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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3616-3622
By
From the First Department of Internal Medicine and the Department of
Blood Transfusion, Kansai Medical University, Osaka, Japan.
We performed HLA-A, -B, and -C antigen and -DR DNA typing in 111 Japanese patients with idiopathic thrombocytopenic purpura (ITP).
DRB1*0410 was significantly increased in ITP patients compared with
healthy controls (relative risk = 9.52, P < .05), but
the other DRB1*04 alleles showed no significant differences. On HLA-DR serotyping, patients with Vogt-Koyanagi-Harada disease (VKH) had a high
frequency of DR4, so we compared the frequencies of DRB1*04 suballeles
between ITP and VKH. The high frequency of DRB1*04 was dependent on
DRB1*0405 in VKH, but on DRB1*0410 in ITP. Plasma autoantibodies were
studied in 111 patients using a microtiter well assay. Thirty-six
patients had anti-GPIIb/IIIa autoantibodies, and antibody positivity
was associated with HLA-DR4 (29 of 36, 80.6% v 28 of 75, 37.3%) but not with DRB1*0410. When HLA-DR4 and DRB1*0410 were
compared between patients with a good or poor response to prednisolone,
HLA-DR4 was decreased and DRB1*0410 was significantly decreased
(
IDIOPATHIC THROMBOCYTOPENIC purpura (ITP)
is a disease caused by circulating autoantibodies that react with the
platelet membrane.1,2 It is thought that
platelet-associated IgG is an important factor in the mechanism of ITP,
since an increase of such IgG is closely related to a reduced platelet
count in this disease.1-4 Although the platelet surface
antigens corresponding to the antiplatelet autoantibodies involved in
ITP are largely unknown, there have been several recent reports on
autoantibodies to glycoprotein (GP)IIb/IIIa and GPIb,5-7
and the antigens for these GPs are gradually being
elucidated.8-12 Thus, the mechanism related to thrombocytopenia is becoming clear,13,14 but the etiology
of ITP remains uncertain, with both genetic and environmental factors apparently involved. Based on serologic studies, associations between
certain HLAs and many autoimmune diseases have long been described.15,16 Several groups have tried to establish a
relationship between HLA class I or HLA-DR and chronic
ITP.17-20 However, the results have been inconsistent,
possibly because only a limited number of HLA-DR antigens could be
determined serologically in the past.17-20
With the development of the polymerase chain reaction (PCR),
identification of HLA alleles at the DNA level has become possible and
has allowed more precise determination of the susceptibility epitopes
showing a strong association with various autoimmune diseases.21,22 The HLA class II region encodes the
heterodimeric ( Although various methods have been used for the treatment of chronic
ITP,27-31 splenectomy and administration of
corticosteroids are still the mainstays of therapy.1,2
However, no parameters have been found to predict the response to
treatment. In this study, we performed HLA-A, -B, and -C antigen and
-DR DNA typing of Japanese ITP patients and investigated the HLA-DR4
gene variations in several clinical or pathologic subtypes of ITP. Our
purpose was to determine whether anti-GPIIb/IIIa autoantibodies and the response to corticosteroid therapy are associated with specific HLA
systems.
Subjects.
We studied 111 unrelated Japanese patients (29 men and 82 women) with
ITP who presented to our hospital from April 1994 to December 1996. The
diagnosis of ITP was made according to the standard criteria of
thrombocytopenia with a normal or increased number of megakaryocytes
and no evidence of any secondary cause of thrombocytopenia. The
subjects were aged 22 to 78 years, and none had received a blood
transfusion. Table 1 shows a brief clinical profile of
the 111 ITP patients. Seventy-one controls were also randomly selected
from among healthy unrelated Japanese individuals. Furthermore, 53 Japanese patients with Vogt-Koyanagi-Harada disease (VKH) were studied
as disease controls. Approval was obtained from the Institutional
Review Board for these studies. Informed consent was provided according
to the Declaration of Helsinki.
Treatment.
Prednisolone was administered first at a dose of 0.5 to 1 mg/kg daily.
The response of each patient was assessed from the change in the
platelet count at 6 months after starting therapy. A good response was
defined as an increase in the platelet count of greater than 50 × 109/L, a platelet count greater than 100 × 109/L off therapy, and no more than one relapse during
follow-up study. A poor response was defined as an increase in the
platelet count of less than 50 × 109/L. Relapse was
defined as a decrease in the platelet count to less than 50 × 109/L after a normal count had been reached. The duration
of follow-up study was at least 6 months from the start of
therapy.
HLA serotyping.
