|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3616-3622
Clinical Significance of HLA-DRB1*0410 in Japanese Patients With
Idiopathic Thrombocytopenic Purpura
By
Shosaku Nomura,
Tatsunori Matsuzaki,
Yoshio Ozaki,
Manabu Yamaoka,
Chie Yoshimura,
Kaoruko Katsura,
Gui Lan Xie,
Hideo Kagawa,
Tomoko Ishida, and
Shirou Fukuhara
From the First Department of Internal Medicine and the Department of
Blood Transfusion, Kansai Medical University, Osaka, Japan.
 |
ABSTRACT |
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
( 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.
| |
INTRODUCTION |
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 ( 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 chains termed allelic hypervariable regions,23
which regulate the variability of immune responses through antigen
recognition by HLA-restricted T cells. Thus, the polymorphic amino acid
residues in allelic hypervariable regions of the HLA class II molecule have been suggested to have an important role in determining
susceptibility or resistance to some autoimmune
diseases.24,25 The HLA haplotype is also regarded as a
potentially important factor in ITP,26 but its role remains
unclear.
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.
| |
MATERIALS AND METHODS |
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  OD control wells)/OD control wells × 100.
Samples with a percent increase greater than 3 SD above the mean of 20 normal plasma samples were considered to be positive.
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 2 method with continuity correction and Fisher's
exact test were used for data analysis. Relative risk was calculated according to Wolf's method with Holdane's correction. Briefly, it was
calculated as (a × d)/(b × c), where a, b, c, and d are the
number of marker-positive patients, marker-negative patients, marker-positive controls, and marker-negative controls,
respectively.39
| |
RESULTS |
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%,
2 = 11.455, P < .01). However,
anti-GPIIb/IIIa antibody was not correlated with the response to
steroid therapy.
| |
DISCUSSION |
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.
We observed an increase of DR4, DR8, DR9, and DR53 in ITP patients
compared with healthy controls, although these differences were not
statistically significant. Since HLA frequencies show racial
differences, the frequencies of DR4 and DR53 were only compared among
Japanese patients. As a result, we found an increase of DR53 in both
ITP and VKH patients, with a particularly marked increase in VKH. It
was previously found that VKH was closely associated with DR4 and DR53
by serotyping of Japanese VKH patients.41 However, the
association of DR4 and DR53 was not significant in our ITP patients.
Furthermore, no increase of DR9 or DR7, which is known to be tightly
linked to HLA-DR53, was observed in ITP patients. These results suggest
that DR53 itself is unlikely to confer susceptibility to ITP.
The serologically defined HLA-DR antigen can be divided into many
alleles reflecting polymorphism of the amino acid sequence in the
allelic hypervariable regions of the chain. For example, DRB1*04
can be divided into 11 alleles (DRB1*0401 to DRB1*0411). When we
analyzed the frequency of HLA-DR*04 alleles, the most important finding
was that DRB1*0410 was significantly increased in ITP patients compared
with healthy controls (relative risk = 9.52, P < .05). Of
further interest was the observation that all patients with DRB1*0410
were females. The immune response is stronger in females than in males,
and there is a greater prevalence of autoimmune disease in the female
population.44 Additionally, Cavan et al45 have
reported strong evidence for a sex difference in the effect of HLA
markers on disease susceptibility. However, ITP is a female-predominant disease,1,2 and the sex distribution of HLA-DRB1*0410 in our laboratory showed slight female predominance (61.2% female). Thus,
the relationship between DRB1*0410-positive ITP and female hormones
seems to deserve further study. DRB1*04 alleles have been suggested to
have an important role in determining susceptibility to several
autoimmune diseases such as insulin-dependent diabetes mellitus,24 rheumatoid arthritis,25 and
VKH.46,47 In particular, VKH appears to be strongly
associated with DRB1*04,46,47 so we compared the
frequencies of DRB1*04 alleles between our ITP and VKH patients.
