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Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2062-2066
Haplotype HLA-B8-DR3 Confers Susceptibility to Hepatitis C
Virus-Related Mixed Cryoglobulinemia
By
Marco Lenzi,
Magda Frisoni,
Vilma Mantovani,
Paolo Ricci,
Luigi Muratori,
Raffaella Francesconi,
Mariaclara Cuccia,
Silvio Ferri, and
Francesco B. Bianchi
From Dipartimento di Medicina Interna, Cardioangiologia,
Epatologia, Istituto di Ematologia, Universita di Bologna,
Policlinico S. Orsola, Bologna, Italia; Servizio di Reumatologia,
Laboratorio Centralizzato, Azienda Policlinico S.Orsola Malpighi,
Bologna, Italia; and Dipartimento di Genetica e Microbiologia,
Università di Pavia, Pavia, Italia.
 |
ABSTRACT |
Our aim was to investigate whether host genetic factors are involved
in the onset of hepatitis C virus (HCV)-related mixed cryoglobulinemia
(MC). We studied 25 consecutive patients presenting with a full-blown
clinical picture of MC by physical examination, blood chemistry,
assessment of cryoglobulins and their composition, nonorgan-specific
autoantibodies, antibodies to HCV, serum HCV RNA, and HLA polymorphism.
Biopsies of liver, bone marrow, and minor salivary glands were also
performed in a number of patients. HLA results were compared with those
of normal controls and patients with chronic HCV infection without MC
and negative for autoimmune phenomena (pathological controls). Type II
MC was found in 14 of 25 patients (56%), and type III MC was found in
the remaining 11 (44%). All patients were positive for antibodies to
HCV and/or serum HCV RNA. HLA-B8 was found in 40% (10 of 25)
of patients compared with 10.1% (38 of 377) of normal controls
(P = .00003, Pcorrected = .0005, relative risk [RR] 5.9) and 6.7% (2 of 30) of pathological controls
(P = .007, Pcorrected = not
significant). As for class II HLA molecules, only DR3 was significantly
more frequent in MC patients (40%, 10 of 25) than in normal controls (15.1%, 57 of 377; P = .003, Pcorrected
= .03, RR 3.7). Odds ratio (OR) for the risk of developing MC was
calculated in patients positive for B8 and/or DR3, and the
highest OR (8.2) was observed in individuals possessing both. The
results suggest that the development of HCV-related MC is associated
with HLA-B8 and DR3 markers.
| |
INTRODUCTION |
MIXED CRYOGLOBULINEMIA (MC) is
characterized by the presence of purpura, arthralgia and weakness
associated with circulating immunoglobulins that precipitate when
cooled and exhibit rheumatoid factor (RF) activity.1 Based
on the observation of frequent liver involvement in MC patients,
hepatitis viruses have been investigated as possible etiologic agents.
An initial report associating MC with hepatitis B virus
infection2 failed later to be confirmed,3 whereas observations from different groups support a close association between MC and hepatitis C virus (HCV) infection.4-6 HCV is
a lymphotropic virus and persistent stimulation of the immune system by
the virus seems to be responsible for the appearance of MC in a
proportion of HCV-infected patients. Clinical signs of MC in
HCV-infected patients are rather rare7 in Mediterranean countries notwithstanding the high prevalence of HCV.8 This would suggest that either viral or host genetic factors may be required
for disease occurrence. To date, no significant association has been
found between any HCV genotype and MC.9 Likewise, the few
attempts to associate host HLA profiles and MC10-13 have
been inconclusive. Therefore, we have analyzed HLA class I and II
polymorphisms in patients with full-blown HCV-related MC.
| |
MATERIALS AND METHODS |
Patients.
Twenty-five consecutive patients with MC took part in the study.
Admission criteria were the presence of the typical cryoglobulinemic syndrome (purpura, arthralgia, and weakness associated with evidence of
circulating cryoglobulins). Only one patient had a past history of
blood transfusion, 11 of 25 had been treated with steroids and
plasma-exchange, and none had been previously treated with interferon.
Thirty consecutive untreated patients with HCV-related chronic liver
disease were prospectively enrolled as pathological controls. They all
presented no signs of MC and were negative for nonorgan-specific autoantibodies and cryoglobulins tested at least twice at an interval of 2 months. The diagnosis of HCV-related chronic liver disease was
based on clinical, serological, and histological criteria. Liver
histology was available in all and was consistent with chronic hepatitis with mild to moderate activity in 23 and cirrhosis in 7. In
both MC patients and pathological controls the apparent duration of
disease was assessed on the basis of the appearance of MC signs or
symptoms or the first detection of alanine
aminotransferase (ALT) abnormality and/or anti-HCV positivity.
