CRYOGLOBULINEMIA IN CHRONIC HEPATITIS-C VIRUS-INFECTION - PREVALENCE,CLINICAL MANIFESTATIONS, RESPONSE TO INTERFERON TREATMENT AND ANALYSIS OF CRYOPRECIPITATES

Chronic hepatitis C virus infection can be associated with mixed cryog lobulinemia and systemic vasculitis. The pathogenesis remains poorly u nderstood. 55 consecutive patients with chronic HCV infection (anti-HC V- and serum HCV RNA-positive) were studied prospectively. Cryoglobuli nemia was detected in 28 patients (51%) with a mean cryocrit level of 2.2%. Clinical symptoms of vasculitis were encountered in six patients . Compared to those HCV-intected patients without cryoglobulinemia the following distinctive features were observed in the presence of cryog lobulinemia: increased age (p < 0.02), female preponderance (p < 0.002 ), longer-lasting HCV infection (mean of 10.7 vs. 4.7 yrs), higher pre valence of cirrhosis (42.8 vs. 0%), increased serum concentration of I gM and increased rheumatoid factor activity, decreased concentration o f serum C4 (each p < 0.05). The response to interferon treatment was s imilar in patients with and without cryoglobulinemia. When cryoprecipi tates were analyzed by immunofixation, type II cryogtobulinemia was pr esent in 1/3 and type III in 2/3 of patients. By SDS-PAGE four differe nt proteins were demonstrable in cryoprecipitates each identified by i mmunoblotting as IgG and IgM heavy or light chains respectively. Cryop recipitate IgGs were shown to react with HCV structural as well a non- structural proteins in a recombinant immunoblotting assay (RIBA). In c ontrast, cryoprecipitate IgMs reacted only to the HGV core protein c22 -3. HCV RNA was detected in cryoprecipitates without a significant enr ichment when compared to the corresponding serum or supernatant HCV RN A content. Given the monoclonality of some cryoprecipitate IgM and the ir reactivity to HCV core, a crossreactivity to IgG was postulated. In fact, when performing a computer-assisted search for sequence homolog y, a motif within the core protein (EGLGWAGWL, conserved in HCV genoty pes) was identified homologous to a sequence of IgG heavy drains. Thus , temperature-dependent affinity changes of IgM anti-HCV core (nonapep tide) and ensuing complex formation with IgG via binding to the homolo gous IgG sequence could be a mechanism of cryoprecipitate formation.