close

Вход

Забыли?

вход по аккаунту

?

High titer of serum antiphospholipid antibody levels in adult Henoch-Schnlein purpura and cutaneous leukocytoclastic angiitis.

код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 4, April 15, 2008, pp 561–567
DOI 10.1002/art.23528
© 2008, American College of Rheumatology
ORIGINAL ARTICLE
High Titer of Serum Antiphospholipid Antibody
Levels in Adult Henoch-Schönlein Purpura and
Cutaneous Leukocytoclastic Angiitis
TAMIHIRO KAWAKAMI,1 MASAHIDE YAMAZAKI,2 MASAKO MIZOGUCHI,1
AND
YOSHINAO SOMA1
Objective. To investigate a possible role of antiphospholipid (aPL) antibodies in adult Henoch-Schönlein purpura (HSP)
and cutaneous leukocytoclastic angiitis (CLA).
Methods. We reviewed the records of 30 HSP and 8 CLA adults with an initial cutaneous manifestation of palpable
purpura on their lower extremities between 2003 and 2007. Eight microscopic polyangiitis (MPA) patients and 30 healthy
persons were recruited as controls. Serum anticardiolipin (aCL), anti–phosphatidylserine-prothrombin complex (antiPS/PT), and anti–␤2-glycoprotein I (anti-␤2GPI) antibody levels in HSP, CLA, MPA patients, and healthy controls were
measured by enzyme-linked immunosorbent assay.
Results. Twenty-two HSP patients (73%) were positive for serum IgA aCL antibodies. Nineteen (63%) had IgA anti-PS/PT
antibodies and 4 (13%) had IgA anti-␤2GPI antibodies. IgA aCL and anti-PS/PT antibodies showed a significant correlation (P ⴝ 0.007). Twenty (67%) HSP patients had IgM anti-PS/PT antibodies and 6 (20%) had IgG anti-PS/PT antibodies.
Six (75%) CLA patients had IgM anti-PS/PT antibodies and 2 (25%) had IgG anti-PS/PT antibodies. In contrast, aPL
antibodies were not found in any MPA patients or normal controls. Serum IgA aCL antibody levels in HSP patients
showed a significant correlation with serum IgA and C-reactive protein (CRP) levels (P ⴝ 0.030 and 0.039, respectively).
A positive correlation between CRP and serum IgA anti-PS/PT antibody levels was observed in HSP patients (P ⴝ 0.023).
Serum IgA aCL antibody levels were also significantly associated with proteinuria according to urinalysis (P ⴝ 0.024).
Conclusion. Serum levels of IgA aCL and anti-PS/PT antibodies were elevated in adult HSP, suggesting that serum IgA
antibodies may play some role in adult HSP. IgA aCL and/or anti-PS/PT antibodies could serve as markers for adult HSP
and should be monitored as an indicator of adult HSP activity. Small-vessel vasculitis could be dependently associated
with the presence of IgM anti-PS/PT antibodies. These findings suggest that aPL antibodies are closely related to the
pathogenic factors that trigger the development of vasculitis.
INTRODUCTION
Henoch-Schönlein purpura (HSP) is characterized by palpable nonthrombocytopenic purpura over the lower extremities, arthritis, abdominal pain with or without gastrointestinal hemorrhage, and, less commonly, glomerulo-
Supported by grants from the Scientific Research Fund of
the Ministry of Education, Science, Sports and Culture, Japan (Grant-in Aid for Scientific Research, 16591121 and
18591261).
1
Tamihiro Kawakami, MD, PhD, Masako Mizoguchi, MD,
PhD, Yoshinao Soma, MD, PhD: St. Marianna University
School of Medicine, Kawasaki, Japan; 2Masahide Yamazaki, MD, PhD: Kanazawa University Graduate School of
Medical Science, Kanazawa, Japan.
Address correspondence to Tamihiro Kawakami, MD,
PhD, Department of Dermatology, St. Marianna University
School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki,
Kanagawa 216-8511, Japan. E-mail: tami@marianna-u.ac.jp.
Submitted for publication June 26, 2007; accepted in revised form September 26, 2007.
nephritis. Histologically, HSP reveals leukocytoclastic
vasculitis, and has been well regarded as a specific clinicopathologic entity based on the vascular deposition of
IgA-dominant immune complexes (ICs) (1,2). HSP in
adulthood differs from the pediatric form of the disease.