We obtained the same results as in previous reports,46,47
detecting a high percentage of DRB1*0405 and DRB1*0410 (Table 4).
However, DRB1*0405 was low in ITP. To confirm the significance of
DRB1*0405 and DRB1*0410 in ITP and VKH patients, we compared DRB1*04
suballelic frequencies in ITP, VKH, and controls with DR4 positivity
(Table 5). DRB1*0410 was also significantly increased in ITP patients
compared with controls and VKH patients. The published amino acid
sequences of the polymorphic domains of DRB1 genes show that the
amino acid specific for both DRB1*0405 and DRB1*0410 is the serine at
position 57, instead of aspartic acid as in the other DRB1 alleles
(Table 8). Amino acid sequence differences among DR4-associated alleles are confined to the COOH-terminal portion
of the 1 domain, primarily within the three allelic hypervariable regions of the DRB1 gene.48,49 Hence, the polymorphic
residues in this region are believed to be critical for both T-cell
recognition and antigenic peptide binding. However, despite both
DRB1*0405 and DRB1*0410 possessing the same amino acid (serine) at
position 57, the frequency of DRB1*0405 was low in ITP patients
compared with controls. Thus, the serine at position 57 of DRB1*0410
may not play a crucial role in the immunopathology of ITP in Japanese patients.
Next, we investigated the significance of DRB1*0410 in ITP patients.
First, plasma autoantibodies were studied in 111 patients using a
microtiter well assay, which showed that 36 patients (32.4%) had
anti-GPIIb/IIIa autoantibodies. Many antiplatelet autoantibodies bind
to platelet GPIIb/IIIa.7 In particular, there have recently been investigations on the precise localization of antigenic epitopes, such as the carboxy-terminal region (C-terminus) of
GPIIIa,8 the Ca2+-dependent epitope of
GPIIb/IIIa complex,9,10 and the 50-kD cysteine-rich region
of GPIIIa.11 Bowditch et al12 concluded that a
limited number of shared epitopes on platelet GPIIb/IIIa were
recognized in ITP. In the present study, we observed a positive association of anti-GPIIb/IIIa antibody with HLA-DR4, although we could
not analyze the epitope. Thus, it seems likely that the response to the
antigenic epitope of GPIIb/IIIa is restricted by HLA-DR4.
Self-reactive T cells are controlled either by elimination in the
thymus or by induction of tolerance in the periphery.50,51 Both mechanisms depend on the ability of antigen-presenting cells to
process and present self-peptides in the context of HLA molecules, although it is now apparent that not all possible peptides from a
self-antigen are presented.52,53 These limitations in
processing suggest that T cells specific for some determinants on
self-proteins may escape tolerance and therefore remain part of the
normal T-cell repertoire. Such autoreactive T cells may only cause
pathologic conditions when the presentation of normally hidden
self-peptides occurs or when the immune system is confronted with
foreign molecular mimics. Interestingly, autoreactive T cells to
GPIIb/IIIa have been isolated from ITP patients,54,55
whereas Filion et al56 reported that autoreactive T cells
to GPIIb/IIIa are present in the peripheral blood of healthy
individuals (this may represent the condition of "anergy").
However, there was no association of anti-GPIIb/IIIa autoantibody with
DRB1*0410 in the present study. There are many epitopes recognized by
anti-GPIIb/IIIa autoantibodies,8-10 but the clinical
significance of these autoantibodies is not always clear.34
The lack of a correlation between anti-GPIIb/IIIa antibody and the
DRB1*0410 allele may suggest that this antibody does not cause ITP.
