment, other
than lymphoid tissue, in which a germinal centerlike reaction is induced. The frequent
detection of oligoclonal B-cell expansion may, indeed, represent a key pathobiologic
feature that sustains nonmalignant B-cell lymphoproliferation. The preferential expansion
of one clone would in turn lead to a monoclonal pattern that could favor stochastic
oncogenic events. It can be postulated that HCV is the stimulus not only for the apparent
benign lymphoproliferative process underlying a wide spectrum of clinical features,
but also for the progression to frank lymphoid malignancy in a subgroup of patients.
Current data indicate a higher prevalence of overt B-cell non-Hodgkin's lymphoma in
HCV-infected patients, especially in some geographic areas.
KEYWORD
autoimmunity - hepatitis C virus - lymphoproliferation