Adults have more pronounced skin lesions, and renal involvement is more frequent than in childhood (3,4). The
pathogenesis of HSP remains poorly understood. The similarity of the histologic findings in HSP to those of Arthus
reaction suggests an IgA IC–mediated disorder (5). Arthus
reaction results from the deposition of ICs in the small
blood vessels of the skin, glomeruli, and gastrointestinal
tract and the subsequent activation of inflammatory responses to these complexes. This reaction has served as
the basis for dissecting the cellular and molecular events
that are triggered by IC deposition and serves as the basis
for our understanding of the pathophysiology of ICmediated diseases. HSP has been associated with a history
of preceding infection, particularly upper respiratory tract
infection (URI). IgA is the principal antibody in the respi561
562
ratory system for defense against microbial agents. These
findings raise the possibility of infection as a direct cause
or a potential trigger of HSP. It has been postulated that
various antigenic stimuli cause an elevation of circulating
IgA and that complement activation leads to vasculitis.
However, no definitive pathogen has been isolated from
the majority of patients with HSP.
We have previously shown high serum levels of IgA
anticardiolipin (aCL) in adult HSP, suggesting that serum IgA aCL antibodies may play some role in the
pathogenesis (6). Antiphospholipid (aPL) antibodies
are a heterogeneous group of immunoglobulins that
bind to several anionic phospholipids including cardiolipin and phosphatidylserine (7,8). Most aPL antibodies require a serum cofactor, ␤2-glycoprotein I
(␤2GPI), for optimal binding (9 –12). It has been shown
that many aPL antibodies may react to a neoepitope
formed on the ␤2GPI molecule by the interaction between the phospholipid and ␤2GPI (13,14). Detection of
aPL cofactor antibodies, in addition to the classic aCL
antibodies, seems to be of considerable clinical importance. Prothrombin is another possible antigenic target
of antiphospholipid syndrome (15). Atsumi et al (16)
and Amengual et al (17) suggested that anti–phosphatidylserine-prothrombin complex (anti-PS/PT) antibodies alone,
rather than antiprothrombin antibodies, are associated
with symptoms of antiphospholipid syndrome.
Small-vessel vasculitides are a group of inflammatory
diseases that affect the arterioles, venules, and capillaries.
These vasculitides can be divided into pauci-immune
vasculitides associated with antineutrophil cytoplasmic
antibodies (ANCAs) and immune deposit-associated
vasculitides. The ANCA-associated vasculitides include
microscopic polyangiitis (MPA), and HSP represents immune deposit-associated small-vessel vasculitides. The
Chapel Hill Consensus Conference (CHCC) on the Nomenclature of Systemic Vasculitis defined the term cutaneous leukocytoclastic angiitis (CLA) as isolated cutaneous leukocytoclastic angiitis without systemic vasculitis
or glomerulonephritis (2). Thus, for the diagnosis of CLA,
systemic involvement must be excluded (18). The diagnosis is one of exclusion because evidence of systemic vasculitic disease apart from arthralgias must be absent (19).
In the present study, we diagnosed patients who did not
have systemic vasculitis for at least 2 years during followup of CLA.
To investigate the aPL antibodies of patients with HSP,
CLA, and MPA, we examined the prevalence of aCL antibodies, anti-PS/PT antibodies, and anti-␤2GPI antibodies
in 30 patients with HSP, 8 patients with CLA, and 8
patients with MPA. Furthermore, we investigated whether
these antibodies are closely correlated with clinical or
serologic features, which could indicate that IgA aCL and
IgA anti-PS/PT antibodies could play a significant role in
the pathogenesis of HSP.
PATIENTS AND METHODS
Clinical investigation and tissue samples. Thirty Japanese patients with HSP (15 men, 15 women, mean ⫾ SD
Kawakami et al
age 56.4 ⫾ 20.1 years), 8 with CLA (6 men, 2 women,
mean ⫾ SD age 56.6 ⫾ 19.1 years), and 8 with MPA (4 men,
4 women, mean ⫾ SD age 62.9 ⫾ 17.3 years) seen at the
Department of Dermatology, St. Marianna University
School of Medicine between 2003 and 2007 were examined. Patients presented with typical characteristics of
nonthrombocytopenic symmetric palpable purpura over
the lower extremities, and other conditions such as connective tissue diseases and infections had been excluded.