Next, we compared HLA-DR4 and DRB1*0410 distribution in patients with a
good or poor response to prednisolone. HLA-DR4, particularly DRB1*0410,
was significantly decreased in patients with a good response. There
have been various reports on the mechanism of action of steroid
hormones in ITP.1,57,58 Treatment with corticosteroids
appears to shorten the duration of thrombocytopenia by inhibiting
phagocytosis and thereby increasing the lifespan of
platelets.1,57 Steroids may also directly inhibit IgG
production and increase IgG catabolism.1,59 The inhibition
of IgG production may result from an effect of steroids on lymphocytes,
but few reports have been published on the antibodies in patients
responding poorly to steroid therapy. In the present study,
anti-GPIIb/IIIa was not correlated with the response to steroids. A
relationship between the HLA system and the outcome of therapy for ITP
was previously reported by Gratama et al.19 Their results
suggested that HLA-DR4 may predict the response to treatment, ie, a
poor response to corticosteroids and a favorable outcome of
splenectomy. However, they did not study DRB1*04 alleles. On the other
hand, Islam et al47 reported that DRB1*0405 and/or
DRB1*0410 were responsible for the chronic type of VKH. The sequences
of DRB1*0405 and DRB*0410 are identical except for amino acid 86:
glycine in DRB1*0405 and valine in DRB1*0410 (Table 8).60
Three hypervariable regions determine HLA antigenicity and possibly
most of the peptide-binding capacity of HLA proteins61;
these regions are identical between DRB1*0405 and DRB1*0410. DR4
specificity is determined primarily by the first and second hypervariable regions (amino acids 8 to 14 and 26 to 37) of the DRB1*
peptide,60 so these regions are likely to determine
susceptibility to anti-GPIIb/IIIa antibody in patients with ITP.
Although it is difficult to conclude that amino acid 86 is the
ITP-susceptibility determinant, there is a possibility that this amino
acid of HLA-DRB1*0410 plays an important role in resistance to
prednisolone therapy. However, other DRB1*0410-related genes may also
participate in steroid resistance, so further studies of this issue are
needed.
In conclusion, this was the first study to compare HLA-DR4-related
alleles in pathologic and clinical subgroups of ITP. Some antigenic
epitopes of GPIIb/IIIa seem likely to be partially restricted by
HLA-DR4, but there was no association of anti-GPIIb/IIIa autoantibody with DRB1*0410. On the other hand, DRB1*0410 was significantly decreased in patients with a good response to prednisolone. Our findings indicate that genetic factors influence the clinical course of
ITP, but this study should be considered preliminary because of
possible racial differences in the HLA status of ITP patients from
Japan and other countries.
| |
FOOTNOTES |
Submitted September 2, 1997;
accepted January 2, 1998.
Supported in part by a Research Grant for Advanced Medical Care from
the Ministry of Health and Welfare of Japan.
Address reprint requests to Shosaku Nomura, MD, The First Department of
Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho,
Moriguchi Osaka 570, Japan.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Prof Masanobu Uyama (Department of Ophthalmology,
Kansai Medical University, Osaka, Japan) for his helpful suggestions.
| |
REFERENCES |
1.
Karpatkin S:
Autoimmune thrombocytopenic purpura.
Blood
56:329,
1980[Abstract/Free Full Text]
2.
McMillan R:
Chronic idiopathic thrombocytopenic purpura.
N Engl J Med
304:1135,
1981[Medline]
[Order article via Infotrieve]
3.
Arnott J,
Horsewood P,
Kelton JG:
Measurement of platelet-associated IgG in animal models of immune and nonimmune thrombocytopenia.
Blood
69:1294,
1987[Abstract/Free Full Text]
4.
Oyaizu N,
Yasumizu R,
Miyama-Inaba M,
Nomura S,
Yoshida H,
Miyawaki S,
Shibata Y,
Mitsuoka S,
Yasunaga K,
Morii S,
Good RA,
Ikehara S:
(NZWxBXSB) F1 mouse. A new animal model of idiopathic thrombocytopenic purpura.
J Exp Med
167:2017,
1988[Abstract/Free Full Text]
5.
Woods VL,
Oh EH,
Mason D,
McMillan R:
Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP.
