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Hepatitis c virus infection in type ii mixed cryoglobulinemia.

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ARTHRITIS & RHEUMATISM Volume 36
Number 10, October 1993, pp 1341-1349
0 1993, American College of Rheumatology
1341
REVIEW
HEPATITIS C VIRUS INFECTION IN
TYPE I1 MIXED CRYOGLOBULINEMIA
GYORGY ABEL, QING-XIU ZHANG, and VINCENT AGNELLO
Type I1 mixed cryoglobulinemia is characterized by symptoms of systemic vasculitis and hepatic
involvement. The cryoglobulins consist of polyclonal
IgG complexed with monoclonal IgM rheumatoid factors (RF) that predominantly bear the WA crossidiotype (XId). Because of the high prevalence of
hepatocellular abnormalities associated with the disease, hepatotropic viruses have been suspected as
causative agents. Although hepatitis B virus was implicated in the pathogenesis of essential mixed cryoglobulinemia in early studies, evidence for ongoing
hepatitis B infection in these patients was rarely
found.
Recently, an association of hepatitis C virus
infection with type I1 mixed cryoglobulinemia has
been established. Hepatitis C virus infection occurs in
type I1 mixed cryoglobulinemia patients most commonly in association with WA monoclonal RF (mRF).
This association raises the hypothesis that WA mRF is
an antibody that cross-reacts with hepatitis C virus
and that the virus is the causative agent of type I1
mixed cryoglobulinemia. The possibility that hepatitis
C virus and WA RF play a role in mixed cryoglobuFrom the Clinical Immunology Laboratory, Department of
Laboratory Medicine, Lahey Clinic Medical Center, Burlington,
and the Edith Nourse Rogers Memorial Veterans Affairs Hospital,
Bedford, Massachusetts.
Supported in part by grant AR-35487 from the NIH and by
a Merit Review Grant from the Veterans Affairs.
Gyorgy Abel, MD; Qing-Xiu Zhang, MD; Vincent Agnello,
MD .
Address reprint requests to Vincent Agnello, MD, Department of Laboratory Medicine, Lahey Clinic Medical Center, 41 Mall
Road, Burlington, MA 01805.
Submitted for publication October 7, 1992; accepted in
revised form April 1, 1993.
linemia in patients with primary Sjogren’s syndrome
has also been proposed.
The demonstration of hepatitis C virus infection
in patients with type I1 mixed cryoglobulinemia
strengthens the rationale for use of antiviral drugs in
the treatment of these patients. The finding that hepatitis C virus is greatly concentrated in the cryoglobulins of these patients may provide a new approach to
the isolation of this pathogen.
Mixed cryoglobulinemia
Mixed cryoglobulins were first described 30
years ago when the cold-precipitable proteins present
in the serum of a patient with renal tubular acidosis
were identified as complexes consisting of 7s gamma
globulins and 19s rheumatoid factors (1). The RF
present in these complexes differed from classic RF in
that they acted as “incomplete” cryoglobulins that
precipitated in the cold in the presence of IgG. The
characteristic syndrome of mixed cryoglobulinemia
(palpable purpura, arthralgias, and weakness) was first
described by Meltzer and Franklin (2), who confirmed
the mixed IgG-IgM composition of the cryoglobulins
and found that the IgM-RF were polyclonal in some
patients and monoclonal in others. They and their
colleagues (3) also provided the first evidence for a
role of mixed cryoglobulins in the pathogenesis of the
renal lesions associated with the disease. Immunofluorescence studies demonstrated that glomeruli contained IgG and IgM both within intraluminal deposits
and along basement membranes (3).
Neither the clinical nor the pathologic features
in 9 of the 11 originally described patients with mixed
cryoglobulins were typical of any known disease en-
1342
ABEL ET AL
Table 1. Clinical findings in studies of patients with essential mixed cryoglobulinemia*
Study (no. of patients)
Purpura
Arthralgia
Weakness
Peripheral neuropathy
Renal involvement
Hepatic involvement
Splenomegaly
Lymphadenopathy
Lung involvement
Sjogren’s syndrome
Raynaud’s phenomenon
Skin ulcers
Female sex
Mean age (years)
Gorevic,
ref. 4 (50)
Tarantino et al,
ref. 5 (116)
Ferri et al,
ref. 6 (52)
Invernizzi et al,
ref. 7 (79)
100
70
NR
28
54
70
NR
16
NR
14
22
30
66
NR
88
78
61
31
47
88
50
Rare
Rare
Rare
35
NR
61
52
95
90
100
69
17
62
NR
NR
NR
40
31
NR
75
59
97
51
NR
2.5
8
NR
NR
NR
NR
NR
* Except for age, numerical values are the percent with the characteristic.
tity, and the term essential mixed cryoglobulinemia
was introduced. The immunochemical classification of
cryoglobulins that is now widely used describes 3
types (4): type I cryoglobulins consist of a single
monoclonal immunoglobulin and are predominantly
associated with malignancies of the immune system.
