Clinical Immunology (2008) 128, 409–414

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / y c l i m

Autoantibodies against complement C1q in acute

post-streptococcal glomerulonephritis
Ina Kozyro a , Ludmila Korosteleva b , Dmitryj Chernoshej c , Doris Danner d ,
Alexander Sukalo a , Marten Trendelenburg d,e,⁎
a
Department of Pediatrics, 2nd Children's Hospital, Belarus State University, Minsk, Belarus
b
Republic Centre of Oncohematology, Minsk, Belarus
c
Department of Microbiology, Immunology and Virology, Belarus State University, Minsk, Belarus
d
Clinical Immunology, Department of Research, University Hospital Basel, Basel, CH, Switzerland
e
Internal Medicine, University Hospital Basel, Basel, CH, Switzerland

Received 11 February 2008; accepted with revision 18 April 2008

Available online 9 June 2008

KEYWORDS Abstract Autoantibodies against complement C1q (anti-C1q) strongly correlate with the
APSGN; occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with
Autoantibody; more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we
Complement; prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN.
Glomerulonephritis Associations between anti-C1q and disease manifestations as well as serum complement con-
centrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q
compared to 0 / 40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3
concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine
as well as more often oliguria, hypertension and delayed resolution of the disease than patients
without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination
of anti-C1q might help to identify patients at risk for prolonged courses of the disease.
© 2008 Elsevier Inc. All rights reserved.

Introduction complementemic urticarial vasculitis where anti-C1q can

Autoantibodies against the first component of the classical
pathway of complement (anti-C1q) have been found in a
number of autoimmune, renal and infectious diseases [1–4].
The prevalence of anti-C1q is highest in patients with hypo-
⁎ Corresponding author. Internal Medicine, University Hospital Basel,
Petersgraben 4, CH-4031, Basel, Switzerland. Fax: +41 61 2655390.
E-mail address: marten.trendelenburg@unibas.ch
(M. Trendelenburg).
be used as a diagnostic marker [5]. However, anti-C1q have
mostly been investigated in patients with systemic lupus
erythematosus (SLE). In adult patients with SLE the pre-
valence of anti-C1q varied between 20 and 100% depending
on the population of SLE patients studied. The highest pre-
valence of anti-C1q was found in those having active lupus
nephritis [6–11]. Furthermore, in most of the studies, the
absence of anti-C1q had a strikingly high negative predictive
value for the development of severe lupus nephritis, ranging
up to 100% [10]. The interest in anti-C1q as a diagnostic tool
in SLE patients was further strengthened by the observation

1521-6616/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.clim.2008.04.005
410
that increasing titres of anti-C1q seemed to precede renal
flares by 2–6 months. In addition, after the successful treat-
ment of a renal flare, anti-C1q mostly decreased or became
undetectable [9,11–16]. The strong link between the
occurrence of anti-C1q and severe lupus nephritis suggests
that anti-C1q have a disease altering effect in SLE. This
hypothesis was supported by findings in a mouse model of
immune-complex glomerulonephritis in which the injection
of anti-C1q exacerbated a pre-existing sub-clinical disease
[17].
A role for anti-C1q in the diagnosis and/or pathogenesis of
other diseases than SLE has not yet been established but in a
previous study we could identify acute post-streptococcal
glomerulonephritis (APSGN) as another disease in which anti-
C1q might play a role [18]. APSGN is the most common and
most studied post-infectious renal disease in humans and
frequently associated with autoimmune phenomena. How-
ever, the pathogenic mechanism that initiates the disease
remains to be elucidated [19]. Both SLE nephritis as well
as APSGN share several clinical and histopathological charac-
teristics such as hypocomplementemia, glomerular suben-
dothelial deposition of IgG-containing immune-complexes,
deposition of complement components of the classical path-
way, mesangial proliferation, and local influx of neutrophils
and monocytes/macrophages [20]. Furthermore, even an over-
lap syndrome between APSGN and SLE has been described
[21].
Complement C1q has been shown to directly bind to group
A streptococci of various serotypes [22] and streptococcal
protein H might cause a C1q-dependent consumption of
complement [23]. In addition, other streptococcal antigens
were shown to have the potential to directly or indirectly
activate complement via the classical pathway because of
their cationic nature or their role as a target for IgG [24–31].
In this context, the occurrence of autoantibodies against C1q
as observed in SLE might have a disease altering effect.
Therefore, the aim of this study was to prospectively inves-
tigate in more detail the role of anti-C1q in a large cohort of
children with APSGN.
Materials and methods
Patients and clinical parameters
Between April 2002 and June 2007, all children with newly
diagnosed acute post-streptococcal glomerulonephritis
(APSGN) from the Department of Pediatrics Nephrology at
the 2nd Children's Hospital, Belarus State Medical University
in Minsk/Belarus were prospectively included into the study
including those already published [18]. The patient's parents
had to give written consent in the study participation ac-
cording to the local ethical standards. Only patients with
incomplete follow-up data were excluded. The diagnosis of
acute post-streptococcal glomerulonephritis was based on
the presence of hematuria, proteinuria, oedema, a positive
test for anti-streptolysin O (Hospitex Diagnostics, Firenze,
Italy) and an upper-airway infection (tonsillitis, pharyngitis)
or a streptococcal skin infection preceding the onset of
glomerulonephritis by 7–21 days. A lack of spontaneous
remission was defined as persistent hematuria with protei-
nuria and/or elevated creatinine for at least 3 months.
I. Kozyro et al.
Serum samples were taken at the time of the diagnosis
and stored in aliquots frozen at −20 °C until further use.
Autoantibodies
Anti-nuclear antibodies (ANA) were measured using commer-
cially available ELISA kits (Pharmacia Diagnostics, Düben-
dorf, Switzerland).
Autoantibodies against C1q (anti-C1q) were tested in
serum using a commercially available ELISA kit (kindly pro-
vided by Bühlmann Laboratories, Schönenbuch, Switzerland).
Briefly, human C1q pre-adsorbed on a microtitre plate was
incubated with patient sera diluted in a high salt buffer (1 M
NaCl) in order to avoid false positive results by binding of
immune-complexes [32]. After washing, bound IgG was de-
tected using an anti-human IgG horseradish peroxidase la-
belled conjugate added in the appropriate dilution. Colour
was developed by adding an enzyme substrate (tetramethyl-
benzidine in citrate buffer). The reaction was stopped by
adding 0.25 M sulphuric acid. The optical densities were
measured at 450 nm and converted into units (U/ml) by
plotting against the autoantibody titre of the standards given
by the manufacturer. The cut-off suggested by the manu-
facturer (15 U/ml) was obtained by testing the samples from
220 normal blood donors according to the assay procedure.
Since this cut-off might not have been valid for children, sera
from 40 healthy children and from 15 children with systemic
lupus erythematosus (SLE) fulfilling at least 4 out of the 11
ACR criteria [33] were collected at the same institution as the
patients and used as controls. None of the healthy children
was positive for anti-C1q whereas 10 out of the 15 children
with SLE had titres above 15 U/ml.
Complement measurements
Serum concentrations of complement C3 and C4 were mea-
sured by immunoturbidimetry (Roche Diagnostics, Basel, CH)
using an automated analyzer (Hitachi 912). C1q antigen was
measured by radial immunodiffusion using a commercially
available kit (The Binding Site Ltd, Birmingham, UK). The nor-
mal range (114–224 mg/l) was determined as the mean +/− 2
standard deviations of the values obtained from healthy control
children.
Statistical analysis
All values described in the text and figures are expressed as
median and range. Statistical analyses were carried out using
GraphPad Prism 4 (GraphPad Software, San Diego, CA, USA).
Nonparametric tests (two-tailed Mann–Whitney U-test,
Kruskal–Wallis test, Fisher's exact test and one-tailed Spear-
man rank correlation test) were applied throughout with
differences being considered significant for p values b 0.05.
Results
Using a cut-off at 15 U/ml, autoantibodies against C1q (anti-
C1q) were found in 19 out 50 children (38%) with newly
diagnosed acute post-streptococcal glomerulonephritis
(APSGN) compared to 0 out of 40 healthy control children
Anit-C1q in APSGN 411

Table 1 Comparison of the characteristics of anti-C1q positive

and negative children with APSGN
Anti-C1q antibodies p value
Positive Negative
Number of patients 19 31 –
Age in years 11/3–17 11/3–17 NS
Gender (male/female) 9/10 15/16 NS
ASLO titres in U/ml 400/200– 250/200– NS
1200 800
Time interval symptoms- 13/2–61 9/2–61 NS
diagnosis (days)
ESR in mm/1 h 27/21–48 26/14–47 NS
Values are given as median/range where not otherwise indicated.
NS = not significant.

(p b 0.0001). For comparison, anti-C1q were found in 10 out

of 15 children (67%) with systemic lupus erythematosus
(SLE). None of the patients with APSGN was positive for ANA.
Anti-C1q positive patients did not significantly differ from Figure 2 Serum creatinine concentrations in μmol/l in anti-
anti-C1q negative patients in basic characteristics (Table 1). C1q positive patients with APSGN versus those without anti-C1q.
However, anti-C1q positive patients had significantly
more frequent oliguria (10 out of 19 (52%) versus 4 out of
31 (13%), p = 0.0038), hypertension (19 of 19 (100%) versus 23 resolution as mentioned before. The results are demon-
of 31 (74%), p = 0.0177), and a lack of complete spontaneous strated in Figs. 1 and 2. Serum urea did not differ sig-
resolution of the GN (8 of 19 (42%) versus 1 of 31 (3%), nificantly between anti-C1q positive and anti-C1q negative
p = 0.001). Furthermore anti-C1q positive children with
APSGN had higher proteinuria (p b 0.0001) and creatinine
(p = 0.0029) at initial presentation although two of the anti-
C1q negative patients also had high creatinine. The anti-C1q
negative patient with the highest serum creatinine at pre-
sentation was identical to the one who had no spontaneous

Figure 3 Serum complement C3 and C4 concentrations in anti-

C1q positive children with APSGN versus those without anti-C1q.
Whereas there was no difference for C4, anti-C1q positive pa-
Figure 1 Proteinuria in g/24 h in anti-C1q positive patients tients had lower C3 concentrations than patients without anti-
with APSGN versus those without anti-C1q. C1q (p = 0.0001).
412
Figure 4 Anti-C1q levels correlated negatively with serum
C1q concentrations in all patients with APSGN (r = −0.273,
p = 0.0276). The dotted lines indicate the cut-off for a positive
test result (15 U/ml for anti-C1q) and the lower limit of normal
respectively (114 μg/ml for serum C1q as measured by radial
immunodiffusion).
patients. However, there was a trend for higher serum urea in
anti-C1q patients (median (range) of 6.85 (3.5–31) versus 5.7
(2.7–21.3), p = 0.1742).
In spite of the relatively long median time interval
between the occurrence of first manifestations and blood
sampling (Table 1) about half of the patients still had reduced
serum concentrations of complement C3 at the time of blood
sampling (26 of 50 (52%)). None of the patients had hypo-
complementemia of C4. However, overall serum C3 concen-
trations showed a negative correlation with anti-C1q levels
(Spearman r = −0.381, p = 0.0032). Comparing anti-C1q posi-
tive and negative patients, the presence of anti-C1q was
associated with lower concentrations of C3 but not with
lower C4 (median (range) of 0.23 (0.141–0.418) g/l
compared to 0.303 (0.068–0.604) g/l in anti-C1q negative
patients, p = 0.1905). The data is demonstrated in Fig. 3.
For the investigation of a possible negative correlation
between anti-C1q and C1q antigen as described in SLE
patients [11], serum C1q was determined in all patients. Low
C1q could be observed in 50% of the patients (25 out of 50,
p = 0.0004 compared to healthy controls). Overall, anti-C1q
levels showed a weak negative correlation with serum C1q
concentrations (Spearman r = − 0.273, p = 0.0276). However,
comparing C1q levels in anti-C1q positive versus anti-C1q
negative patients, there was only a trend for lower C1q
concentrations in anti-C1q positive patients (p = 0.126). The
raw data is shown in Fig. 4.
Discussion
In our prospectively collected cohort of children with newly
diagnosed APSGN we found an increased prevalence of auto-
antibodies against complement C1q. Levels of anti-C1q cor-
related negatively with serum concentrations of C1q and C3
suggesting an altered complement activation in the presence
of the autoantibody. In addition, the occurrence of anti-C1q
I. Kozyro et al.
in children with APSGN was clearly associated with more
severe glomerulonephritis as judged by more pronounced
proteinuria and elevated creatinine as well as more frequent
oliguria, hypertension and lack of spontaneous resolution.
These findings confirmed and extended our previous obser-
vations in a small subgroup of the cohort presented here
where we could not observe more pronounced complement
depletion in anti-C1q positive patients [18]. The differences
are most likely explained by the more than doubled number
of investigated patients, and the different technique used
for the analysis of complement levels. In addition, in the
presented study not all pathological clinical findings could
be explained by the presence of anti-C1q since we also ob-
served patients with high serum creatinine in the absence of
anti-C1q.
Our data suggest a pathogenic role of anti-C1q in APSGN,
maybe similar to the hypotheses proposed for the role of anti-
C1q in patients with proliferative lupus nephritis [34–36].
These hypotheses assume that additional binding of anti-C1q
to glomerular deposits of C1q alters the function and/or ex-
acerbates the activation of the complement cascade which
might be responsible for the negative correlation between
levels of anti-C1q and C1q antigen. The interference of anti-
C1q with the complement cascade or even complement
activation might lead to a critical aggravation of the glo-
merular pathology. However, the precise pathogenic mechan-
ism of anti-C1q remains to be elucidated. Complement
activation in APSGN mostly occurs via the alternative pathway
and might be due to a break down of control mechanisms. This
hypothesis could explain that we observed a negative
correlation between anti-C1q and C3 but not between anti-
C1q and C4 levels. One could speculate that the effect of anti-
C1q on the activation of the classical pathway is rather mild
but exacerbated on the level of C3 when control of the
alternative pathway is insufficient.
As mentioned above, hypocomplementemia including the
activation of the classical pathway is a frequent finding in
APSGN. However, not all patients with APSGN present with
hypocomplementemia and complement depletion is a time-
dependent phenomenon [37,38]. Interestingly, in spite of the
relatively long time interval between the first symptoms of
disease and blood sampling, half of our patients presented
with low C1q concentrations suggesting that involvement of
the classical pathway is a more common phenomenon than
previously recognised. Although the difference to former
studies on C1q levels in APSGN could be explained by the
different techniques used for C1q determination one can
hypothesise that the occurrence of anti-C1q with associated
depletion of serum C1q is a phenomenon occurring rather
late in the course of the disease and thus have been un-
derestimated in previous studies.
Independent of the potential pathogenic role, determina-
tion of anti-C1q might be an interesting parameter for
clinicians allowing the early identification of patients at risk
for more severe courses of the disease and/or lack of spon-
taneous resolution. A prolonged course of APSGN occurred in
9 (18%) of our patients. This number is in line with previous
reports describing that about 10% of children with APSGN
and up to 50% of affected adults have not necessarily a
benign long-term prognosis [39–45]. In this context, we also
cannot exclude the possibility that some patients of our
cohort were misdiagnosed as APSGN but in fact presented
Anit-C1q in APSGN
with membranoproliferative glomerulonephritis (MPGN)
[45]. However such a misclassification is unlikely in the 41
of 50 patients having shown a spontaneous remission. Fur-
thermore, MPGN was shown to be anti-C1q positive in only
about 50% of affected patients [35,46,47]. Thus, we can
estimate that only few patients from our cohort can be ex-
pected to indeed having had MPGN. In addition, the pa-
thogenic mechanisms leading to MPGN remain unclear, and
might include bacterial infection such as streptococci [48].
Removal of the 9 patients with a more chronic course from
the analyses did not substantially affect the differences seen
between anti-C1q positive and negative patients (data not
shown). Therefore, this interpretation cannot account for
the majority of our observations. However, the distinction
between MPGN and APSGN is not only of importance for the
explanation of pathogenic mechanisms but also of relevance
for the diagnostic process in children with suspected APSGN.
In these children, a positive test result for anti-C1q might
help to identify patients at risk for a chronic course and thus
point to the necessity of an early renal biopsy.
In conclusion, in children with APSGN anti-C1q were found
in about one third of the patients and associated with more
severe disease manifestations as well as a lack of spontaneous
recovery. These observations could be due to a potential
pathogenic mechanism of anti-C1q in APSGN. Determination
of anti-C1q in the diagnostic process of APSGN might help
identifying patients at risk for a more severe course of
disease.
Financial disclosure
None of the authors has any potential financial conflict of
interest related to this manuscript.
Acknowledgments
Marten Trendelenburg is a recipient of a SCORE fellowship
from the Swiss National Foundation (No 3232BO-107248/1).
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Glossary
APSGN: acute post-streptococcal glomerulonephritis
ASLO: anti-strepolysin O
ELISA: enzyme-linked immunosorbent assay
ANA: anti-nuclear antibody
ESR: erythrocyte sedimentation rate
NS: not significant