ITP patients and healthy controls were subjected to serotyping for HLA
class I and class II antigens using the standard complement-dependent microcytotoxicity method.32
HLA DNA typing by PCR-restriction fragment length polymorphism.
HLA DNA typing was performed according to the manufacturer's
instructions (SMITEST HLA DNA-typing system; Sumitomo Metal, Tokyo,
Japan). Genomic DNA from patients and controls was isolated by phenol
extraction of sodium dodecyl sulfate-lysed and proteinase K-treated
cells. DNA was amplified by the PCR procedure with Taq DNA polymerase
and typed by the PCR-restriction fragment length polymorphism (RFLP)
method.33 The reaction mixture was subjected to 30 cycles
of denaturation for 1 minute at 96° to 97°C, annealing for 1 minute
at 55° to 62°C, and extension for 2 minutes at 72°C in an
automated PCR thermal sequencer (Iwaki Glass Inc, Tokyo, Japan). After
amplification, aliquots of the reaction mixture were digested with
allele-specific restriction endonucleases for 3 hours after addition of
the appropriate reaction buffer. Samples of the cleaved and amplified
DNAs were subjected to electrophoresis on 12% polyacrylamide gel in a
minigel apparatus (Mupid-2; Cosmo Bio Co, Tokyo, Japan). Cleavage or
noncleavage of amplified fragments was detected by staining with
ethidium bromide. Discrimination of genotypes was made on the basis of
RFLP band patterns thus generated.
Detection of plasma autoantibodies against GPIIb/IIIa by microtiter
well assay.
The assay was previously described by Nomura et al34 and
Kokawa et al.35 A suspension of washed platelets
(1 × 107/µL) in 100 µg/mL leupeptin and 10 mmol/L
EDTA was sonicated on ice and centrifuged at 12,500g for 30 minutes. The supernatant was solubilized in 2% Triton X-100 and
centrifuged at 100,000g for 30 minutes to remove the Triton
X-100-insoluble fraction. After centrifugation, the supernatant was
used as the platelet lysate. Autoantibodies were assayed by a
modification of the method of Woods et al.5,6 In brief,
microtiter wells were coated with a monoclonal anti-GPIIb/IIIa antibody
(NNKY1-32)36,37 by overnight incubation. The platelet
lysate was then added to microtiter wells and incubated. After washing,
appropriate dilutions of plasma from ITP patients (n = 111), disease
controls (n = 30), or normal controls (n = 20) were added and
incubated. After washing again, horseradish peroxidase-conjugated
rabbit anti-human IgG was added, and the amount of IgG that bound to
the platelets was determined by measuring peroxidase activity using a
plate reader. Assay results were expressed in terms of the percent
change in peroxidase activity above or below the level in control
(normal serum) wells, using the following formula: percent change = (OD platelet extract wells Assay of platelet-associated IgG.
A competitive enzyme-linked immunosorbent assay was used to quantify
platelet-associated IgG (PAIgG) in patients with ITP.38 The
upper limit of normal was 25 ng/107 platelets.
Statistical analysis.
The HLA-DR serotyping.
The frequency of the HLA-DR antigens and the relative risk were
calculated in 111 unrelated Japanese ITP patients and 71 unrelated Japanese controls (Table 2). DR8, DR9, and
DR53 were increased in ITP patients compared with healthy controls
(relative risk > 1.50). On the other hand, DR1, DR6, and DR52 were
decreased in ITP patients compared with healthy controls (relative
risk < 0.50). However, these differences were not statistically
significant. The frequencies of DR4 and DR53 were high in both healthy
controls and ITP patients. It is thought that DR53 is associated with
DR4, DR7, and DR9. Because there are racial differences in HLA
frequency, we studied HLA frequencies in VKH patients as Japanese
disease controls. VKH is an inflammatory disease affecting multiple
organs, causing bilateral panuveitis, meningitis, hearing loss,
tinnitus, and vitiligo.40 It was previously reported that
VKH is closely associated with DR4 and DR53 by HLA serotyping of
Japanese patients.41 In the present study, DR4 and DR53
were also found in almost all VKH patients examined (94.3%).
HLA DNA typing.
Based on the serologic data, we performed DNA typing of DR4, DR8, and
DR9. HLA-DRB1 genotyping was performed by the PCR-RFLP method. DRB1*04
(DR4), *08 (DR8), and *09 (DR9) allele frequencies in ITP patients and
healthy controls are shown in Table 3.DRB1*0410 was significantly increased in ITP patients compared with
healthy controls (relative risk = 9.52, P < .05).