Clinical evaluation and laboratory studies.
MC patients and pathological controls were evaluated at presentation by
history, complete physical examination, and routine blood chemistry
including proteinuria, serum transaminase, and creatinine levels.
The presence of cryoglobulins was evaluated in both groups as follows:
20 mL of blood was kept at 37°C for 2 hours in a glass tube. Serum
was cleared by centrifugation at 2,000g for 15 minutes at room
temperature and stored at 4°C for 7 days and examined daily.
Samples were considered to be positive for cryoglobulins when a
cryocrit of at least 0.5% was found and the heat resolubility of the
cryoprecipitate was checked. Mixed cryoglobulins were classified as
type II when a monoclonal component with RF activity was identified in
the cryoglobulins by immunofixation using IgG, IgM, and  and  light chain monospecific antisera (Paragon IFE; Beckman Analytical, Milan, Italy). In addition serum RF was tested at 37°C by
nephelometry using a commercial assay that detects IgM RF (RHF; Beckman
Analytical) and antibodies to HCV were investigated by means of a
second generation enzyme-linked immunosorbent assay (ELISA; Ortho
Diagnostic System, Milan, Italy). A second-generation recombinant
immunoblot assay (RIBA; Chiron Ortho Diagnostic System, Milan, Italy)
was used as confirmatory test. All sera were tested for circulating HCV RNA by "nested" polymerase chain reaction (PCR) using primers derived from the highly conserved 5 noncoding region of the HCV genome.14 Nonorgan specific and double-stranded DNA
autoantibodies were tested by indirect immunofluorescence on cryostat
sections of rat liver, kidney and stomach, HEp-2 cell cultures
(Kallestad, Austin, TX), and Crithidia luciliae cultures
(Medic, Turin, Italy) at a serum dilution of 1:40. Each
positive serum was titrated to extinction. The presence of
antiextractable nuclear antigen antibodies (anti-ENA) and antiactin
antibodies were tested by counterimmunoelectrophoresis using a freshly
prepared saline extract of lyophilized rabbit thymus acetone powder
(Pel-Freez Biologicals, Rogers, AR) and purified actin, respectively.
In 15 of the 25 MC patients C3 and C4 levels were measured by
nephelometry using antisera to human complement factors (Behringwerke
AG, Marburg, Germany).
Liver biopsy specimens were obtained in 15 MC patients who accepted to
undergo the procedure. Similarly, a bone marrow biopsy was performed in
9 patients and a minor salivary gland biopsy in 3. Liver involvement
was defined as alanine aminotransferase levels more than twice the
upper normal limit for longer than 6 months. Kidney involvement was
defined as urinary protein excretion greater than 0.15 g/dL
and/or abnormal values of serum creatinine. Peripheral
neuropathy was diagnosed on the basis of numbness, paresthesia,
weakness, and loss of osteotendineous reflexes and confirmed by
electromyography in four cases. Lymphoma was diagnosed by bone marrow
biopsy. Sicca syndrome was diagnosed on the basis of xerophthalmia,
xerostomia, abnormal Shirmer's test, and positive histology of minor
salivary glands.15
HLA typing.
The standard microcytotoxicity assay16 was performed to
determine HLA class I and II antigens using a panel of antisera from
the 11th International Histocompatibility Workshop and several commercial antisera (Onelambda Inc, Los Angeles, CA). Results of MC
patients were compared with those obtained by the same antisera in 377 healthy subjects (normal controls) and in the above described 30 pathological controls. Patients and controls were all Italian and their
geographic origin had been carefully checked to compare subjects from
the same areas.
Statistics.
Statistical analysis was performed using  2 analysis with
Yates' correction, Fisher's exact test, and Wilcoxon rank sum test when appropriate; probability (P) values were corrected
(Pcorrected) by the number of comparisons made (ie,
depending on the number of variants and the number of groups tested)
using Bonferroni's inequality method.17 The strength of
association between HLA antigens and MC was estimated by calculating
the relative risk (RR) using the methods of
Holdane.18 Odds ratio (OR) for the risk of
developing MC was calculated from 2 × 2 contingency tables, according to Svejgaard and Ryder.19
| |
RESULTS |
The median age of patients with MC was 59 years (range 43 to 75) with a
median disease duration of 87 months (range 26 to 240). Both age and
apparent duration of disease were not significantly different from
those of pathological controls (median age 56 years, range 33 to 73;
disease duration 102 months, range 30 to 294). Purpura, arthralgia, and
weakness were present in all patients because they were required for
admission into the study. As shown in Table
1 type II cryoglobulinemia was found in 14 patients (56%) and type III
in 11. Liver involvement was found in 21 of 25 (84%): liver histology
was available in 15 and consistent with chronic hepatitis with mild to
moderate activity in 11 cases and cirrhosis in 4; in another 2 patients
the diagnosis of cirrhosis was based on clinical and biochemical signs,
and in 4 more patients there were ALT abnormalities but no histology
was available.