Blood
63:368,
1984[Abstract/Free Full Text]
6.
Woods VL,
Kurata Y,
Montgomery RR,
Tani P,
Mason D,
Oh EH,
McMillan R:
Autoantibodies against platelet glycoprotein Ib in patients with chronic immune thrombocytopenic purpura.
Blood
64:156,
1984[Abstract/Free Full Text]
7.
McMillan R,
Tani P,
Millard F,
Berchtold P,
Renshaw L,
Woods VL:
Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP.
Blood
70:1040,
1987[Abstract/Free Full Text]
8.
Fujisawa K,
O'Toole TE,
Tani P,
Lofus JC,
Plow EF,
Ginsberg MH,
McMillan R:
Autoantibodies to the presumptive cytoplasmic domain of platelet glycoprotein IIIa in patients with chronic immune thrombocytopenic purpura.
Blood
77:2207,
1991[Abstract/Free Full Text]
9.
Fujisawa K,
Tani P,
O'Toole TE,
Ginsberg MH,
McMillan R:
Different specificities of platelet-associated and plasma autoantibodies to platelet GPIIb-IIIa in patients with chronic ITP.
Blood
79:1441,
1992[Abstract/Free Full Text]
10.
Fujisawa K,
McMillan R:
Platelet-associated antibody to glycoprotein IIb/IIIa from chronic immune thrombocytopenic purpura patients often binds to divalent cation-dependent antigens.
Blood
81:1284,
1993[Abstract/Free Full Text]
11.
Kekomaki R,
Dawson B,
McFarland J,
Kunicki TJ:
Localization of human platelet autoantigens to the cysteine-rich region of glycoprotein IIIa.
J Clin Invest
88:847,
1991
12.
Bowditch RD,
Tani P,
Fong KC,
McMillan R:
Characterization of autoantigenic epitopes on platelet glycoprotein IIb/IIIa using random peptide libraries.
Blood
88:4579,
1996[Abstract/Free Full Text]
13.
Ballem PJ,
Segal GM,
Stratton JR,
Gernsheimer T,
Adamson JW,
Slichter SJ:
Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura: Evidence of both impaired platelet production and increased platelet clearance.
J Clin Invest
80:33,
1987
14.
George JN,
Woolf SH,
Raskob GE,
Wasser JS,
Aledort LM,
Ballem PJ,
Blanchette VS,
Bussel JB,
Cines DB,
Kelton JG,
Lichtin AE,
McMillan R,
Okerbloom JA,
Regan DH,
Warrier I:
Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology.
Blood
88:3,
1996[Free Full Text]
15. Bodmer WF, Bodmer J (eds): Proceedings of the Seventh
International Histocompatibility Workshop, 1977. Histocompatibility Testing. Copenhagen, Denmark, Munksgaard, 1978
16. (suppl)
Gibofsky A,
Winchester R,
Hansen J,
Patarroyo M,
Dupont B,
Paget S,
Lahita R,
Halper J,
Fotino M,
Yunis E,
Kunkel HG:
Contrasting patterns of newer histocompatibility determinants in patients with rheumatoid arthritis and systemic lupus erythematosus.
Arth Rheum
21:S133,
1978
17.
Karpatkin S:
Association of HLA-DRw2 with autoimmune thrombocytopenic purpura.
J Clin Invest
63:1085,
1979
18.
Helmerhorst FM,
Nijenhuis LE,
De Lange GG,
Van den Berg-Loonen PM,
Jansen MFM,
Von dem Borne AEGKR,
Engelfriet CP:
HLA antigens in idiopathic thrombocytopenic purpura.
Tissue Antigens
20:372,
1982[Medline]
[Order article via Infotrieve]
19.
Gratama JW,
D'Amaro J,
De Koning J,
Den Ottolander GJ:
The HLA-system in immune thrombocytopenic purpura: Its relation to the outcome of therapy.
