CRYOGLOBULINEMIA IN CHRONIC HEPATITIS-C VIRUS-INFECTION - PREVALENCE,CLINICAL MANIFESTATIONS, RESPONSE TO INTERFERON TREATMENT AND ANALYSIS OF CRYOPRECIPITATES
H. Hartmann et al., CRYOGLOBULINEMIA IN CHRONIC HEPATITIS-C VIRUS-INFECTION - PREVALENCE,CLINICAL MANIFESTATIONS, RESPONSE TO INTERFERON TREATMENT AND ANALYSIS OF CRYOPRECIPITATES, Zeitschrift fur Gastroenterologie, 33(11), 1995, pp. 643-650
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.