Type I1 and type I11 are mixed cryoglobulins. In type
11, the cryoglobulins consist of polyclonal IgG and
monoclonal IgM rheumatoid factors. In type 111, the
IgG and RF are both polyclonal. Most of the type I1
and type I11 mixed cryoglobulinemia is classified as
essential. Secondary mixed cryoglobulins, predominantly type 111, occur in infective, autoimmune, and
chronic liver diseases. The secondary type I1 mixed
cryoglobulins occur mainly in association with malignancies of the immune system.
In Table 1, the clinical features reported in later
studies of patients with essential mixed cryoglobulinemia are summarized (4-7). For the most part, the later,
larger series confirmed the original observations of
Meltzer and Franklin (2). Extensive immunohistologic
studies over the last 25 years have established that
mixed cryoglobulins can produce vasculitis in smallsized and medium-sized arteries. The main symptoms
of essential mixed cryoglobulinemia are the same as
those that accompany systemic vasculitis. The most
frequent, and in most patients the presenting, symptom in both type I1 and type I11 essential mixed
cryoglobulinemia is palpable purpura, occurring most
commonly on the lower extremities but sometimes
10
10
66
42
NR
=
not reported.
extending to the lower part of the abdomen or to the
buttocks. Palpable purpura occurs infrequently in type
I cryoglobulinemia.
Polyarthralgias occur frequently in patients
with mixed cryoglobulinemia and infrequently in those
with type I cryoglobulinemia. Most commonly, polyarthralgias are symmetric, are not migratory, and are
not accompanied by morning stiffness. Proximal interphalangeal joints, metacarpophalangeal joints, and
knees are the joints most frequently involved, followed
by the ankles and elbows (4). Profound weakness occurs
in most patients with mixed cryoglobulinemia.
Peripheral neuropathy, not noted in the original
study of mixed cryoglobulinemia (3), was found to be
a major feature of the disease in many subsequent
investigations (4-8). In our experience, signs of
peripheral neuropathy , paresthesias, and numbness
(mostly of the lower extremities) may be a presenting
symptom of the disease.
Primary Sjogren’s syndrome was present in 2 of
9 patients in the original study ( 3 ) . For this historical
reason, mixed cryoglobuliriemia associated with primary Sjogren’s syndrome has been classified as essential mixed cryoglobulinemia.. Subsequent studies have
confirmed a 1440% prevalence of primary Sjogren’s
syndrome among patients with mixed cryoglobulinemia ( 4 4 9 ) . Clinical renal disease occurs in the late
phase of the disease and is manifested by hypertension, hematuria, proteinuria, and the nephrotic syndrome.
HEPATITIS C IN MIXED CRYOGLOBULINEMIA
The high prevalence of hepatic involvement in
mixed cryoglobulinemia that was manifested by hepatomegaly in patients in the original series has been
confirmed in subsequent studies (4,6,10) using laboratory measures of hepatocellular dysfunction and liver
biopsies. This high prevalence of hepatocellular abnormalities has led to the hypothesis that hepatotropic
viruses are involved in the development of mixed
cryoglobulinemia (10).
Rheumatoid factor cross-idiotypes in type I1
mixed cryoglobulinemia
Cross-idiotypes of mRF in mixed cryoglobulinemia were defined more than 10 years before the
search for hepatotropic viruses in the disease was
begun (11). The major XId, WA, which occurs in
approximately 65% of mRF from type I1 mixed cryoglobulins, is an antigen in the combining site of the
antibody involving both heavy and light chains (12). A
striking and surprising finding in immunochemical,
protein sequence, and molecular genetic studies was
that WA mRF are products of germline genes; most
WA mRF are encoded by germline VKIIIb and VH,
genes with little or no somatic mutation (13).