Skin biopsy samples were obtained from patients during
an active phase of their disease. Two skin biopsy samples
from each of the 30 HSP and 8 CLA patients were taken for
routine and direct immunofluorescence (DIF) staining according to standard procedures. All biopsy samples were
taken from the lower extremities. The tissue section was
incubated with commercially prepared fluoresceinated antisera specific to human IgG, IgM, IgA, or C3. Each of the
skin biopsy samples showed fibrinoid necrosis, an admixture of neutrophils and lymphocytes in and around the
blood vessels, intravascular fibrin thrombi, and nuclear
dust characteristics of leukocytoclastic vasculitis in the
upper and middle dermis. Based on DIF of the skin biopsy
samples, vascular deposits of IgA in the dermis led to the
diagnosis of HSP. The following selection criteria for HSP
were used in the study: the presence of a leukocytoclastic
vasculitis and vascular IgA and the absence of thrombocytopenia or known hematologic or connective tissue disorders. CLA is an isolated vasculitis limited to skin, and
systemic involvement must be excluded. Apart from arthralgia, no systemic manifestations were observed after a
minimum followup of 2 years. Eight MPA patients were
diagnosed according to the CHCC definition (2), Sørensen
et al criteria (20), and Japanese criteria (21).
None of the patients had been given corticosteroids,
immunosuppressants, or vasodilators at the time of serum
sampling. Furthermore, no patient demonstrated any evidence of coexisting malignancy, other autoimmune diseases, or viral hepatitis, nor were any of the patients positive for mixed cryoglobulinemia. Thirty healthy persons
with comparable sex and age distributions were recruited
as normal controls. The following tests were negative or
within the normal range in the HSP and CLA patients:
antinuclear antibodies, ANCAs, and virus serology including hepatitis A, B, and C.
Serologic studies. The first immunologic assessments
were performed on the serum collected at the same time as
the skin biopsy samples. IgG, IgM, and IgA isotypes of
anti-PS/PT antibodies and IgG, IgM, and IgA aCL antibodies were measured with a specific enzyme-linked immunosorbent assay (ELISA; Medical & Biological Laboratories, Nagoya, Japan) according to the manufacturer’s
protocol. Briefly, the serum samples were diluted 1:101,
added to 96-well plates coated with PS/PT or aCL, and
incubated for 1 hour at 20°C. Polyclonal gout anti-human
IgG, IgM, and IgA antibodies labeled with horseradish
peroxidase were used as conjugate solutions to recognize
the 3 isotypes of PS/PT or aCL antibodies. Color was
developed with 3,3⬘,5,5⬘-tetramethylbenzidine and H2O2
and the plates were read at 450 nm. IgA anti-␤2GPI anti-
aPL Antibodies in HSP and Cutaneous Leukocytoclastic Angiitis
563
Table 1. Clinical, serologic, and DIF features in 30 patients with Henoch-Schönlein purpura*
Patient
no.
