..................................................................................................................................................................................................

Ontogeny of Complement Regulatory Proteins

Concentrations of Factor H, Factor I, C4b-Binding
Protein, Properdin and Vitronectin in Healthy Children
of Different Ages and in Adults
P. F. de Paula,* J. E. Barbosa,y P. R. Junior,y V. P. L. Ferriani,y M. R. D. O. Latorre,z V. Nudelman &
L. Isaac*

Abstract
*Departamento de Imunologia, Instituto de
Ciencias Biomedicas; yDepartamento de
Pediatria, Faculdade de Medicina de Ribeirao
Preto; zDepartamento de Epidemiologia,
Faculdade de Saude Publica, Universidade de Sao
Paulo; and Hospital Israelita Albert Einstein, Sao
Paulo, SP, Brazil
Received 6 May 2003; Accepted in revised form 7
July 2003
Correspondence to: Dr L. Isaac, Universidade de
Sao Paulo, Instituto de Ciencias Biomedicas,
Departamento de Imunologia, Avenue Prof.
Lineu Prestes 1730, Cidade Universitaria, Sao
Paulo
05508-900,
SP,
Brazil.
E-mail:
louisaac@icb.usp.br

Previous studies of human in vivo complement protein levels have only compared data for neonates with that from adult sera. Here, we establish the normal
concentration ranges of the following complement regulatory proteins in healthy
Brazilian children of different age groups (neonates: 1 month
1 year, 16 years
and 613 years) and in adults: factor H (fH), factor I (fI), C4b-binding protein
(C4 BP), properdin and vitronectin. We found that the concentrations of fH, fI,
properdin and vitronectin in neonates are significantly lower than in adults.
Remarkably, the concentration of C4 BP is below the method resolution
(<50 mg/ml) in 76% of the sera from neonates, while adults presented 199
532 mg/ml of C4 BP in their sera. The concentration of properdin in the sera
from neonates and up to 1-year-old children was less than that observed in older
children. Adults presented vitronectin levels significantly higher than all the
other age groups in the study. No significant sex differences in the concentrations of all the studied regulatory proteins were detected. This study reveals the
ontogeny of complement system in greater detail than previously available and
may point to the reasons why neonates have higher susceptibility to develop lifethreatening pyogenic infections. These reference values will be of use in clinical
and laboratory investigations of disorders associated with low levels of these
regulatory proteins.

Introduction
The complement system is essential for innate and
acquired immune responses. In general, deficiency of complement proteins leads to higher susceptibility to infections
and/or to the development of autoimmune diseases [1].
When the complement system is activated by alternative,
classical or lectin pathways, the fragments C3b and C4b
can bind covalently to acceptor surfaces such as immune
complexes and foreign and host cells located in the vicinity
of the activation site. This binding leads to the formation
of C3 convertases (C4b2a and C3bBb) and C5 convertases
(C4b2a3b and C3bBb3b) on these surfaces and the
consequent formation of the membrane attack complex
(C5b-9) culminating in cell lysis. Complement activation
leads to an enhancement in the ingestion of opsonized
particles by neutrophils, monocytes and macrophages.
This internalization is mediated principally by the binding

572

of iC3b, C4b and C3b fragments to the complement

receptors (CR1, CR3 and CR4) present in those cells [1].
The activation of the complement system also triggers
the activation and proliferation of B cells, inducing the
production of antibodies, particularly during the early
stages of the immune response when antigen is generally
present in low amounts. C3d and C3dg fragments have
also been implicated in the mechanism of deletion of
immature autoreactive B cells [2].
A tight regulation of the complement system is essential in
order to protect host cells from injury by complement activation. Moreover, regulation of the amplification of the alternative pathways is of utmost importance; otherwise intact C3
molecules would shortly vanish. The lack of some regulatory
proteins, such as factor H (fH), factor I (fI) or properdin
(as well as C3) is associated with greater susceptibility to
infections and may represent a life-threatening condition.

# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577

P. F. de Paula et al.
Levels of Complement Regulatory Proteins 573
..................................................................................................................................................................................................

Our aim in this work was to establish the normal range

values for the following soluble regulatory proteins of the
complement system in healthy children at different ages:
fH, fI, properdin, C4b-binding protein (C4 BP) and vitronectin (also known as protein S). These data are of clinical
importance as most of the complement immunodeficiencies have their onset during the first years of childhood.
Reference values of serum complement proteins are necessary in clinical and laboratory investigations of the ontogeny
of the complement system to discriminate potentially new
cases of immunodeficiencies and to study the role of
complement in human diseases.

Materials and methods

Study group. The population under study comprises
healthy Brazilian children of different age groups and
healthy Brazilian adults. Cord blood was obtained from
term neonates weighing at least 2500 g at birth after normal, forceps or caesarean labour. Peripheral blood samples
were also collected from healthy children aged 1
month
13 years who attended out patient clinics at the
Hospital das Clnicas de Ribeirao Preto (USP), Ribeirao
Preto, Centro de Saude da Vila Lobato/Ribeirao Preto
(USP) and Posto de Saude da Comunidade de Paraisopolis
do Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil,
during the course of routine medical examinations. Additionally, blood samples were obtained from 30 adult blood
donors at the Hospital Universitario (USP), Sao Paulo.
Informed consent was obtained from the parents in all
cases. The study has been approved by the Ethics
Committees from each hospital. Children were considered
healthy when well nourished, considering the weight and
height for their age, and without any signs of infection or
pathology. Data were analysed from individuals in the
following age groups: neonates, 111 months, 15.9
years, 613 years and adults.
Single radial immunodiffusion. Serum samples were
aliquoted, frozen and stored at
80  C until use. The
concentrations of regulatory complement proteins were
determined as described before [3] with modifications. In
brief, 1% of polyclonal goat anti-human fH (CalbiochemNovabiochem Corporation, San Diego, CA, USA), 2% of
polyclonal goat anti-human fI (Calbiochem-Novabiochem
Corporation) or 0.5% of polyclonal rabbit anti-human C4
BP (Calbiochem-Novabiochem Corporation) was mixed
with 1% agarose gel in 1.2 mM KH2PO4, 5 mM K2HPO4
and 150 mM NaCl (phosphate-buffered saline) at 56  C. In
the case of vitronectin, 2.5% of polyclonal sheep antihuman vitronectin (The Binding Site) was mixed with
1% agarose in 90 mM Trisborate and 2 mM EDTA
(TBE) at 56  C. About 5 ml of each serum sample was
loaded into agarose gel in 1 : 1, 1 : 2 or 1 : 4 dilutions.
Standard curves were constructed using dilutions of 100,
75, 50 and 25% of a pool of normal human serum

(n 42). fH, fI, C4 BP and properdin concentrations

(mg/ml) were estimated by comparison with samples of the
respective purified proteins purchased from CalbiochemNovabiochem. After washing with 150 mM NaCl, the plates
were dried and stained with Coomassie Blue. All experiments were performed in duplicate, and the data only from
standard curves with r  0.95 were accepted. In the case of
properdin, all the serum determinations were performed
after using commercial radial immunodiffusion plates
(The Binding Site). The concentration of vitronectin was
expressed in percentage of a pool of normal human sera
(n 42).
Statistical analysis. The mean concentrations of fH, fI,
C4 BP , properdin and vitronectin from male and female
donors were compared using the MannWhitney test, and
the comparisons according to age groups were performed
using the KruskalWallis test. Multiple comparisons were
carried out using Dunn correction. The homogeneity of
variances was evaluated using Bartletts test.
Before establishing the normal ranges for the population
under study, the appropriate sample size was estimated by
using a descriptive test for a continual variable [4]. The
normal ranges were determined following the recommendations of Healy [5]. The significance level adopted was
5%. We applied the test of Spearman to investigate
whether there were significant correlations between the
concentrations of the different proteins in all the study
groups (a < 0.05).

Results
The normal ranges of the regulatory proteins and the
standard deviation found for each age group studied were
wide (Table 1 and Figs 15). A summary of all the significant differences between age groups for complement regulatory proteins serum levels is presented in Table 2.
The mean value  standard deviation, the size sample
and the normal ranges of concentrations of fI, fH, C4 BP,
properdin and vitronectin estimated for 95% of the reference population are summarized in Table 1. Profiles of
these normal ranges are illustrated in Figs 15. No significant differences in the mean concentrations of all the
regulatory proteins studied were found in samples derived
from male and female donors (data not shown). On the
other hand, we found significant differences in the means
according to age group for all the regulatory proteins
studied.
The concentrations of fH, fI, properdin and vitronectin
in neonates were significantly lower than those found in
adults (Figs 1,2,4 and 5). We found that 76% of the sera
samples obtained from neonates had C4 BP values below
the method resolution (<50 mg/ml, data not shown). For
the other age groups, different normal range profiles for
the regulatory proteins were observed (Figs 15).

# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577

574 Levels of Complement Regulatory Proteins

Concentration of fH ( g/ml)

3481
47103
32106
43108
60171
149

54  11
71  12
60  16
70  15
104  25

1400
1200
1000
800
600

200
Adults

612 years

15 years

111 months

Neonates
140
120
100
80
60

40

Adults

612 years

15 years

111 months

20
Neonates

n, sample size; SD, standard deviation; <<<, values below the method resolution.
*The normal ranges were established according to Healy [5].

202
190
172
Total

fH and fI levels were low in neonates and reached adult

levels in the first year of life (Figs 1 and 2, respectively).
For C4 BP, besides the low levels in neonates, significantly
higher C4 BP serum concentrations were observed for 613
year group than for 1 month
1 year (P < 0.01) and 16
year (P < 0.05) groups (Fig. 3). Lower levels of properdin
(Fig. 4) were found in sera from children during the first
year of life compared to 16 years and adults. In addition,
serum from neonates presented lower concentrations of
properdin than 613 year children and adults. Finally,
adults presented vitronectin levels significantly higher
than all the other age groups studied (Fig. 5).

Concentration of fI (g/ml)

148

15  2
19  7
23  5
22  6
25  5

Figure 1 Normal range profile for concentration of factor H (fH) (mg/ml)

in healthy Brazilian children and adults. *Significantly lower than 111
months, 15 years, 612 years and adults (P < 0.001). Squares represent
the mean concentration and bars indicate the lower and upper limits
(95% confidence interval).

<<<
126643
157565
173808
199532

20
37
24
43
24

400

1121
839
1338
1240
1541

30
21
31
30
37

1600

<<<
306  110
311  90
399  141
335  83
42
42
36
48
34
170397
2561110
2331319
2251636
242759
43
47
27
25
30
Neonates
1 month
1 year
16 years
613 years
Adults

30  10
56  22
58  16
57  13
64  13

1555
24114
30104
3491
39100

31
39
50
40
30

265  54
563  173
606  265
684  358
443  106

Normal range*
Mean  SD
Mean  SD Normal range* n

Properdin (mg/ml)

Mean  SD Normal range* n

C4 BP (mg/ml)

Mean  SD Normal range* n

fH (mg/ml)

Mean  SD Normal range* n

n

fI (mg/ml)

1800

Population

Table 1 Concentrations of factor I (fI), factor H (fH), C4 BP, properdin and vitronectin in the sera from healthy Brazilian children and adults

Vitronectin (% normal human serum)

P. F. de Paula et al.
..................................................................................................................................................................................................

Figure 2 Normal range profile for concentration of factor I (fI) (mg/ml)

in healthy Brazilian children and adults. *Significantly lower than 111
months, 15 years, 612 years and adults (P < 0.001). Squares represent
the mean concentration and bars indicate the lower and upper limits
(95% confidence interval).

# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577

Figure 3 Normal range profile for concentration of C4 BP (mg/ml) in

healthy Brazilian children and adults. #Significantly higher than 111
months (P < 0.01) and 15 years (P < 0.05). About 76% of the sera from
healthy neonates presented concentrations of C4 BP well below the
method resolution. Squares represent the mean concentration and bars
indicate the lower and upper limits (95% confidence interval).

Significant correlations (a < 0.05) were observed after

using Spearman test between the concentrations of: (i)
properdin and vitronectin (P 0.048) in the serum from
newborns; (ii) fH and fI (P 0.017) in the 111 month
group; (iii) fI and properdin (P 0.047) in the 612 year
group. In adults, there was a significant correlation only
between C4 BP and fH concentrations.

Discussion

45
#

35
30
25
20

15
10
5
Adults

612 years

15 years

111 months

0
Neonates

Concentration of properdin ( g/ml)

It is well known that the immune system is immature in

human neonates. In particular, T lymphocytes, monocytes

40

Figure 4 Normal range profile for concentration of properdin (mg/ml) in

healthy Brazilian children and adults. *Significantly lower than 111
months, 15 years, 612 years and adults (P < 0.001). #Significantly
lower than 15 years (P < 0.05) and adults (P < 0.01). Squares represent
the mean concentration and bars indicate the lower and upper limits
(95% confidence interval).

Adults

612 years

15 years

111 months

180
160
140
120
100
80
60
40
20
0

Adults

612 years

15 years

Neonates

Concentration vitronectin (%NHS)

900
800
700
600
500
400
300
200
100
0
111 months

Concentration of C4 BP ( g/ml)

P. F. de Paula et al.
Levels of Complement Regulatory Proteins 575
..................................................................................................................................................................................................

Figure 5 Normal range profile for concentration of vitronectin [%

normal human serum (NHS)] in healthy Brazilian children and adults.
*Significantly lower than 111 months, 612 years (P < 0.05) and adults
(P < 0.001). #Significantly higher than 111 months (P < 0.01), 15
years and 613 years (P < 0.001). Squares represent the mean
concentration and bars indicate the lower and upper limits (95%
confidence interval).

and macrophages are less active and neonates present low

levels of cytokines such as interferon-g (IFN-g), tumour
necrosis factor-a (TNF-a) and interleukin-6 (IL-6). When
compared to adults, neonates expressed less than 10% of
IFN-g, approximately 50% of TNF-a and normal-toslightly lower levels of IL-6 [6]. These mediators are
essential for the innate and acquired immune response.
IFN-g can upregulate the expression and local synthesis
of fH by human synovial fibroblasts [711] and is also able
to increase the fI mRNA levels in human cells [12, 13].
The expression of C4 BP mRNA by liver cells is increased
in the presence of IFN-g [14]. IL-1 and TNF-a can
increase the expression of properdin mRNA [15], while
IFN-g has opposite effects in several cell lines [16]. Finally,
other complement proteins are also dependent on the
stimulus of IFN-g (C2, fB, C4, C8 and C9), IL-6 (C3,
C4, fB and C8) and TNF-a (C3, fB, C8) (revised in [17]).
We found significantly lower levels of fH, fI, C4 BP,
properdin and vitronectin in healthy neonates when compared to healthy adults. Interestingly, most of newborn sera
presented low or undetectable levels of C4 BP. Lower levels
of fH, fI, C4 BP and properdin were also reported in other
studies as well as other complement proteins such as C1q,
C1r, C1s, C2, C3, C4, C5, C6, C8 and C9 in newborns
when compared to adults [1821]. However, C7 is present
in newborns and adults in similar concentrations [22]. The
concentration of fB was considered significantly lower in
the serum of neonates by some authors [21], but other
researchers found this protein within the normal range for
adults [19]. The above studies suggested that the low levels
of complement proteins contribute to a higher susceptibility of neonates to infection. In addition, neonates have low
complement-dependent haemolytic activity of complement at birth mediated either by the classical or by the
alternative pathways [22, 23].

# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577

576 Levels of Complement Regulatory Proteins

P. F. de Paula et al.
..................................................................................................................................................................................................

Table 2 Comparisons between the levels of factor H (fH), factor I (fI), C4 BP, properdin and vitronectin found for each age group in this study
Complement regulatory proteins
Comparisons

fI

fH

C4 BP

Properdin

Vitronectin

Neonates  111 months

Neonates  15 years
Neonates  612 years
Neonates  adults
111 months  15 years
111 months  612 years
111 months  adults
15  612 years
15 years  adults
612 years  adults

P < 0.001
P < 0.001
P < 0.001
P < 0.001
NS
NS
NS
NS
NS
NS

P < 0.001
P < 0.001
P < 0.001
P < 0.001
NS
NS
NS
NS
NS
NS

*
*
*
*
NS
P < 0.01
NS
P < 0.05
NS
NS

NS
P < 0.001
P < 0.001
P < 0.001
P < 0.05
NS
P < 0.01
NS
NS
NS

P < 0.05
NS
P < 0.05
P < 0.001
NS
NS
P < 0.01
NS
P < 0.001
P < 0.001

P-values are shown for significant differences. NS, no significant differences between the age ranges were found (P < 0.05).
*It was not possible to apply the KruskalWallis and Dunn test in this case because values were below the method resolution.

There have been some published reports of fH and fI

levels in serum from healthy newborns [18, 19, 23],
healthy infants aged between 1 and 6 months [18] and
healthy adults [19, 2427]. According to most of the
earlier studies [18, 19, 23, 26], the concentrations of fH
and fI changed during the ontogenetic development.
There are, however, some differences between our data
and previous reports [19, 2427]. For example, while
35 mg/ml has been considered the reference value for fI
level in adult serum [27], we found a wide range
(39100 mg/ml) in a group of 30 healthy Brazilian adults.
These variations could be explained by several factors such
as differences between populations, size and distribution of
the study population, technical differences used and statistical analysis [28].
However, the majority of the studies on fH and fI levels
have compared healthy neonates with healthy adults. To
our knowledge, we found only one study with older children group (16 months) that presented lower levels of fH
and fI until 6 months [18]. As we found similar fH and fI
levels between children from 1 month to 1 year and adults,
fH and fI levels probably attain adult levels between 6 and
12 months of age. Hence, at an early stage of life, children
are already able to regulate the amplification loop of the
alternative pathway that depends on fI/fH to inactivate C3
and C5 convertases. These levels can be considered sufficient because it is well recognized that heterozygous
fI-deficient individuals are able to control complement
activation [2931].
One important consideration to be discussed here is that
the polyclonal goat anti-human fH used have crossreactivity with fH-like protein (FhL-1) and fH-related
proteins (FhR 15). However, when we analysed the fH
family proteins using Western blotting, we did not observe
any qualitative differences between sera from neonates and
adults (data not shown).
In the case of C4 BP, we observed that the 6- to 13-yearold group presented higher concentrations than the children

from 1 month to 6 years. As no other studies have determined C4 BP levels in children older than neonates, we
may speculate that these higher levels are a consequence of
the typical hormonal influence of this period of life. Why
76% of neonates serum present unmeasurable concentrations of C4 BP is an open question. One possibility of
explaining this is that the concentration of C4 BP is clearly
affected by the presence of IFN-g [14], and at this age, this
cytokine reaches approximately 10% of which is found in
adults.
Less properdin is present in the sera from children
during first year of life than in children from 1 to 6
years and adults. This result is in agreement with that
reported by other authors [32] who found lower properdin
concentrations in 1-year-old children than in adults. In
addition, other researchers [18] found that 6-month-old
children had lower properdin levels.
Adults presented higher vitronectin levels than all the
other age groups in our study. In contrast, no significant
differences among the vitronectin levels from neonates,
infants (<1 year), children (110 years), preadults
(1118 years) and adults (>18 years) were found in
another study [33]. There are some possible explanations
for these discrepancies such as differences in methodology
and the size and distribution of the study population.
Finally, these differences may in fact be a reflection of
inherent variability of biological characteristics of each
population under study and it was previously observed
for C3, C4 and fB in the same population [34]. This
may in fact underline the importance to establish normal
concentrations of complement proteins for each population.
We have recently studied 418 children with histories of
recurrent infections in which 128 presented various types
of immunodeficiencies. From this total, 11 (8.6%)
patients presented impairment in the activation of the
classical and/or alternative pathways [35]. In another
words, it is clinically valuable to determine the normal

# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577

P. F. de Paula et al.
Levels of Complement Regulatory Proteins 577
..................................................................................................................................................................................................

range of complement proteins in healthy children, especially because these ranges might be different than those
found in adult serum. In addition, this study contributes
to the understanding of the ontogeny of complement
system in humans.

Acknowledgments
The work was supported by Fundacao de Amparo a
Pesquisa do Estado de Sao Paulo, Sao Paulo. We are
grateful to MPC Florido for her technical assistance. We
also thank Hospital Universitario/USP and Hospital
Israelita Albert Einstein for part of the blood samples.
Dr Latorre and Dr Isaac were supported by a Conselho
Nacional de Pesquisa e Desenvolvimento Tecnologico
(Brazil) research fellowships.

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# 2003 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 58, 572577