The WA XId does not appear to occur among
polyclonal RF of patients with rheumatoid arthritis;
however, the WA XId may be present among the
polyclonal RF in patients with primary Sjogren’s syndrome, in addition to being present among the mRF in
the disease. In studies using an anti-XId reagent
(mouse monoclonal antibody 17.109) that detects
VKIIIb light chains, both the polyclonal RF in sera of
patients with primary Sjogren’s syndrome and the
lymphocytes infiltrating the parotid glands of these
patients were found to be positive (14). These results
have not been corroborated with an anti-WA XId
reagent.
Since mRF in a number of patients with type I1
mixed cryoglobulinemia and primary Sjogren’s syndrome have been shown to be WA XId positive
(15,16), the results with 17.109 may indicate a broader
involvement of WA XId-positive RF in primary Sjogren’s syndrome. WA mRF occur in both type I1
essential mixed cryoglobulinemia and type I1 mixed
cryoglobulinemia secondary to malignancies of the
immune system; however, neither the precise prevalence in each group nor the relationship between the
groups has been defined,
1343
Studies on hepatotropic virus infections in
essential mixed cryoglobulinemia
Hepatitis B. An association of hepatitis B virus
infection with essential mixed cryoglobulinemia was
first suggested by Realdi and colleagues (17). They
compared hepatitis B virus markers in serum, cryoprecipitates, and supernatants in patients with mixed
cryoglobulinemia secondary to chronic liver disease
and in patients with essential mixed cryoglobulinemia.
In that early study, hepatitis B surface antigen
(HBsAg) was detected by cross-electrophoresis, and
antibody to HBsAg (HBsAb) was detected by Ouchterlony precipitation. In the group of patients with
chronic liver disease, HBsAg was found in serum,
cryoprecipitates, and supernatants, but HBsAb only
was found in serum and cryoprecipitates. In 50%
of patients with essential mixed cryoglobulinemia,
HBsAg was found in the serum and cryoprecipitates
but not in the supernatants. Those authors concluded
that hepatitis B virus antigen-antibody complexes
were formed in antigen excess in patients with secondary mixed cryoglobulinemia and in antibody excess in
patients with essential mixed cryoglobulinemia.
In contrast to the high prevalence shown in the
study by Realdi et a1 (17), subsequent studies using
radioimmunoassays and enzyme-linked immunosorbent assays (ELISA) (18,19) have demonstrated a low
prevalence of HBsAg. However, the findings of Realdi
et a1 in patients with mixed cryoglobulinemia secondary to chronic liver disease have been confirmed in a
study by Dienstag (20). In particular, Dienstag’s demonstration, by electron microscopy, of hepatitis B
virus particles in cryoglobulins was consistent with the
notion that immune complexes are formed in antigen
excess. The discrepancy between the prevalence of
HBsAg found by Realdi and colleagues and that found
in the later study by Dienstag was likely the result of
an artifact caused by high-titer RF, which was not
recognized with early methods for detection of
HBsAg. The absence of HBsAg in the supernatant of
the sera of patients with essential mixed cryoglobulinemia after cryoprecipitation would have been consistent with precipitation of RF in cryoprecipitates and
elimination of the artifact.
The prevalence of markers for hepatitis B virus
in subsequent studies (19-22) has varied from 0% to
74%. The variation in results may be the result of
differences in patient populations or geographic locations of the populations studied. Some of the studies in
which a high prevalence of markers for hepatitis B
1344
virus was shown were performed in southern Europe,
where hepatitis B virus infection is endemic. Galli and
colleagues (19,22) noted a high prevalence of markers
for hepatitis B virus in essential mixed cryoglobulinemia patients in southern Europe, but the prevalence
did not differ significantly from that in the control
group in the same geographic area.
In a Boston study, the prevalence of serologic
markers for hepatitis B virus among patients with
essential mixed cryoglobulinemia was lower than the
prevalance in studies from southern Europe. Most of
the patients in the Boston study had primary Sjogren’s
syndrome (18). A relatively low prevalence of serologic markers for hepatitis B virus in primary Sjogren’s
syndrome was also found in a later study from southern Europe (23). That study showed a prevalence of
serologic markers for hepatitis B virus, among patients
with essential mixed cryoglobulinemia of 82%, more
than twice the prevalence in control subjects (35%),
but only a 42% prevalence was demonstrated among
patients with primary Sjogren’s syndrome and essential mixed cryoglobulinemia.