However, none of the other alleles (DRB1*04, *08, and *09) showed a
significant difference between ITP patients and healthy controls.
HLA-DR serotyping showed that VKH patients had a high frequency of DR4,
so we compared the frequency of DRB1*04 suballeles between ITP and VKH
patients. Using the International Histocompatibility Workshop (1984)
definitions, HLA-DR4 was classified as DR4.1 and DR4.2 subgroups with
panel sera. We then compared DRB1*04 suballeles in these two subgroups among ITP patients, VKH patients, and controls (Table
4). ITP patients showed an increase of
DR4.1 subgroup alleles and a decrease of the DR4.2 subgroup. VKH
patients also showed an increase of the DR4.1 subgroup. The high
frequency of DR4.1 was dependent on DRB1*0405 in VKH patients, but was
related to DRB1*0410 in ITP patients. Among 71 healthy controls, 34 had
DRB1*04 (DR4). To analyze the suballelic distribution of DRB1*04 (DR4)
more precisely in ITP and VKH patients, we investigated the DRB1*04
frequency in DR4-positive patients alone (Table 5).
DRB1*0410 was again significantly increased in ITP
patients compared with VKH patients and healthy controls.
Characteristics of HLA-DRB1*0410-positive ITP patients.
Table 6 shows the clinical
characteristics of HLA-DRB1*0410-positive ITP patients. All of them
were female, and six had the homotype DRB1*0410; however, these six
patients did not have any common distinguishing characteristics. The
sex distribution of HLA-DRB1*0410 in our laboratory showed a slight
female predominance (61.2% female), but there were no family members
with HLA-DRB1*0410 and ITP. Furthermore, the frequencies of HLA-A or
HLA-B antigens were not different from those in the controls. Plasma
autoantibodies were studied in 111 ITP patients using a microtiter well
assay, and 36 patients (32.4%) had anti-GPIIb/IIIa autoantibodies.
Table 7 shows the association of HLA-DR4 with
autoantibodies to GPIIb/IIIa. There was a positive association between
anti-GPIIb/IIIa antibodies and HLA-DR4 (29 of 36, 80.6% v 28 of 75, 37.3%), but there was no association with DRB1*0410. HLA-DR4
and DRB1*0410 were compared in patients with a good or poor response to
prednisolone (Table 7). HLA-DR4 was slightly decreased in patients with
a good response to prednisolone (poor v good, 22 of 54, 59.3%
v 25 of 57, 43.9%), and DRB1*0410 was significantly decreased
(poor v good, 21 of 54, 38.9% v 3 of 57, 5.3%,
ITP is a clinically well-defined autoimmune disease caused by
antiplatelet antibodies, and the antigenic epitope has recently been
studied in detail, revealing that the main epitope contains GPIIb/IIIa.7-12 Various autoimmune diseases are associated
with HLA class I and/or class II, and thus several groups have
investigated the role of HLA class I and HLA-DR in
ITP.18-20 However, the findings have been inconsistent,
possibly because only a limited number of HLA-DR antigens could be
determined serologically in the past.18,20 The
polymorphisms of class II genes (HLA-DR, -DQ, and -DP) in the major
histocompatibility complex can now be defined precisely by typing using
the PCR-RFLP method. It was previously reported that patients with
aplastic anemia who possess HLA-DR2 are more likely to respond to
immunosuppressive therapy.42,43 Thus, analysis of HLA
antigens and alleles may provide useful information for the treatment
of autoimmune diseases. In the present study, we performed HLA typing
of Japanese ITP patients to determine whether positivity for
anti-GPIIb/IIIa antibodies and the response to corticosteroid therapy
are associated with specific HLA systems.
Submitted September 2, 1997;
accepted January 2, 1998.
The authors thank Prof Masanobu Uyama (Department of Ophthalmology,
Kansai Medical University, Osaka, Japan) for his helpful suggestions.
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|
Abstract
Introduction
2 = 11.455, P < .01) in patients with a
good response. In conclusion, this study showed that genetically
determined factors influence the course of ITP. However, our findings
should be considered preliminary because of possible racial differences
in HLA status between Japanese and other ITP patients.
Abstract
and 
chains) GPs expressed on the surface of
antigen-presenting cells in the immune system. The T-cell receptor
interacts with a complex formed by the antigenic peptide fragment bound
by HLA molecules on antigen-presenting cells. The genetic polymorphism of class II molecules is known to be clustered in discrete regions of
the 
OD control wells)/OD control wells × 100.
Analysis using flow cytometry.
Thromb Res
47:47,
1987