Age
Sex
IgA aCL
(APL)
IgA PS/PT
(units/ml)
IgA ␤2GPI
(units/ml)
IgM PS/PT
(units/ml)
IgG PS/PT
(units/ml)
CRP
(mg/dl)
IgA
(mg/dl)
DIF with IgA
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
75
44
65
79
62
72
81
79
68
72
19
57
41
69
61
64
38
34
32
28
44
58
50
39
81
24
80
22
72
82
M
F
M
F
M
M
F
M
M
M
F
F
M
F
M
M
F
M
F
M
M
F
F
F
M
F
M
F
F
F
18
11
21
16
11
16
24
11
24
–
11
11
–
11
18
12
11
12
13
13
13
11
15
–
13
–
–
–
–
–
18
14
42
14
13
–
–
14
110
18
11
–
17
24
10
96
12
14
–
16
13
–
12
–
32
–
–
–
–
–
–
–
11
–
–
–
–
18
–
–
–
–
–
–
60
–
–
–
–
–
–
–
–
18
–
–
–
–
–
–
10
29
23
26
–
23
–
10
–
10
23
11
–
–
–
15
24
–
20
28
–
16
–
16
10
12
11
17
10
–
45
–
–
–
–
29
–
–
28
–
–
–
–
–
25
120
20
–
–
–
–
–
–
–
–
–
–
–
–
–
4.0
3.0
2.9
2.1
4.68
1.85
2.0
7.4
2.1
1.27
3.0
3.8
0.7
25.99
16.9
8.4
3.14
1.6
3.3
6.2
2.14
2.0
3.0
3.6
4.9
1.35
2.0
1.0
0.9
0.33
559
474
805
591
532
427
758
575
855
520
241
424
351
429
961
337
708
260
177
181
204
550
525
643
675
227
474
503
295
329
IgG, IgM, C3
C3
–
IgM
C3
IgM, C3
IgM, C3
–
–
C3
IgM, C3
C3
IgM, C3
C3
C3
IgM, C3
IgM, C3
IgM, C3
IgM, C3
C3
IgM, C3
C3
C3
IgM, C3
IgM, C3
–
C3
C3
C3
IgM, C3
* DIF ⫽ direct immunofluorescence; aCL ⫽ anticardiolipin antibodies; APL ⫽ IgA phospholipid units; PS/PT ⫽ phosphatidylserine-prothrombin
complex; ␤2GPI ⫽ ␤2-glycoprotein I; CRP ⫽ C-reactive protein.
bodies were measured with a specific ELISA (Bio-Rad
Laboratories, Hercules, CA) according to the manufacturer’s protocol. IgG and IgM anti-␤2GPI antibodies were determined according to the standardized anti-␤2GPI antibody ELISA (Diagnostica Stago, Asnieres, France). The
cutoff points were established by the mean ⫹5 SD of 50
controls. The following cutoff values were used: 12 units/
ml, 10 units/ml, and 10 units/ml for IgG, IgM, and IgA
anti-PS/PT antibodies, respectively; 10 IgG phospholipid
units, 10 IgM phospholipid units, and 10 IgA phospholipid units (APL units) for IgG, IgM, and IgA aCL antibodies, respectively; and 10 units/ml, 10 units/ml, and 10
units/ml for IgG, IgM, and IgA anti-␤2GPI antibodies, respectively. When ANCA was detected, specificity was
characterized by ELISA for reactivity with myeloperoxidase or proteinase 3, using the technique recommended by
the European ANCA Assay Standardization Group (22).
All serum samples were stored at ⫺70°C prior to assay.
Serum IgA and C-reactive protein (CRP) levels were assayed with laser nephelometry (Nihon Kohden, Tokyo,
Japan).
Statistical analysis. Kolmogorov-Smirnov test with Lilliefors significance level was used to evaluate age, serum
aPL antibodies, serum CRP level, and serum IgA. Statisti-
cal analyses were performed using the Mann-Whitney U
test for comparisons of serum aPL antibody levels. The
Mann-Whitney U test was also used to compare blood
parameter levels between positive and negative clinical
symptoms (proteinuria, arthralgia, abdominal pain, and
URI); the level of significance was set at P ⬍ 0.05 in all
cases. The correlation between serum IgA or CRP level and
variation of the blood parameters was assessed by Spearman’s rank correlation test. All data are expressed as the
mean ⫾ SD.
The experimental protocol was approved by St. Marianna University, and informed consent was obtained from
all patients (No. 1117).
RESULTS
IgA aCL antibodies, IgA anti-PS/PT antibodies, and/or IgA
anti-␤2GPI antibodies were present in 25 (83%) of the 30
HSP patients; IgA aCL antibodies alone were present in 5
patients, IgA anti-PS/PT antibodies alone were present in
2 patients, and a combination of both types of antibodies
was present in 17 patients (Table 1). IgA aCL antibodies
were found in 22 (73%) of the 30 HSP patients, IgA antiPS/PT antibodies were found in 19 (63%), and IgA anti-
564
Kawakami et al
Table 2. Clinical, serologic, and DIF features in 8 patients with cutaneous leukocytoclastic angiitis
Patient
no.