Br J Haematol
56:287,
1984[Medline]
[Order article via Infotrieve]
20.
Porges A,
Bussel J,
Kimberly R,
Schulman I,
Pollack M,
Pandey J,
Barandun S,
Hilkartner M:
Elevation of platelet associated antibody levels in patients with chronic idiopathic thrombocytopenic purpura expressing the B8 and/or DR3 allotypes.
Tissue Antigens
26:132,
1985[Medline]
[Order article via Infotrieve]
21.
Saiki RK,
Bugawan TL,
Horn GT,
Mullis KB,
Erlich HA:
Analysis of enzymatically amplified -globin and HLA-DQ DNA with allele-specific oligonucleotide probes.
Nature
324:163,
1986[Medline]
[Order article via Infotrieve]
22.
Mullis KB,
Fallona F:
Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction.
Methods Enzymol
144:335,
1987
23.
Bell JI,
Denny DD,
Foster L,
Belt T,
Todd JA,
McDevitt HO:
Allelic variation in the DR subregion of the human major histocompatibility complex.
Proc Natl Acad Sci USA
84:6234,
1987[Abstract/Free Full Text]
24.
Todd JA,
Bell JA,
McDevitt HO:
HLA-DQ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.
Nature
329:599,
1987[Medline]
[Order article via Infotrieve]
25.
Watanabe Y,
Tokunaga K,
Matsuki K,
Takeuchi F,
Matsuta K,
Maeda H,
Omoto K,
Juji T:
Putative amino acid sequence of HLA-DRB chain contributing to rheumatoid arthritis susceptibility.
J Exp Med
169:2263,
1989[Abstract/Free Full Text]
26.
Gaiger A,
Neumeister A,
Heinzl H,
Pabinger I,
Panzer S:
HLA class-I and -II antigens in chronic idiopathic autoimmune thrombocytopenia.
Ann Hematol
68:299,
1994[Medline]
[Order article via Infotrieve]
27.
Ahn YS,
Harrington WJ:
Treatment of idiopathic thrombocytopenic purpura.
Annu Rev Med
28:299,
1977[Medline]
[Order article via Infotrieve]
28.
Imbach P,
Barandun S,
D'Appuzo V,
Baumgartner C,
Hirt A,
Morell A,
Rossi E,
Schoni M,
Vest M,
Wagner HP:
High dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood.
Lancet
2:1228,
1981[Medline]
[Order article via Infotrieve]
29.
Ahn YS,
Harrington WJ,
Simon SR,
Mylvaganam R,
Pall LM,
So AG:
Danazol for treatment of idiopathic thrombocytopenic purpura.
N Engl J Med
308:1396,
1983[Abstract]
30.
Berchtold P,
McMillan R:
Therapy of chronic idiopathic thrombocytopenic purpura in adults.
Blood
74:2309,
1989[Abstract/Free Full Text]
31.
Andersen JC:
Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy.
N Engl J Med
330:1560,
1994[Abstract/Free Full Text]
32.
Terasaki PI,
McClelland JD:
Microdroplet assay of human serum cytotoxins.
Nature
204:998,
1964[Medline]
[Order article via Infotrieve]
33.
Ota M,
Seki T,
Fukushima H,
Tsuji K,
Inoko H:
HLA DRB1 genotyping by modified PCR-RFLP method combined with group-specific primers.
Tissue Antigens
39:187,
1992[Medline]
[Order article via Infotrieve]
34.
Nomura S,
Yanabu M,
Soga T,
Kido H,
Fukuroi T,
Yamaguchi K,
Nagata H,
Kokawa T,
Yasunaga K:
Analysis of idiopathic thrombocytopenic purpura patients with antiglycoprotein IIb/IIIa or Ib autoantibodies.
Acta Haematol
86:25,
1991[Medline]
[Order article via Infotrieve]
35.