Although a high prevalence of serologic markers for hepatitis B virus has been reported in patients
with essential mixed cryoglobulinemia, evidence for
active hepatitis B virus infection in these patients has
rarely been found. Ferri et a1 (6) reported a high
prevalence of both hepatitis B virus and hepatitis C
virus markers; however, only 1 of 52 patients had
HBsAg, and total antibodies to hepatitis B core antigen (HBcAb) were assayed rather than IgM HBcAb,
which could indicate active infection. In one study in
which IgM HBcAb was investigated (16), none of the
patients were found to be positive for the antibodies.
In that study, markers for active hepatitis C virus
infection were present in 84% of the patients, in
contrast to 5% of patients showing markers of active
hepatitis B virus infection.
Criteria for establishment of a pathogenetic role
of hepatitis B immune complexes have not been fulfilled for essential mixed cryoglobulinemia (20). In
none of the studies have increased concentrations of
hepatitis B virus antigen and antibodies been demonstrated after dissociation of high molecular complexes
in the cryoglobulins. The findings in studies that
demonstrated hepatitis B virus antigens in renal lesions of patients with essential mixed cryoglobulinemia could not be confirmed when precautions were
taken to avoid artifacts produced by RF (24).
Hepatitis C. Hepatitis C virus has been demonstrated as the major cause of posttransfusion and
ABEL ET AL
sporadic non-A, non-B chronic hepatitis (25). The
recent cloning and sequencing of the hepatitis C virus
genome have rekindled the study of hepatotropic
viruses in essential mixed cryoglobulinemia. Despite
the failure, thus far, to detect this virus by the usual
electron microscopic or culture techniques, assays
have been developed for detecting markers of hepatitis
C virus infection. The genome of hepatitis C virus
encodes 3 putative structural proteins: the nucleocapsid protein, and the envelope proteins gp35 and gp70 at
the 5‘ end. The genome also encodes nonstructural
proteins and has been divided into 5 regions (NSlNS5) by analogy to the distantly related flaviviruses
and pestiviruses.
By recombinant techniques, a nucleocapsid
peptide and a number of the nonstructural peptides
have been produced. First-generation assays (ELISA
and recombinant immunoblot assay [RIBA]) detect
antibody to the c100-3 antigen located in the NS-3
region. The second-generation ELISAs and RIBAs
combine c100-3 with another nonstructural protein,
c33c, to form a new composite antigen, c200. Secondgeneration assays also detect antibodies against c22-3,
a nucleocapsid antigen. The second-generation assays
have enhanced sensitivity and specificity (26).
Since the first report describing hepatitis C
virus antibodies in patients with type I1 mixed cryoglobulinemia (3 of 10 patients) (27), investigators at
several laboratories have reported an increased prevalence of hepatitis C virus antibodies, ranging from
30% to 98%, in the sera of patients with type I1 and
type 111 mixed cryoglobulinemia (6,16,26-36). Findings of several of the larger studies are presented in
Table 2. In most of the studies on mixed cryoglobulinemia, test results obtained using first-generation
ELISAs or RIBAs were identical to those obtained
with second-generation ELISAS or RIBAs (Table 2)
(6,16,33,35). Misiani et a1 (36), however, found a
significantly higher prevalence of anti-hepatitis C virus antibodies with the second-generation (c22/c-200)
ELISA and the second-generation RIBA than with the
first-generation (c100) ELISA (Table 2). With use of
first-generation assays, a high prevalence of falsepositive results in studies of patients with some autoimmune diseases, particularly those associated with
hepatocellular disease, has been reported (37). The
prevalence of hepatitis C virus antibodies in the latter
population of patients as determined using secondgeneration assays has not yet been reported.