Peripheral neuropathy was found in 15 of 25 patients (60%) and
confirmed by electromyography in 4. The lower limbs were mostly involved. None of the patients had received a diagnosis of lymphoma before that of MC but in 9 of them (7 with type II MC) a bone marrow
biopsy showed evidence of low-grade B-cell lymphoma according to the
Updated Kiel Classification20 and the Revised
European-American Lymphoma Classification (REAL).21 Three
patients (12%) showed signs of renal involvement and 3 of sicca
syndrome.
All but 2 MC patients had a positive serum IgM RF. Antibodies to HCV
were detected in 24 (96%) of the 25 patients. Serum HCV RNA was
positive in 24 patients (96%), including the one who was anti-HCV
negative. One patient was anti-HCV positive and HCV RNA negative.
Nonorgan-specific autoantibodies were found in 5 (20%) cases. Four
patients were positive for anti-smooth-muscle antibody with nonactin
specificity (titer ranging from 1:40 to 1:160) and the remaining one
had both anti-smooth-muscle antibody (antiactin, titer 1:320) and
antinuclear antibody with homogeneous pattern (titer 1:320). All cases
were negative for double-stranded DNA and antibodies to
extractable nuclear antigens. In the 15 MC patients tested, normal
levels of C3 were found, whereas C4 levels were below the lower limit
of the normal range (15 to 45 mg/dL) in 10 (median 8 mg/dL, range 2 to
90).
HLA class I and class II allele frequencies in MC patients compared
with pathological and normal controls are shown in
Tables 2 and
3. Class I HLA-B8 was found in 40% (10 of 25) of patients compared with 10.1% (38 of 377) of normal controls
(P = .00003, Pcorrected = .0005, RR 5.9) and 6.7% (2 of 30) of pathological controls (P = .007, Pcorrected not significant [NS]). HLA-B18 was
also more frequent in MC patients versus normal controls ( 32%, 8 of
25 v 13.3%, 50 of 377; P = .017, Pcorrected = NS). As for class II HLA antigens,
only DR3 was significantly more frequent in MC patients (40%, 10 of
25) than in normal controls (15.1%, 57 of 377, P = .003, Pcorrected = .03, RR 3.7), whereas no significant difference was found between MC patients and pathological controls. The
frequency of the B8-DR3 phenotype was significantly higher in MC
patients (32%, 8 of 25) than in healthy controls (6.1%, 23 of 377, P = .00001, Pcorrected = .0003, RR 7.2) and
pathological controls (6.7%, 2 of 30, P = .03, Pcorrected = NS). None of the MC patients were
homozygous for B8/DR3 haplotype. No significant difference in HLA
frequencies was found between pathological and normal controls.
Because both HLA-B8 and DR3 genetic markers were found to be associated
with MC, we have calculated the OR for the risk to develop the disease
in individuals positive for either or both HLA alleles
(Table 4). The highest OR (8.2) was
observed in subjects positive for both B8 and DR3, whereas
B8-positive/DR3-negative or DR3-positive/B8-negative patients showed an
OR of 3.1 and 1.3, respectively.
MC patients who were positive for B8 and/or DR3 did not show
any significant clinical or biochemical difference in comparison with
their negative counterparts (Table 1). However, type II MC was more
frequent in the former than in the latter (67% v 46% , 8 of
12 v 6 of 13, P = NS).