Age
Sex
IgA aCL
(APL)
IgA PS/PT
(units/ml)
IgA ␤2GPI
(units/ml)
IgM PS/PT
(units/ml)
IgG PS/PT
(units/ml)
CRP
(mg/dl)
IgA
(mg/dl)
DIF
1
2
3
4
5
6
7
8
32
77
55
52
77
40
80
40
M
M
F
M
M
F
M
M
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
16
18
13
–
21
10
–
16
–
–
–
–
14
–
–
12
0.16
3.2
0.6
3.0
1.1
0.08
0.3
3.1
239
392
121
364
253
187
221
350
IgM
C3
C3
–
IgG
–
–
C3
* See Table 1 for definitions.
␤2GPI antibodies were found in 4 (13%). Of the 4 HSP
patients with IgA anti-␤2GPI antibodies, 3 were found to
be positive for IgA aCL antibodies and IgA anti-PS/PT
antibodies. IgA aCL antibodies, IgA anti-PS/PT antibodies,
and IgA anti-␤2GPI antibodies were not found in the serum
of the CLA patients (Table 2), the MPA patients, or the
healthy controls. Twenty (67%) of the HSP patients had
positive titers for IgM anti-PS/PT antibodies and 6 (20%)
had positive titers for IgG anti-PS/PT antibodies. By contrast, 6 (75%) of the 8 CLA patients were positive for IgM
anti-PS/PT antibodies and 2 (25%) were positive for IgG
anti-PS/PT antibodies. Serum IgA aCL levels were significantly elevated in all HSP patients (mean ⫾ SD 12.1 ⫾ 5.3
APL) in comparison with those of the CLA patients
(mean ⫾ SD 4.8 ⫾ 2.4 APL) (Figure 1A). Serum IgA antiPS/PT levels were also significantly higher among the HSP
patients (mean ⫾ SD 18.5 ⫾ 24.6 units/ml) than the CLA
patients (4.4 ⫾ 2.2 units/ml) (Figure 1B). The titers for IgM
anti-PS/PT antibodies were similar between the HSP patients (mean ⫾ SD 13.1 ⫾ 8.1 units/ml) and CLA patients
(13.6 ⫾ 5.0 units/ml), whereas these values were significantly higher than those of the MPA patients and normal
controls (Figure 1C). Levels of IgA anti-␤2GPI antibodies
(mean ⫾ SD 6.6 ⫾ 10.9 units/ml versus 3.8 ⫾ 2.1 units/ml)
and IgG anti-PS/PT antibodies (mean ⫾ SD 12.8 ⫾ 22.7
units/ml versus 5.5 ⫾ 4.7 units/ml) were not significantly
different between HSP patients and CLA patients. Laboratory investigations in the HSP patients revealed elevated
serum IgA (mean ⫾ SD 486.3 ⫾ 206.7 mg/dl), as well as
elevated CRP levels (mean ⫾ SD 4.2 ⫾ 5.2 mg/dl). We
found a significant correlation between serum IgA aCL
antibodies and IgA anti-PS/PT antibodies in our HSP patients (rs ⫽ 0.50, P ⫽ 0.007) (Figure 2).
There was a significant positive correlation between serum IgA aCL antibodies and IgA levels (rs ⫽ 0.40, P ⫽
0.030) (Table 3). A similar correlation was also seen between IgA aCL antibodies and CRP levels (rs ⫽ 0.38, P ⫽
0.039). In addition, there was a positive correlation between serum IgA anti-PS/PT antibodies and CRP level
(rs ⫽ 0.42, P ⫽ 0.023). The IgA anti-␤2GPI titer was significantly correlated with serum IgA and CRP level (rs ⫽ 0.52,
P ⫽ 0.005 and rs ⫽ 0.44, P ⫽ 0.020, respectively). IgG
anti-PS/PT antibodies were positively correlated with serum IgA (rs ⫽ 0.46, P ⫽ 0.014). Proteinuria according to
urinalysis was noted in 24 (80%) of the 30 HSP patients.
Serum IgA aCL antibody; IgG, IgM, and IgA anti-PS/PT
antibody; and IgA anti-␤2GPI antibody concentrations in
relation to the presence or absence of proteinuria in the
HSP patients are listed in Table 4. Serum IgA aCL antibody
levels differed significantly between the proteinuriapositive and proteinuria-negative HSP patients (P ⫽
0.024). A similar trend was seen with respect to IgG antiPS/PT antibodies (P ⫽ 0.045). Serum IgA aCL antibody,
IgA anti-PS/PT antibody, and IgA anti-␤2GPI antibody levels did not differ significantly between the HSP patients
who were positive or negative for arthralgia, abdominal
pain, and URI. There was no significant correlation between IgM anti-PS/PT antibody in our CLA patients and
arthralgia and URI.