In one study (6), a much lower prevalence of
hepatitis C virus antibody was found in cryoprecipi-
HEPATITIS C IN MIXED CRYOGLOBULINEMIA
Table 2. Prevalence of hepatitis C virus antibody and hepatitis C
virus RNA in patients with mixed cryoglobulinemia
Reference
Hepatitis C
virus
antibody
27
29
31
33
6
16
36
Hepatitis C
virus
RNA
35
36
16
Type of
cryoglobulinemia
studied (n)*
Serum
Cryoprecipitatet
I1 (10)
111 (9)
EMC (29)
EMC: 11, I11 (30)
MC: 11, 111 (52)
11: l", 2" (19)
11, 111: 1" (51)
30
I8
48
70
54
42
37$, 98§
NR
NR
NR
NR
25
11
41$, 941
MC: 11, 111 (42)
11, 111: 1" (16)
11: I", 2" (19)
% positive
86
81
84
* I1 and 111 = type I1 and type 111; EMC = essential mixed
cryoglobulinemia; MC = mixed cryoglobulinemia; 1" and 2" =
primary and secondary.
t NR = not reported.
$ By first-generationenzyme-linked immunosorbent assay (ELISA)
(c 100).
§ By second-generation ELISA (c22k200).
tates than in sera (Table 2). These observations were
interpreted as indicating that hepatitis C virus antibody was not increased in the cryoglobulins in essential mixed cryoglobulinemia and, therefore, could not
have a direct role in the pathogenesis of essential
mixed cryoglobulinemia (38). A lower prevalence of
hepatitis C virus antibody in cryoprecipitates than in
sera was confirmed at our laboratory (16). However,
quantitative studies of hepatitis C virus antibody from
dissociated cryoglobulins showed that the hepatitis C
virus antibody was concentrated in the cryoglobulin.
The results suggest that in nondissociated cryoglobulins, the anti-hepatitis C antibodies are blocked by
antigen, and are therefore unavailable for detection in
anti-hepatitis C virus antibody assays.
In contrast to these results, one study (36)
showed no significant difference between the prevalence of hepatitis C virus antibody in sera and cryoprecipitates. In that study, reduction of the cryoprecipitates with dithiothreitol (DTT) increased the c 100
antibody detected by first-generation ELISA. This
effect is difficult to explain in terms of elimination of
pentameric RF, unless aggregation of clOO antigenantibody complexes by RF prevents dissociation of
clOO antibody from the complexes under the assay
1345
conditions. The possibility that DTT destroys the clOO
antigen was not considered by those authors.
Detection of hepatitis C virus RNA is a more
direct indication of hepatitis C virus infection. Advances in polymerase chain reaction (PCR) methodology have made this method a practical technique for
detecting and measuring hepatitis C viremia. The
uniform handling and storage of sera, the method of
RNA preparation, and maximal reduction of the risk of
contamination are of great importance in obtaining
reliable and reproducible results by PCR. The selection of appropriate primers is particularly important.
Nested primers selected from the highly conserved 5'
noncoding region (5' NC) show the highest sensitivity
and specificity (39,40).
In all of the hepatitis C virus RNA studies
included in Table 3, the nested primer method was
used. Ferri and colleagues (35) found a high prevalence of hepatitis C virus RNA in a population of
patients with essential mixed cryoglobulinemia. Although primers from the 5' NC were used in that
study, details of the PCR methodology and the prevalence of hepatitis C virus RNA in a control population
were not reported. In addition, the possibility of
hepatitis C virus sequence contamination, a significant
source of artifact in the PCR methodology, was not
excluded. Oligonucleotide primers located in the NS-3
and NS-4 were used for the detection of hepatitis C
virus RNA by PCR in the sera of 16 essential mixed
cryoglobulinemia patients in another study (36). Thirteen of these serum samples were positive for hepatitis
C virus RNA by PCR, whereas positivity for antihepatitis C virus antibodies was demonstrated by
second-generation RIBA in only 10 of the 13 samples
that were positive by PCR.
In a study of 19 patients with type I1 mixed
cryoglobulinemia, carefully controlled quantitative
PCR methodology utilizing primers from the 5' NC
was used. A high prevalence of hepatitis C virus
infection was found in the sera of patients with type I1
mixed cryoglobulinemia (16). In the type I1 cryoglobulins examined, hepatitis C virus antibody was concentrated approximately 10-fold and hepatitis C virus
RNA was concentrated more than 1,000-fold compared with the respective levels in sera. Hepatitis C
virus infection in patients with type I1 mixed cryoglobulinemia occurred predominantly, although not exclusively, in association with WA mRF in the cryoglobulins. A surprising finding in that study was that the
high prevalence of hepatitis C virus infection was
ABEL ET AL
1346
accompanied by a high rate of false-negative results on
serologic tests for antibodies against the virus.