Kokawa T,
Nomura S,
Yanabu M,
Yasunaga K:
Detection of platelet antigen for antiplatelet antibodies in idiopathic thrombocytopenic purpura by flow cytometry, antigen-capture ELISA, and immunoblotting: A comparative study.
Eur J Haematol
50:74,
1993[Medline]
[Order article via Infotrieve]
36.
Nomura S,
Nagata H,
Oda K,
Kokawa T,
Yasunaga K:
Effects of EDTA on the membrane glycoprotein IIb-IIIa complex Analysis using flow cytometry.
Thromb Res
47:47,
1987[Medline]
[Order article via Infotrieve]
37.
Nomura S,
Suzuki M,
Kido H,
Yamaguchi K,
Fukuroi T,
Yanabu M,
Soga T,
Nagata H,
Kokawa T,
Yasunaga K:
Differences between platelet and microparticle glycoprotein IIb/IIIa.
Cytometry
13:621,
1992[Medline]
[Order article via Infotrieve]
38.
Tsubakio T,
Kurata Y,
Yonezawa T,
Kitani T:
Quantification of platelet-associated IgG with a competitive solid-phase enzyme-immunoassay.
Acta Haematol
66:251,
1981[Medline]
[Order article via Infotrieve]
39.
Thomson G:
A review of theoretical aspects of HLA and disease association.
Theor Popul Biol
20:168,
1981[Medline]
[Order article via Infotrieve]
40.
Synder DA,
Tessler HH:
Vogt-Koyanagi-Harada syndrome.
Am J Ophthalmol
90:69,
1980[Medline]
[Order article via Infotrieve]
41.
Ohno S:
Immunological aspects of Behcet's and Vogt-Koyanagi-Harada's disease.
Trans Ophthalmol Soc UK
101:335,
1981
42.
Nimer SD,
Ireland P,
Meshkinpour A,
Frane M:
An increased HLA DR2 frequency is seen in aplastic anemia patients.
Blood
84:923,
1994[Abstract/Free Full Text]
43.
Nakao S,
Takamatsu H,
Chuhjo T,
Ueda M,
Shiobara S,
Matsuda T,
Kaneshige T,
Mizoguchi H:
Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia.
Blood
84:4257,
1994[Abstract/Free Full Text]
44.
Ahmed SA,
Penhale WJ,
Talal N:
Sex hormones, immune responses, and autoimmune diseases.
Am J Pathol
121:531,
1985[Abstract]
45. Cavan DA, Penny MA, Jacobs KH, Kelly MA, Jenkins D, Mijpvic C,
Chow C, Cockram CS, Hawkins BR, Barnett AH: The HLA association with
Graves' disease is sex-specific in Hong Kong Chinese subjects. Clin
Endocrinol (Oxf) 40:63, 1994
46.
Shindo Y,
Inoko H,
Yamamoto T,
Ohno S:
HLA-DRB1 typing of Vogt-Koyanagi-Harada's disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410.
Br J Ophthalmol
78:223,
1994[Abstract/Free Full Text]
47.
Islam SMM,
Numaga J,
Fujino Y,
Hirata R,
Matsuki K,
Maeda H,
Masuda K:
HLA class II genes in Vogt-Koyanagi-Harada disease.
Invest Ophthalmol Vis Sci
35:3890,
1994[Abstract/Free Full Text]
48.
Petesdorf EW,
Smith AG,
Mickelson EM,
Martin PJ,
Hansen JA:
Ten HLA-DR alleles defined by sequence polymorphisms within the DRB1 first domain.
Immunogenetics
33:267,
1991[Medline]
[Order article via Infotrieve]
49.
Lanchbury JSS,
Hall MA,
Welsh KI,
Panayi GS:
Sequence analysis of HLA-DR4B1 subtypes: Additional first domain variability is detected by oligonucleotide hybridization and nucleotide sequencing.
Hum Immunol
27:136,
1990[Medline]
[Order article via Infotrieve]
50.
