HEPATOLOGY Concise Review
A striking feature of EMC discovered 20 years before the Hepatitis C Virus Infection and discovery of HCV was that monoclonal RF from different patients with the disease were identical as determined by Type II Cryoglobulinemia: An typing with an antibody that reacted with an epitope in the antigen-combining site of the RF called a ''cross-idiotype.'' 6
Immunological Perspective
It was subsequently shown that these monoclonal RF were encoded by the same germline genes. 7 Hence, the monoclonal RF in these patients were highly restricted, rather than arising VINCENT AGNELLO randomly from the entire antibody repertoire. Among patients with HCV infection and type II cryoglobulinemia, 87% From an immunological perspective, the first clinical manhad monoclonal RF of the same cross-idiotype, 8 dubbed ifestation of hepatitis C virus (HCV) infection that attracted ''WA'' after the patient whose monoclonal RF was used to attention was palpable purpura. Thirty years ago, Meltzer raise the original typing antiserum. 6 These findings suggested et al. described essential mixed cryoglobulinemia (EMC). 1 that the WA monoclonal RF in different individuals arose Palpable purpura was the prominent manifestation of this from stimulation with the same antigen and not a malignant systemic vasculitic disorder associated with mixed cryoprocess, as was previously proposed. 9 Moreover, the later globulins that consisted of polyclonal immunoglobulin (Ig) demonstration of the specific concentration of HCV in the G and either polyclonal or monoclonal (IgM) rheumatoid cryoglobulins with WA monoclonal RF 3 suggested that the factors (RF). The mixed cryoglobulins were later categorized etiologic antigen for production of these RF was related to as type II if the RF was monoclonal and type III if polyclonal the HCV.
RF was present. It has been recently shown that approxi-
There are three major immunological features associated mately 80% of patients with EMC are infected with HCV, 2 with this enigmatic virus. The first and most important is that and that the virus is specifically concentrated in the cryothe virus, in almost all instances, circumvents the immune globulins. 3 Earlier studies had implicated hepatitis B virus in response, with chronic infection as the result. The second EMC, 4 but it is now established that hepatitis B virus is feature, the occurrence of restricted monoclonal RF, may be unique to HCV infection, because monoclonal RF associated present in relatively few patients with the disease. 2,5 FIG. 1. In this hypothesis, complexes of HCV-VLDL secreted by infected hepatocytes or formed postsecretion stimulate WA monoclonal RF-producing B cells to produce WA monoclonal RF, which then prevents the spread of infection to other hepatocytes by blocking endocytosis of the HCV-VLDL via the low density lipoprotein receptor (LDLR). (Reprinted from Sansonno 14 with permission.