In contrast to other studies, however, the
above-mentioned study suggested a direct role of
hepatitis C virus infection in the pathogenesis of type
I1 mixed cryoglobulinemia and in the etiology of the
disease. Although the association between hepatitis C
virus infection and type I1 mixed cryoglobulinemia
with hepatitis C virus antigen-antibody complex
present in the cryoglobulin has been established, a
definitive role for these complexes in the generation of
the pathologic abnormalities in the disease has not
been established because hepatitis C virus antigens
have not been demonstrated in the vascular and renal
lesions characteristic of mixed cryoglobulinemia.
amounts of polyclonal IgM but higher quantities of
mRF than normal peripheral blood mononuclear cells
after pokeweed mitogen or Staphylococcus aureus
activation. In clinical studies, however, no deficiency
in immunoglobulin synthesis or increase in susceptibility to infection has been reported in patients with
type I1 essential mixed cryoglobulinemia, although
findings in a study of antibodies to hepatitis C virus in
patients with type I1 mixed cryoglobulinemia suggested an atypical immune response to this infective
agent (16). Hepatitis C virus antibody detectable by
currently available assays was present in only 50% of
patients with type I1 mixed cryoglobulinemia who had
active hepatitis C virus infection; this is a high rate of
false-negative results on serologic testing for this infection.
Immune abnormalities in type I1 mixed
cryoglobulinemia
Therapy
Data on the immunologic abnormalities in patients with type I1 mixed cryoglobulinemia, other than
the immunochemical characterization of mRF present
in the cryoglobulins, are limited. It has been proposed
(41) that CDS-positive B cells that express germline
light and heavy chain genes are prone to autoantibody
production and malignant transformation. The germline VdIIb gene that encodes the light chains of most
of the WA XId-positive mRF in type I1 mixed cryoglobulinemia is also expressed in a high percentage of
classic CD5-positive B cells in chronic lymphocytic
leukemia (42). However, in a study of 3 patients with
type I1 essential mixed cryoglobulinemia (41), most B
cells were CD5 negative.
Similar results were obtained in our laboratory
in a study of an additional 6 patients with type I1
essential mixed cryoglobulinemia (Cook L, Agnello V:
unpublished observations). B cells in all 6 patients
were CD5 negative. In 2 patients in whom 3&35% of
lymphocytes were B cells, 70%of the B cells were WA
XId positive but CD5 negative.
In contrast to these negative findings regarding
malignant lymphoproliferation in type I1 mixed cryoglobulinemia, one group (43) concluded that type I1
mixed cryoglobulinemia is a manifestation of lowgrade lymphoma, based on the “lymphoplasmocytoid” appearance of cells infiltrating the liver portal
tracts in patients with type I1 mixed cryoglobulinemia.
In an in vitro study (44), peripheral blood
mononuclear cells from patients with essential mixed
cryoglobulinemia were found to produce smaller
For the last 25 years, plasmapheresis and immunosuppression have been the main forms of therapy
for patients with the more severe forms of mixed
cryoglobulinemia. Recently, several reports (16,4548)
have described effective therapy using interferon-a
(IFNa). The responses to IFNa treatment included
resolution of purpura and neuropathy , normalization
or improvement of kidney function, reduction of cryoglobulin levels, and normalization of liver enzyme and
hemoglobin values. In one study (48), a 77% response
rate was obtained in 21 patients with type I1 mixed
cryoglobulinemia, using a regimen of 3 million units of
IFNa per day for 3 months. After cessation of therapy,
periods of remission lasted up to 40 months (48). In
another study (47), a lower-dose regimen also produced remission of disease in a patient with type I1
essential mixed cryoglobulinemia.
Recent data on the concentration of hepatitis C
virus in cryoglobulins suggest that the effectiveness of
IFNa in type I1 mixed cryoglobulinemia may be due to
the antiviral action, rather than the well-known immunomodulatory effects, of this drug. There are not
sufficient data presently available, however, to determine to which extent either mechanism is involved.
Discussion
The etiology of type I1 mixed cryoglobulinemia
is not known, but new clues have appeared. The
presence of the same mRF in type I1 essential mixed
cryoglobulinemia and type :[I mixed cryoglobulinemia
secondary to malignancies, of the immune system
HEPATITIS C IN MIXED CRYOGLOBULINEMIA
suggested that the lymphoproliferative process in type
I1 mixed cryoglobulinemia was an early stage of a
malignant lymphoproliferative disease. However, in
only a small number of patients with type I1 essential
mixed cryoglobulinemia will lymphoid malignancy develop (4,lO).