| |
DISCUSSION |
Recent evidence4-6 supports the ethiopathogenetic role of
HCV in MC. However, it is noteworthy that cases of full-blown MC seem
to be rare in comparison with the high prevalence of the virus as
observed by Lunel et al7 who have reported clinical signs
of MC in 14% of their patients with HCV infection. This discrepancy
does not appear to depend on viral factors, because multiple HCV
genotypes have been detected in association with MC and the high
prevalence of genotype II reported by Pozzato et al9
mirrors the overall distribution of that same genotype in the same
geographic area. Therefore, we have investigated whether, in the
presence of HCV infection, host genetic factors may predispose to the
onset of MC, as suggested by Agnello.22
We have found a significant association with class I HLA-B8 and class
II HLA-DR3 alleles. Although the association was stronger with HLA-B8
than with DR3, it is remarkable that 8 of 25 (32%) MC patients were
positive for HLA-B8 and DR3 and that the calculated OR (8.2) was higher
for the haplotype B8-DR3 than for each single specificity (3.1 and 1.3, respectively). HLA typing of pathological controls did not differ from
that of normal controls, confirming the lack of genetic predisposition
to HCV-related liver disease.23
The significantly increased frequency of HLA-B8 in our patients does
not seem to depend on an inappropriate selection of normal controls
because they were matched with patients for geographic origin (Northern
and Central Italy). Moreover, the 10.1% prevalence of B8 observed in
our controls is in accordance with the North (20%) to South (8%)
gradient of B8 frequency reported in our country.24 Furthermore, our results cannot be attributed to the enrollment of
autoimmune patients. In fact, markers of autoimmunity and sicca syndrome, which are both known to be associated with B8 and DR3, were
present only in a minority of our cases. Of the five positive for
nonorgan-specific autoantibodies, only one was B8 positive and only one
out of three with sicca syndrome was B8-DR3 positive.
Before HCV was discovered, an early Italian attempt10 to
investigate genetic predisposition to MC failed to detect any
significant association of the disease with either class I or class II
HLA molecules. However, it should be pointed out that in our cohort HCV
positivity was 100% but unknown in theirs; these conflicting results
are, thus, not easily explained. Both Migliorini et
al10 and we studied patients from the same geographic area,
selected on the basis of the same criteria and compared with controls
showing similar frequency of HLA-B8 and DR3. Recently Ossi et
al11 have reported an increased frequency of HLA A9/A24,
B51, and B35 in 16 patients with HCV-related MC. The design of their
study is superimposable to ours in terms of both selection of patients and controls but unfortunately the investigators do not give any statistical evaluation of their data. The hypothetical protective role
of DR7 is, similarly, statistically unproven. We have not found a
positive association between MC and A9/A24, B51; B35 as well as DR7
were less frequent in patients than in controls. Of these, only DR7
showed a P < .05 value before correction. A further study by
Congia et al12 on Sardinian patients, selected among a
polytransfused thalassemic anti-HCV population, reports a protective role for the DR2 subtype DRB1*1601 for HCV infection. Our data do not
confirm this observation but are consistent with the reported increase
in frequency of DRB1*0301 in patients with extrahepatic features.
Similarly an increased frequency of DR3 in HCV infected patients with
cryoglobulins was preliminarily reported by Hwang et
al.13
It is known from HLA population genetics that a strong linkage
disequilibrium exists between B8 and DR3 alleles and that both belong
to the extended haplotype B8,C2C,BSF, C4AQ0,C4B1,DR3,DQ2. The close
association between the loci included in this haplotype makes it hard
to say whether one or multiple loci have a role in susceptibility to
disease. This extended haplotype is known to be overrepresented in
several autoimmune diseases in which different primary associations
have been proposed. In celiac disease25 and
insulin-dependent diabetes mellitus26 the strongest
association is reported with DQ molecules, in autoimmune hepatitis DRB1
and DRB3 loci are primarily involved,27 whereas a deletion
of C4A (described at proteinic level as C4AQ0) seems associated with systemic lupus erythematosus.28 Such deletion results in a
partial insufficiency of C4, which impairs the clearance of viruses and immunocomplexes.29 Patients with C4 deficiency are thus
susceptible to develop immunocomplex diseases,30 and animal
models with genetic C4A deletion share features of MC, ie, IgM
rheumatoid factors and immunocomplexes.31 Our data suggest
that the genetic predisposition to MC is associated with the phenotype
B8-DR3, the strongest association being with B8, and that HLA-B8 and
DR3 may be considered risk factors for HCV-related MC in addition to
cirrhosis.7 Moreover, it is possible that patients
exhibiting the B8-DR3 phenotype may carry the C4A deletion and that the
low C4 levels measured in a proportion of our MC patients may be
secondary to both complement consumption by the disease process itself
and C4A deletion. This view is also supported by preliminary results on
C4 allotyping in MC patients (data not presented) that showed an
increased frequency of C4AQ0 phenotype, thus suggesting a possible role
of class III molecules in MC susceptibility.
| |
FOOTNOTES |
Submitted February 3, 1997;
accepted November 4, 1997.
Address reprint requests to Marco Lenzi, MD, Dipartimento di Medicina
Interna, Cardioangiologia, Epatologia, Policlinico S. Orsola, via
Massarenti n° 9, 40138 Bologna, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