HSP is defined as deposition of IgA into the dermal
vessels as measured by DIF. In addition, DIF revealed C3
within the affected vessels in 25 (83%) of 30 HSP patients,
IgM in 14 (47%), and IgG in 2 (6.7%). Patients 1 and 16 of
the HSP patients with IgG deposits showed high serum
levels of IgG anti-PS/PT antibody. We found no association between IgA alone (with or without C3) and IgG
and/or IgM in the DIF testing. In the CLA biopsy samples,
we found C3 deposits in 3 (38%) of the 8 patients, IgM in
1 (13%), and/or IgG in 1 (13%).
DISCUSSION
Twenty-two (73%) of our 30 Japanese adult HSP patients
were positive for serum levels of IgA aCL antibodies. IgA
aCL titers in the adult HSP patients were significantly
higher than those in the 8 CLA patients, 8 MPA patients,
and 30 normal controls. In a previous study, 21 (81%) of
26 Chinese children with HSP had a higher prevalence of
IgA aCL than healthy and juvenile rheumatoid arthritis
control patients (23). In the present study, there was a
significantly greater presence of IgA anti-PS/PT antibodies
in the HSP patients compared with the CLA patients, MPA
patients, and normal controls. In addition, IgA aCL antibodies and IgA anti-PS/PT antibodies were significantly
correlated. We also found that there was a significant positive correlation between serum IgA aCL antibodies and
serum IgA level. IgA abnormalities suggest an immunologic basis for the pathogenetic mechanisms underlying
HSP (23,24). Elevated serum IgA aCL antibody and/or IgA
anti-PS/PT antibody levels may imply involvement of im-
aPL Antibodies in HSP and Cutaneous Leukocytoclastic Angiitis
565
Figure 1. A, IgA anticardiolipin antibodies (aCL; antiphospholipid units), B,
IgA anti–phosphatidylserine-prothrombin
complex (anti-PS/PT; units/ml) antibody
levels expressed as relative optical density, and C, IgM anti-PS/PT antibody
levels (units/ml) were measured by ELISA
in serum samples from normal controls
and patients with Henoch-Schönlein purpura (HSP), cutaneous leukocytoclastic angiitis (CLA), and microscopic polyangiitis
(MPA). The detection limit was 5 units/ml
and the cutoff value was 10 units/ml. Horizontal lines indicate the mean value in
each group.
566
Kawakami et al
Table 4. Serum antiphospholipid antibody (aPL)
concentrations associated with proteinuria in 30 patients
with Henoch-Schönlein purpura*
Serum aPL antibodies
IgA aCL antibodies, APL†
IgA anti-PS/PT antibodies,
units/ml
IgA anti-␤2GPI antibodies,
units/ml
IgM anti-PS/PT
antibodies, units/ml
IgG anti-PS/PT antibodies,
units/ml‡
Figure 2. Positive correlation between serum IgA anti–phosphatidylserine-prothrombin complex (anti-PS/PT) antibody and IgA
anticardiolipin (aCL) antibody levels in patients with HenochSchönlein purpura. Serum IgA anti-PS/PT antibody levels are
shown on the ordinate, and serum IgA aCL antibody levels are
shown on the abscissa (rs ⫽ 0.50, P ⫽ 0.007).
munologic elements in the pathogenesis of HSP. Furthermore, we found a significant correlation between serum
IgA aCL antibodies, IgA anti-PS/PT antibodies, and CRP
level in the 30 HSP patients. CRP is an inflammatory
marker and an elevated CRP titer likely contributes to the
aggressive clinical condition. Based on these findings, serum IgA aCL antibody and/or IgA anti-PS/PT antibody
levels could serve as a marker for adult HSP and therefore
should be monitored to appropriately gauge disease activity in adult HSP. Of the 30 HSP patients, 24 (80%) were
positive for proteinuria according to urinalysis. Patients
who subsequently developed proteinuria showed significantly higher IgA aCL antibody levels than those without
proteinuria. These findings suggest that monitoring serum
IgA aCL antibody levels might be useful to predict renal
involvement.
We found IgM anti-PS/PT antibodies in 20 (67%) of the
30 HSP patients, but this finding was not correlated with
IgA anti-PS/PT antibodies and/or IgA aCL antibodies. IgM
anti-PS/PT antibodies were detected in 6 (75%) of our 8
CLA patients, but neither IgA anti-PS/PT antibodies nor
IgA aCL antibodies were found in these patients. Smallvessel vasculitis (leukocytoclastic vasculitis), HSP, and
CLA share a common pathologic background that may be
related to the increased IgM anti-PS/PT antibody produc-
Presence
(n ⴝ 24)
Absence
(n ⴝ 6)
12.99 ⫾ 5.27
20.58 ⫾ 26.93
8.67 ⫾ 3.92
10.12 ⫾ 6.82
7.38 ⫾ 12.07
3.75 ⫾ 1.83
12.88 ⫾ 8.14
14.00 ⫾ 8.51
14.71 ⫾ 25.03
5.33 ⫾ 3.61
* Values are the mean ⫾ SD. See Table 1 for definitions.
† P ⫽ 0.024.
‡ P ⫽ 0.045.
tion in HSP and CLA. Phosphatidylserine is a regular
constituent of the inner leaflet of the cell membrane,
which is only exposed on the outside of the cell membrane
during apoptosis or by damaged endothelial cells (25).
Some studies have demonstrated that prothrombin binds
specifically to the surface of apoptotic cells (26,27). We
believe that prothrombin binds to apoptotic endothelial
cells and combines phosphatidylserine in the dermis. The
complexes may cause IgM anti-PS/PT antibody production
in small-vessel vasculitis, which would probably be locally produced.
In conclusion, we found high titers of serum IgA aCL
antibodies and/or IgA anti-PS/PT antibodies in adult HSP
patients, and there was a significant association between
these 2 markers. The 2 IgA antibodies were also positively
correlated with CRP level. These IgA antibodies in HSP
patients may reflect disease activity and play some pathogenic role. In contrast, serum IgM anti-PS/PT antibody
levels were elevated in HSP and CLA patients, regardless
of IgA aPL antibody levels. We speculate that IgM antiPS/PT antibodies could be implicated in disease susceptibility for leukocytoclastic vasculitis. These findings further suggest that aPL antibodies are closely related to the
pathogenic factors that trigger the development of vasculitis. Further studies are required to confirm the pathogenesis of HSP and CLA.
Table 3. Correlation between antiphospholipid antibodies and serum IgA, CRP*
Serum IgA
rs
P
CRP
rs
P
IgA aCL
antibody
IgA
anti-PS/PT
antibody
IgA
anti-␤2GPI
antibody
IgM
anti-PS/PT
antibody
IgG
anti-PS/PT
antibody
0.40
0.030
0.30
0.105
0.52
0.005
⫺0.09
0.64
0.46
0.014
0.38
0.039
0.42
0.023
0.44
0.020
0.09
0.62
* See Table 1 for definitions.
0.30
0.11
aPL Antibodies in HSP and Cutaneous Leukocytoclastic Angiitis
AUTHOR CONTRIBUTIONS
Dr. Kawakami had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study design. Kawakami.
Acquisition of data. Kawakami, Yamazaki.
Analysis and interpretation of data. Kawakami, Yamazaki.
Manuscript preparation. Kawakami, Mizoguchi, Soma.
Statistical analysis. Kawakami.
REFERENCES
1. Knight JF. The rheumatic poison: a survey of some published
investigations of the immunopathogenesis of HenochSchönlein purpura. Pediatr Nephrol 1990;4:533– 41.
2. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross
WL, et al. Nomenclature of systemic vasculitides: proposal of
an international consensus conference. Arthritis Rheum 1994;
37:187–92.
3. Nielsen HE. Epidemiology of Schönlein-Henoch purpura.
Acta Paediatr Scand 1988;77:125–31.
4. Tancrede-Bohin E, Ochonisky S, Vignon-Pennamen MD, Flageul B, Morel P, Rybojad M. Schönlein-Henoch purpura in
adult patients: predictive factors for IgA glomerulonephritis
in a retrospective study of 57 cases. Arch Dermatol 1997;133:
438 – 42.
5. Lie JT. Nomenclature and classification of vasculitis: plus ça
change, plus c’est la même chose [editorial]. Arthritis Rheum
1994;37:181– 6.
6. Kawakami T, Watabe H, Mizoguchi M, Soma Y. Elevated
serum IgA anticardiolipin antibody levels in adult HenochSchönlein purpura. Br J Dermatol 2006;155:983–7.
7. McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991;49:193–280.
8. Harris EN. Antiphospholipid antibodies. Br J Haematol 1990;
74:1–9.
9. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation:
␤2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci
U S A 1990;87:4120 – 4.
10. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH,
van Breda-Vriesman PJ, et al. Anticardiolipin antibodies
(ACA) directed not to cardiolipin but to a plasma protein
cofactor. Lancet 1990;335:1544 –7.
11. Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T.
Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease [letter]. Lancet 1990;336:177– 8.
12. Roubey RA. Immunology of the antiphospholipid antibody
syndrome [review]. Arthritis Rheum 1996;39:1444 –54.
13. Wagenknecht DR, McIntyre JA. Changes in beta 2-glycoprotein I antigenicity induced by phospholipid binding. Thromb
Haemost 1993;69:361–5.
567
14. Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid
antibodies are directed against a cryptic epitope expressed
when beta 2-glycoprotein I is bound to a suitable surface.
Thromb Haemost 1995;73:29 –34.
15. Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003;102:
2717–23.
16. Atsumi T, Ieko M, Bertolaccini ML, Ichikawa K, Tsutsumi A,
Matsuura E, et al. Association of autoantibodies against the
phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000;43:1982–
93.
17. Amengual O, Atsumi T, Koike T. Specificities, properties, and
clinical significance of antiprothrombin antibodies [review].
Arthritis Rheum 2003;48:886 –95.
18. Stone JH, Nousari HC. “Essential” cutaneous vasculitis: what
every rheumatologist should know about vasculitis of the
skin. Curr Opin Rheumatol 2001;13:23–34.
19. Carlson JA, Chen KR. Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. Am J Dermatopathol
2006;28:486 –506.
20. Sorensen SF, Slot O, Tvede N, Petersen J. A prospective study
of vasculitis patients collected in a five-year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis 2000;
59:478 – 82.
21. Tsuchiya N, Kobayashi S, Kawasaki A, Kyogoku C, Arimura Y, Yoshida M, et al. Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated
vasculitis: association of HLA-DRB1*0901 with microscopic
polyangiitis. J Rheumatol 2003;30:1534 – 40.
22. Hagen EC, Daha MR, Hermans J, Andrassy K, Csernok E,
Gaskin G, et al. Diagnostic value of standardized assays for
anti-neutrophil cytoplasmic antibodies in idiopathic systemic
vasculitis: EC/BCR Project for ANCA Assay Standardization.
Kidney Int 1998;53:743–53.
23. Yang YH, Huang MT, Lin SC, Lin YT, Tsai MJ, Chiang BL.
Increased transforming growth factor-␤ (TGF-␤)-secreting T
cells and IgA anti-cardiolipin antibody levels during acute
stage of childhood Henoch-Schönlein purpura. Clin Exp Immunol 2000;122:285–90.
24. Tizard EJ. Henoch-Schönlein purpura. Arch Dis Child 1999;
80:380 –3.
25. Austin A, Campbell E, Lane P, Elias E. Nodular regenerative
hyperplasia of the liver and coeliac disease: potential role of
IgA anticardiolipin antibody. Gut 2004;53:1032– 4.
26. D’Agnillo P, Levine JS, Subang R, Rauch J. Prothrombin binds
to the surface of apoptotic, but not viable, cells and serves as
a target of lupus anticoagulant autoantibodies. J Immunol
2003;170:3408 –22.
27. Price BE, Rauch J, Shia MA, Walsh MT, Lieberthal W, Gilligan
HM, et al. Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a ␤ 2-glycoprotein Idependent manner. J Immunol 1996;157:2201– 8.
Документ
Категория
Без категории
Просмотров
0
Размер файла
144 Кб
Теги
purpura, henoch, level, high, serum, antibody, angiitis, adults, cutaneous, schnlein, leukocytoclastic, antiphospholipid, titer
1/--страниц
Пожаловаться на содержимое документа