The occurrence of mixed cryoglobulin in the
course of some infections has suggested that infectious
agents may be the cause of the immune complexes that
form the cryoglobulins in type I1 mixed cryoglobulinemia. In particular, results of a recent study (16) establishing a high association of hepatitis C virus infection
and type I1 mixed cryoglobulinemia suggested that
hepatitis C virus infection may be directly responsible
for the production of WA mRF. The finding in that
study that hepatitis C virus was concentrated, along
with WA mRF, in the cryoglobulins of patients with
type I1 mixed cryoglobulinemia, in the absence of
antibodies to hepatitis C virus detectable by current
assays, raised the possibility that WA mRF are antibodies that are cross-reactive with hepatitis C virus.
Other mRF that are encoded by germline genes
have been found to cross-react with non-IgG antigens
(49-5 1). These antibodies encoded by germline genes
and reactive with self antigens are considered to be
natural autoantibodies. These natural autoantibodies
are highly conserved in the antibody repertoire by
natural selection and may therefore serve hostdefense functions in response to common pathogens
(52,53).
Hence, WA mRF may be natural antibodies to
hepatitis C virus produced by a specific set of B cells
that, when stimulated by hepatitis C virus, proliferate
in a T cell-independent process, because an isotype
switch or a high frequency of somatic mutation in the
complementarity-determining regions of WA mRF has
not been observed (1334). The progression to malignant transformation that occurs in type I1 mixed
cryoglobulinemia secondary to malignancies of the
immune system would require a second, as-yetuncharacterized, event occurring in only a fraction of
the total population with mixed cryoglobulinemia.
Hepatitis C virus infection and the presence of
WA RF in mixed cryoglobulinemia may also provide
clues to the possible relationship between type I1 and
type 111 mixed cryoglobulinemia in some groups of
patients. In addition to the high association of hepatitis
C virus infection with type I1 mixed cryoglobulinemia,
this infection may frequently accompany type 111
mixed cryoglobulinemia. Although the presence of
1347
WA RF in type I11 mixed cryoglobulinemia has not
been studied directly, indirect study using the 17.109
monoclonal reagent (14) suggests that polyclonal WA
RF, in addition to WA mRF, may be present in
patients with primary Sjogren’s syndrome.
It remains to be determined whether WA RF
are present among the polyclonal RF in type I11 mixed
cryoglobulinemia in patients with primary Sjogren’s
syndrome who are infected with hepatitis C virus.
Because a number of patients with type I1 mixed
cryoglobulinemia and primary Sjogren’s syndrome
have been found to have hepatitis C virus infection
(16), it is possible that the initial response to hepatitis
C virus in these patients is a polyclonal RF production
that includes WA RF and then progresses to a WA
mRF with persistent infection. Serial studies on patients with primary Sjogren’s syndrome and type I11
mixed cryoglobulinemia may be useful in investigating
this possibility.
A major question about infections in patients
with type I1 mixed cryoglobulinemia is whether they
are primary or secondary infections. This has been
difficult to determine in this patient population in
which there are numerous additional risk factors for
blood-borne infections, including such procedures as
plasmapheresis and blood transfusions, and diseaseassociated or iatrogenic immunosuppression.
No data are available to determine whether
hepatitis C virus infection in type I1 mixed cryoglobulinemia is primary or secondary. However, it can
now be determined whether hepatitis C virus has a
primary role in WA mRF production; WA mRFproducing cells can be isolated from patients and
tested to determine whether hepatitis C virus alone
can stimulate production of WA mRF. Direct stimulation of WA mRF by hepatitis C virus would indicate
that type I1 mixed cryoglobulinemia results from a
primary infection and that the hepatitis C virus infection does not occur after immune dysfunction resulting
from the gammopathy.
The demonstration of hepatitis C virus infection
in patients with mixed cryoglobulinemia strengthens
the rationale for the use of IFNa and other antiviral
drugs in the treatment of these patients. The finding
that hepatitis C virus is concentrated in the cryoglobulins of patients with type I1 mixed cryoglobulinemia
may also provide a new approach to the physical
isolation of this virus, which is yet to be detected by
routine electron microscopic and culture techniques.
ABEL ET AL
1348
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