Kappler JW,
Roehm N,
Marrack P:
T cell tolerance by clonal elimination in the thymus.
Cell
49:273,
1987[Medline]
[Order article via Infotrieve]
51.
Schwartz RH:
Acquisition of immunologic tolerance.
Cell
57:1073,
1988
52.
Schild H,
Rotzschke O,
Kalbacher H,
Rammensee HG:
Limit of T cell tolerance to self proteins by peptide presentation.
Science
247:1587,
1990[Abstract/Free Full Text]
53.
Nagy Z,
Lehmann PV,
Falcioni F,
Muller S,
Adorini L:
Why peptides? Their possible role in the evolution of MHC-restricted T cell recognition.
Immunol Today
10:132,
1989[Medline]
[Order article via Infotrieve]
54.
Semple JW,
Freedman J:
Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia.
Blood
78:2619,
1991[Abstract/Free Full Text]
55.
Ware RE,
Howard TA:
Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura.
Blood
82:2137,
1993[Abstract/Free Full Text]
56.
Fillion MC,
Proulx C,
Bradley AJ,
Devine DV,
Sekaly R-P,
Decary F,
Chartrand P:
Presence in peripheral blood of healthy individuals of autoreactive T cells to a membrane antigen present on bone marrow-derived cells.
Blood
88:2144,
1996[Abstract/Free Full Text]
57.
Cines DB,
Schreiber AD:
Immune thrombocytopenia: Use of a Coombs antiglobulin test to detect IgG and C3 on platelets.
N Engl J Med
300:106,
1979[Abstract]
58.
Sartorius JA:
Steroid treatment of idiopathic thrombocytopenic purpura in children: Preliminary results of a randomized cooperative study.
Am J Pediatr Hematol Oncol
6:165,
1984[Medline]
[Order article via Infotrieve]
59.
Saxon A,
Stevens RH,
Ramer SJ,
Clements PL,
Yu DTY:
Glucocorticoids administered in vivo inhibit human suppressor T lymphocyte function and diminish B lymphocyte responsiveness in in vivo immunoglobulin synthesis.
J Clin Invest
61:922,
1977
60.
Marsh S,
Bodmer J:
HLA class II nucleotide sequences, 1992.
Hum Immunol
35:1,
1992[Medline]
[Order article via Infotrieve]
61.
Fremont DH,
Matsumura M,
Stura EA,
Peterson PA,
Wilson IA:
Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb.
Science
257:919,
1992[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Nomura, K. Ishii, N. Inami, T. Matsuzaki, M. Yamaoka, F. Urase, Y. Maeda, and S. Fukuhara
Antiglycoprotein IIb-IIIa Autoantibody in a Patient With Immune Thrombocytopenia After Cord Blood Transplantation
Clinical and Applied Thrombosis/Hemostasis,
February 1, 2009;
15(1):
123 - 124.
[PDF]
|
|
|
|
|
|
|
D. Veneri, M. Gottardi, E. Guizzardi, C. Zanuso, M. Krampera, M. Franchini, G. Emilia, M. Luppi, M. Morselli, G. Longo, et al.
Idiopathic thrombocytopenic purpura, Helicobacter pylori infection, and HLA class II alleles
Blood,
August 13, 2002;
100(5):
1925 - 1927.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. W. Yeo, S.-N. Park, Y.-S. Park, B.-D. Suh, H. Han, H.-B. Choi, and T.-G. Kim
Different Distribution of HLA Class II Alleles According to Response to Corticosteroid Therapy in Sudden Sensorineural Hearing Loss
Arch Otolaryngol Head Neck Surg,
August 1, 2001;
127(8):
945 - 949.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Miura, C. J. Thoburn, E. C. Bright, M. Sommer, S. Lefell, M. Ueda, S. Nakao, and A. D. Hess
Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD
Blood,
August 1, 2001;
98(3):
868 - 876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract