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Clinical Science (1992) 83, 281-287 (Printed in Great Britain)
281
Autoimmunity to glomerular antigens in
HenocMchoenlein nephritis
D. J. O'DONOGHUE', F. JEWKES', R. J. POSTLETHWAITE' and F. W. BALLARDIE'
'Department of Medicine, Manchester Royal Infirmary, Manchester, U.K., and 2Department of
Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester, U.K.
(Received 2 December 1991/12 March 1992; accepted 24 March 1992)
1. Henoch-Schoenlein nephritis and IgA nephropathy
share clinical and immunological features, but the
pathogenesis of neither condition is established. We
have recently described IgG autoantibodies to glomerular components in active IgA nephropathy and
have now sought evidence for a similar autoimmune
component in Henoch-Schoenlein purpura.
2. Sera from 26 patients with Henoch-Schoenlein nephritis and six patients with Henoch-Schoenlein purpura
without accompanying nephritis were studied and
compared with sera from 20 patients with other
forms of glomerulonephritis and 40 normal subjects.
E.1.i.s.a.s were developed to detect IgA and IgG
binding to the ligand from whole human glomeruli
previously described, laminin, DNA, cardiolipin
(diphosphatidylglycerol) and a panel of dietary constituents (BSA, a-caesin, fi-lactoglobulin, ovalbumin and
wheat gliadin).
3. Sera from 16 of the 26 patients with HenochSchoenlein nephritis displayed increased IgG binding
to the human glomerular extract compared with the
normal control group (P<0.001), whereas IgG binding was not significantly raised in the patients with
Henoch-Schoenlein purpura without evidence of renal
involvement. IgA binding was not raised compared
with control subjects. Serum IgA and IgG binding to
other potential autoantigens or antigens present on
dietary constituents was not significantly different in
patients with Henoch-Schoenlein nephritis or patients
with Henoch-Schoenlein purpura without nephritis
compared with control subjects.
4. Western blotting of the denatured and reduced
glomerular extract revealed binding of IgG, from the
sera of patients with active HenochSchoenlein
nephritis, to glomerular components of M, 48 000 and
58000, similar to the M , of the glomerular antigens
identified in IgA nephropathy. Immunoglobulin binding was shown to be specific antibody binding using
F(ab'), fragments from the IgG fraction of e.1.i.s.a.positive sera.
5. Clinical associations showed in 10 of 11 patients
with Henoch-Schoenlein nephritis whose sera were
studied in remission: IgG antiglomerular antibody
binding fell to within the normal range (Pe0.05).
6. These results demonstrate an autoimmune component in HenochSchoenlein nephritis, and the close
temporal relationship with active nephritis implies
that this may be a critical component in the pathogenesis of glomerular injury. The absence of specific
antibody, or non-specific immunoglobulin binding, to
any of the range of dietary constituents or other
putative autoantigens tested suggests that polyclonal
B-cell activation is not an important feature of
Henoch-Schoenlein nephritis.
INTRODUCTION
Henoch-Schoenlein nephritis and IgA nephropathy share clinical features and immunohistological
characteristics, but the pathogenesis and interrelationship of these nephritides remain controversial [l, 21. Synpharyngitic haematuria is a feature
of both conditions [3], transition between syndromes occurs [4] and case reports of simultaneous
development of IgA nephropathy or HenochSchoenlein purpura (HSP) within sibships have been
documented [5]. This, coupled with the strikingly
similar glomerular changes of mesangial proliferation with diffuse global IgA deposition [6,7],
suggests that they share a common immunopathogenic process [S]. In both nephritides, polymeric IgAl predominates in glomerular deposits
[1,6]. The cellular control of IgA production shows
similar abnormalities [9,10]: high total plasma IgA
levels [ll], IgA rheumatoid factor [l2, 131 and
circulating IgA-containing immune aggregates are
observed [14,15].
Although there are similar IgA system abnormalities, other factors, epidemiological disparity [161,
the systemic nature of HSP [3] and its usually
transient and benign course in children and some
adults [17], imply either differences of the immunopathogenic processes or their control. The
mechanism of glomerular injury is assumed to be
secondary to the mesangial deposition of IgAcontaining complexes [11. However, IgA is relatively
Key words: antiglomerular antibodies, autoimmunity, dietary antigens, Henoch-Schoenlein purpura.
Abbreviations: HSP, Henoch-Schoenlein purpura; PBS, phosphatebuffered saline.
Correspondence: Dr F. W. Ballardie, Department of Medicine, Manchester Royal Infirmary, Manchester M I3 9WL, U.K.
282
D. J.
ODonoghue et al.
non-phlogistic, fixes complement poorly, if at all
[l8], and mesangial IgA deposits are usually clinically silent in hepatic cirrhosis and coeliac disease
[19,20]. These anomalies have focused attention on
other factors, such as a role for an antigen in
immune aggregates in sera, and on the possibility
that mesangial IgG or IgM deposits may be a
necessary cofactor for initiation or amplification of
injury [6,7]. Despite an extensive search, no specific
bacterial, viral or food antigen has been identified
[7], nor do IgA-containing immune complexes
found in sera correlate with either clinical features
of nephritis or progression [21]. Others [l, 221 have
emphasized the importance of IgG-mediated complement fixation in IgA nephropathy. Clinicopathological observations also support the concept that
co-deposition of complement-fixing IgG may contribute to nephritogenesis. The initial description of
IgA nephropathy by Berger & Hinglas [23] emphasized the diffuse mesangial deposition of both IgA
and IgG and indeed they first termed the lesion
IgA-IgG nephropathy. In both IgA nephropathy
[24] and HSP [14], clinical exacerbations and
nephritis are associated with acute elevations in the
IgG content of circulating complexes, and in some
studies [25,26] heavy deposition of IgG has been
observed in more severely affected patients with
progressive disease.
Recently, we have described an autoimmune component in the immune perturbation of IgA nephropathy with detection of specific autoantibodies with
affinity for glomerular antigens [27], and others
have demonstrated increased binding of IgA and
IgG to human umbilical vein endothelial cells [28],
or of IgA only to laminin [29], fibronectin [30] and
the Fc portion of IgG [l2]. The antiglomerular
antibodies which are directed against epitopes
distinct from those of the Goodpasture antigen are
of IgG isotype and detection correlated with clinical
evidence of nephritis in IgA nephropathy, suggesting
a role in the pathogenesis of glomerular injury [27].
These considerations prompted us to test the
hypothesis that, in the systemic disease of HSP, the
development of nephritis, specifically, is associated
with autoimmunity, defined by the presence of IgG
antiglomerular antibody in the circulation.
METHODS
Patients and control subjects
The study population consisted of 26 patients
with HSP nephritis (14 males, 12 females) with an
age range of 4-27 years (median 14 years), and six
patients with HSP without clinical evidence of renal
involvement (three males, three females) with an age
range of 3-18 years (median 11 years). Sera were
obtained from all patients during active disease.
This was manifest as at least two of the characteristic triad of rash, joint involvement and abdominal
pain. Those with significant microscopic or macro-
scopic haematuria, with or without recently declining renal function, were deemed to have renal
involvement. In addition, sera were available from
11 of those with and three of those without nephritis when in remission. Sera from 40 blood donors
were used as controls (20 males, 20 females; age
range 18-30 years, median 24 years). None of these
had a history of nephritis, abnormal urinalysis or
impaired renal function (serum creatinine level
< 120,umol/l). Sera from 20 patients with other
forms of glomerulonephritis were used as patient
controls. Eight of these had IgM mesangial proliferative glomerulonephritis (five males, three females;
median age 37 years), eight had membranous
nephropathy (six males, two females; median age 44
years) and two each had antiglomerular basement
membrane disease or Wegener’s granulomatosis
(two males, two females; median age 54 years). Sera
was stored at -70°C prior to assay.
Detection of antibodies by e.l.i.s.a.
Antiglomerular antibodies. Ligand from normal
human glomeruli was prepared as previously described [27]. Briefly, whole glomeruli were isolated
from fresh post-mortem kidney by seiving, disrupted
by prolonged sonication, acidified, ultracentrifuged
and the resulting supernatant dialysed against
0.1 mol/l phosphate-buffered saline (PBS). IgG and
IgA binding was detected using a standardized
e.1.i.s.a. [27]. Results are expressed as e.1.i.s.a. absorbance measured at 420 nm.
The IgG fraction of six e.1.i.s.a.-positive sera (three
males, three females; age range 9-27 years, median
17 years) and six normal control sera (three males,
three females; age range 18-28 years, median 23
years) was separated by ammonium sulphate precipitation. F(ab), fragments were cleaved by papain
digestion [31] and were separated from the Fc
fragments on a Sepharose column. Specific autoantibody binding was demonstrated using these
F(ab’)2 fragments in a modified e.1.i.s.a. as described
in [27].
Immunoglobulin binding to antigens displayed on
dietary constituents. An e.1.i.s.a. for IgA and IgG
affinity to the antigens displayed on dietary constituents, BSA, a-casein, P-lactoglobulin, ovalbumin
and wheat gliadin (Sigma Chemical Co, St Louis,
MO, U.S.A.) was performed as described by
Fornasieri et al. [32]. A standard curve of an
internal reference serum, known to contain high
levels of IgA or IgG antibodies to the respective
antigens, was incubated in each plate and the test
results were converted to arbitrary units after subtraction of uncoated (background) wells.
Immunoglobulin binding to laminin, DNA and
cardiolipin. An e.1.i.s.a. for IgA and IgG affinity to
the basement membrane glycoprotein laminin (puritied from extracts of the Englebreth-Holm-Swarm
mouse tumour), native DNA, single-stranded DNA
and cardiolipin (diphosphatidylglycerol;Sigma) were
Autoimmunity to glomerular antigens in Henoch-Schoenlein nephritis
performed as previously described, using coating
concentrations of 2 pg/ml for laminin [33], 10pg/ml
for double-stranded and single-stranded DNA [34]
and 25 pg/ml for cardiolipin [35]. Standardization
was made, similarly, with a reference sera.
lmmunoblotting
SDS/10% polyacrylamide gels were prepared and
electrophoresed by the method of Laemmli et al.
[36]. After SDS/PAGE of 25pl of the glomerular
extract under denaturing and reducing conditions,
transfer to nitrocellulose was made and the nitrocellulose strips were blocked with 2% Tween 20 in
PBS for 1h before overnight incubation with patient
or control sera at 1 in 20 in PBS/Tween 20 at 4°C.
IgG binding was detected using GG7 monoclonal
antibody (ICN, High Wycombe, Bucks, U.K.) at 1
in 500 dilution in PBS/Tween 20 for 4 h at room
temperature followed by washing and incubation
with peroxidase-conjugated rabbit anti-mouse
immunoglobulin (Sigma), 1 in 500, in PBS/Tween 20
for 2 h. The nitrocellulose strips were developed
with 3,3-diaminobenzidinetetrahydrochloride dihydrate (Sigma; lmg/ml in PBS with 1pl of
H,02/10ml) and the reaction was stopped by extensive washing with distilled water and drying.
1.5
-
1.2
-
0.9
-
0.6
-
i
0.3
-
i
I
i
f
P
n
.-,"
203
ui
II
I
0.0 I
Controls
(n=40)
0.60
HSP with
nephritis
(n=26)
HSP without
nephritis
(n=6)
Other GN
(n=20)
(b)
0.48
1
O*O0
'
Statistical analysis
The groups were compared by Mann-Whitney
U-tests, and the relationship between antibody
levels was examined by Kendall's rank correlation.
The tabulated results are expressed as means & SD.
RESULTS
Antiglomerular antibodies
Sera from 16 out of 26 patients with active HSP
nephritis displayed increased IgG binding to the
human glomerular extract in e.1.i.s.a. compared with
the normal control group (P<O.OOl, Fig. la). In
contrast, only one out of six patients with active
HSP without clinical renal involvement had raised
IgG binding ( P >0.05). This patient's disease was
not clinically different from the other five in terms
of pattern of organ involvement or severity. IgA
binding to the glomerular extract was not raised in
either group in comparison with normal control
subjects (P>0.05, Fig. lb) or the group with nonIgA-related glomerulonephritis.
F(ab'), fragments isolated from e.1.i.s.a.-positive
sera bound to glomerular extract in the e.1.i.s.a.
when compared with control IgG F(ab'), fragments
(P<0.02, Fig. 2).
The M , of the antigens recognized by IgG antiglomerular antibodies was determined by Western
blot analysis of the reduced and denatured whole
glomerular extract prepared as for e.1.i.s.a. Several
protein bands of M , between 48 000 and 58 000 were
Controls
(n=40)
HSP with
nephritis
(n =26)
HSP without
nephritis
Other GN
(n=20)
(n =6)
Fig. 1. Distributions of IgG isotype ( a ) and IgA isotype (b) antiglomerular antibody activity in patients with HSP with (n=Z6) or
without (n=6) active nephritis, patients with other glomerub
pathies (GN) (n=u)) (see the text) and normal control subjects
(n=40).
0.80
8
2 0.60
f
1
-
8
n
:0.40 .d
ui
0.20
0.00
-
i
Control
HSP
Fig. 2. Distribution of IgC F(ab'), antiglomerular antibody activity
in patients with HSP and normal control subjects. The difference
between the two groups was significant (P<0.02).
D. J. ODonoghue et al.
284
A
B
C
D
E
F
G
H
Immunoglobulin binding to laminin, DNA and cardiolipin
No significant differences were found in the values
of either immunoglobulin isotype binding to laminin,
single- or double-stranded DNA or cardiolipin
between both groups of patients with HSP and
normal or glomerulonephritic control subjects
(Table 2). Again, there was no correlation between
IgG antibodies to these antigens and the IgG
antiglomerular antibody titres.
Mr
58 000
48 M)o
Longitudinal study of IgG antiglomerular antibodies
Fig. 3, Western blot of glomerular extract and e.1.i.s.a.-positive HSP
sera (lanes A and B), F(ab’)* fragments from e.1.i.s.a.-positive sera
(lanes C and D) and control sera (lanes E and F) and F(ab’)z
fragments (lanes G and H)
specifically stained by IgG and F(ab’), fragments
from e.1.i.s.a.-positive sera but not normal control
sera (Fig. 3). Weak binding to higher-M, moieties
was inconsistently found with IgG but was not
confirmed with F(ab’), fragments.
Immunoglobulin binding to antigens displayed on dietary
constituents
No significant differences were found in the values
of either immunoglobulin isotype binding to BSA,
a-caesin, P-lactoglobulin, ovalbumin or gliadin
between both groups of patients with HSP and
normal or glomerulonephritic control subjects
(Table 1). Moreover, no correlation was found
between the IgG antibodies to dietary antigens and
the IgG antiglomerular antibody titres.
During prospective follow-up, IgG antiglomerular
antibodies fell significantly in the remission compared with the nephritic phase (P<O.O5, Fig. 4).
IgG antiglomerular antibodies remained above the
upper limit of the normal control group in a single
patient who subsequently demonstrated a relapsing
course. Furthermore, in individual patients with
recurrent episodes there was a close temporal relationship between autoantibody levels and nephritis,
which was independent of other systemic disease,
such as rash, as illustrated in Fig. 5.
DISCUSSION
The detection of specific IgG autoantibodies directed against glomerular antigens, in the serum of
patients with active HSP, extends our original
observation of autoimmunity in IgA nephropathy
[27] and implies shared immunopathogenic mechanisms in these diseases. Furthermore, the high
prevalence of antiglomerular antibodies in HSP
complicated by nephritis, 61%, compared with the
single positive in the group of six patients without
overt renal involvement, suggests that these autoantibodies may play a direct role in the mechanism
of glomerular injury. Indeed, the disappearance of
Table I. IgG and IgA binding of sera from patients with HSP with or without nephritis, normal control subjects and
patients with non-lgA-related glomerulopathies to five purified dietary antigens. Results are expressed in arbitrary units
(means ~ s D ) .
Test
antigen
BSA
Gliadin
Immunoglobulin
class
HSP with
nephrit is
HSP without
nephritis
Normal
control
(n =26)
(n=6)
(n=40)
Other
glomerulopathies
(n = 20)
16.3 k 8.4
25 f7.7
2 2 k I5
31.5 k 5 . 8
14.4+5.8
21.1 f 6 . 7
16.1 k5.8
20.9 k 6.6
20.5 f 10.7
26.5 f9.8
26.3 k 6 . 9
29.6 k6.43
21.1 *8.4
23.3 k I I .O
27. I f 14.8
23.4 k7.7
12.3f 9 . I
26.6 f 14.8
12.1 f 4 . 4
22. I k8.7
10.4 +4.2
22.1 k 7 . 2
9.6 k 4 . 2
25.1 k 14.3
14.3 k I I.5
19.6k5.3
19.8k3.3
29.1 f 11.0
23.2 f7.4
23.6 f 7 . 6
21.9k 5.9
22.5 f6.6
19k7.6
22.2 f5.9
l6.76+ 5.4
22.3 k 9.4
19k6.5
24.2+7.4
21.1 f7.6
22.6 6.5
285
Autoimmunity to glomerular antigens in Henoch-Schoenlein nephritis
Table 1. IgG and IgA binding of sera from patients with HSP with or without nephritis, normal control subjects and
patients with nowlgA-related glomerulopathies to laminin, single and doublestranded D N A and cardiolipin. Results are
expressed in arbitrary units (means *SD).
Test
antigen
0.0 I
Immunoglobulin
class
HSP with
nephritis
HSP without
nephritis
(n =26)
(n=6)
Normal
control
(n=40)
Other
glomerulopathies
(n =20)
15.83 f5.15
18.73 f 5.43
l5.82+ 6.10
18.79f5.71
15.66 6.25
20.45 f8.II
8.83 f4.47
+
Laminin
IgA
IgG
16.86f 7.23
19.I9 f6.82
Single-stranded DNA
IgA
IgG
8.18f5.36
14.26k7.03
I1.8+4.88
7.83 k4.72
13.22f6.26
7.29 f4.52
13.86 f 5.64
Doublestranded DNA
IgA
IgG
6.98 f 5.63
10.31 f7.02
5.7 f 4.27
9.21 f 3.48
6.24f 5.66
10.44 f 6.97
5.23 4.85
9.95k5.98
Cardiolipin
IgA
IgG
8.15 f 5.59
4.48 f 3.7
2.73 I.88
7.16f5.18
2.98 +2.26
8.89 f4.26
2.86 f I.76
Active
Remission
3.27 f2.9
Active
Remission
Fig. 4. Antiglomerular IgG autoantibody levels in patients with HSP
with (a) or without (6)nephritis during episodes of active disease
and in remission.
these antibodies during clinical remission, and the
dissociation-of nephritis with autoantibody, and
rash without accompanying antibody-in the case
illustrated (Fig. 5), supports this hypothesis.
In contrast, no consistent pattern of abnormal
IgA or IgG antibody activity emerged from the
study of responses to food or self antigens. By
analogy with Berger’s disease [1,2] and experimental IgA nephropathy [7,22], the nephritis of HSP is
thought to occur owing to accumulation of IgA
immune complexes in glomeruli. In IgA nephropathy, increased IgA antibody levels to several
ubiquitous food antigens [37-391 and autoantigens
[12,28-301 have been reported. Several authors
have suggested a specific role for gliadin in IgA
nephropathy [40,41], but this has not been confirmed by others [32,42], nor does gluten withdrawal affect the progression of the disease [43].
Abnormal antibody responses are not confined to
the IgA system [37,38] or indeed to gliadin [37,38],
findings that have been interpreted as a non-specific
amplification of the normal immune response to
dietary antigens [37,44]. Contrary to these results,
but in agreement with the present study, Russell et
al. [42] were unable to demonstrate significant
differences in the levels of IgA antibodies to a panel
of environmental antigens between a mixed group of
patients with IgA nephropathy or HSP and a nonmatched normal control group. Neither could we
find evidence for polyreactive sera in a subgroup of
HSP patients, as recently described by Fornasieri et
al. [32] and ourselves [44] in IgA nephropathy.
Abnormal IgA binding to constituents displaying
self antigens, including type I11 collagen [45], DNA
[46], endothelial cells [28] or murine laminin [29],
has also been reported in IgA nephropathy. However, the physicochemical mechanism of such interactions may be secondary to deposition of IgAfibronectin immune complexes [30], increased levels
of polymeric IgA [2l] or the charge abnormalities
of IgA [47]. In the present study, the frequency of
immunoglobulin binding to DNA, cardiolipin and
laminin did not differ significantly between patients
with HSP and those with other primary glomerulonephritides or normal control subjects. Furthermore, no relationship was noted between these
antibody titres and the presence of nephritis or the
clinical activity of the disease.
In this analysis, the development of IgG antiglomerular antibodies in HSP is therefore not
accompanied by a polyclonal production of antibodies to non-specific food antigens and autoantigens, although there is a known increase in
serum total IgA [2] and the presence of IgA
circulating immune complexes [141. The unexpected
restriction of antiglomerular antibodies to the IgG
isotype may be conceptualized as part of the disturbed B-cell activation of more than one immunoglobulin isotype in the disease, and may be related
to the abnormalities of in uitro IgG production [48]
and disturbed IgG subclass profile [49]. Intriguingly, one study correlates circulating IgGcontaining immune complexes with glomerular
involvement in HSP [14] and an IgG cold reactive
antinuclear antibody has also been found in HSP
[SO], contrasting with the IgM isotype described in
IgA nephropathy [Sl]. The restriction of antiglomerular antibodies to the IgG subclass may
explain the association of these autoantibodies with
clinically evident nephritis. It is now apparent that
D. J.ODonoghue et al.
286
IRathl
0
1.5
0.0
0
3
6
9
I2
3
6
9
I2
715
4
I
0
15
glomerular antigen interaction in the F(ab’)2 studies,
which therefore excludes non-specific Fc-mediated
binding or immunoglobulin attachment by physicochemical mechanisms, such as via fibronectin, as has
recently been demonstrated for IgA binding to
collagen [30]. Analogous experiments provided
similar results in IgA nephropathy [27]. Likewise,
immunoblotting of the reduced and denatured glomerular extract revealed the M , of the glomerular
autoantigens to be approximately between 48 000
and 58000 in HSP, comparable with that obtained
in IgA nephropathy. The autoantigen in these diseases is likely to be identical. We have previously
shown that the glomerular autoantigen(s) in the
IgA-related nephropathies are distinct from the
Goodpasture antigen [27] and have recently localized the antigen to the mesangial cell [52]. The
close temporal relationship between antiglomerular
autoantibody production and clinical evidence of
nephritis in both IgA nephropathy and HSP supports the hypothesis of a common autoimmune
component in the pathogenesis of glomerular injury
in these diseases.
ACKNOWLEDGMENT
I
3
6
9
12
15
D.J.O’D. was the recipient of a North West
Regional Training Fellowship.
REFERENCES
U
I
0.00 1
0
3
6
9
I2
I
15
Time (months)
Fig. 5. Antiglomerular IgG autoantibodies, serum creatinine level,
proteinuria, erythrocyturia and rash during relapse and remission
in a patient with HSP
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