Mechanisms of Allergy – Original Paper
Int Arch Allergy Immunol 2017;172:27–32
DOI: 10.1159/000455099
Synergistic Actions of Histamine-Releasing Factor
and Histamine Releasing Factor-Reactive IgE in
Chronic Urticaria
Xianqiong Huang Zhaoyang Li Renshan Sun
Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing, China
Keywords
Chronic urticaria · Histamine-releasing factor ·
Histamine-releasing factor-reactive IgE
Abstract
The etiology of chronic urticaria (CU) remains elusive. Hista-
mine-releasing factor (HRF) is reported to have a proinflam-
matory role in asthma and immediate hypersensitivity of the
skin. The aim of this study was to examine the role of HRF in
the pathogenesis of CU. Forty patients with CU were en-
rolled and their serum HRF concentrations were determined
by ELISA. The results demonstrated that the concentrations
of HRF and HRF-reactive IgE in the CU group were signifi-
cantly higher than those in the control group, and there was
a significant linear correlation between HRF and HRF-reac-
tive IgE concentrations (r = 0.859, p < 0.001) in CU patients.
Additionally, the HRF-reactive IgE concentration was signifi-
cantly correlated with the disease activity (r = 0.693, p <
0.0001). HRF and HRF-reactive IgE alone failed to activate
LAD2 cells. After being primed by the patient sera with the
highest IgE concentrations and stimulated by HRF, β-hexos-
aminidase can be released from LAD2 cells. Our findings sug-
gest that the synergistic actions of HRF and HRF-reactive IgE
may play important roles in the pathogenesis of CU.
© 2017 S. Karger AG, Basel
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/iaa
Received: June 27, 2016
Accepted after revision: December 13, 2016
Published online: February 21, 2017
Introduction
Chronic urticaria (CU) is a debilitating disease charac-
terized by the occurrence of wheals lasting for >6 weeks.
Although several mechanisms have been implicated, the
etiology of CU is not well understood [1]. The activation
of skin mast cells plays a key role in inflammation associ-
ated with the disease. Upon activation, mast cells secrete
preformed mediators as well as de novo synthesized lipids
and polypeptides, leading to the development of allergic
inflammation [2]. Only certain patients have CU of an
autoimmune origin, suggesting that other factors may
contribute to its pathogenesis [3].
Histamine-releasing factor (HRF), also known as
translationally controlled tumor protein and fortilin, is a
highly conserved protein with both intracellular and ex-
tracellular functions [4–8]. HRF is secreted by macro-
phages and other cell types and can stimulate histamine
release as well as IL-4 and IL-13 production from IgE-
sensitized basophils and mast cells [9]. HRF-like activities
were found in nasal, skin blister, and bronchoalveolar la-
vage fluids during late-phase allergic reactions, implicat-
ing HRF in these reactions and chronic allergic inflam-
mation [10, 11]. However, the definitive role of HRF in
allergic reactions remains elusive [8, 9, 12]. Kashiwakura
et al. [13] found a subset of IgE and IgG antibodies as
HRF-interacting molecules in vitro. HRF could bind to
IgE via interactions of its N-terminal and internal regions
with the Fab region of IgEs. The researchers’ asthma and
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Correspondence to: Dr. Renshan Sun
Department of Dermatology, Daping Hospital, Third Military Medical University
University of Hong Kong
No. 10 Changjiang Branch Road, Yu-Zhong District
Chongqing 400042 (China)
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E-Mail pharsunr @ 126.com
allergy studies in a mouse model indicated that HRF had
a proinflammatory role in asthma and immediate hyper-
sensitivity in skin [14]. We hypothesized that HRF to-
gether with HRF-reactive IgE may be able to activate mast
cells in CU patients.
To explore the role of HRF in the pathogenesis of CU,
we measured the serum HRF and HRF-reactive IgE con-
centrations in CU patients and evaluated their correla-
tions with the clinical urticaria activities. In addition,
mast cell line LAD2 was employed as an in vitro model to
test the synergistic actions of HRF and HRF-reactive IgE
for mast cell degranulations.
Materials and Methods
Subjects
From March to September 2014, we enrolled 40 patients with
CU; 21 were men and 19 were women (mean ± SD, 40 ± 14 years
old), and they were enrolled based on their clinical history and
typical urticarial lesions. We also included 40 healthy controls; 18
men and 22 women (48 ± 12 years old). This study was approved
by the Ethics Committee of Daping Hospital, Third Military Med-
ical University, Chongqing, China. All subjects signed informed
consent forms. Patients had not received steroids or immunomod-
ulatory drugs for 1 month and had stopped all medications. In the
CU subjects the disease had been present for 12.8 ± 12.4 months
(range 4–35) and the patients had urticaria symptom scores of 14.2
± 6.5. The urticaria activity score (UAS) was calculated using the
EAACI/GA2LEN/EDF guidelines [1] and as previously described
by Maurer’s group [15]. Weekly UAS were graded as follows: 0–14
(mild), 15–29 (moderate), and 30–42 (severe).
Our study comprised 14 patients with mild CU, 13 patients
with moderate CU, and 13 patients with severe urticaria symptoms
as per the weekly UAS. Patients with severe CU represented a
group that showed highly intensified symptoms prior to the test,
which were barely controlled by doses of antihistamines above the
standard (20 mg of levocetirizine or desloratadine). All blood sam-
ples were obtained by antecubital puncture. EDTA was used as an
anticoagulant.
Assay of HRF
The serum HRF concentration was determined by ELISA
(Uscn Life Science Inc., Houston, TX, USA) according to the man-
ufacturers’ protocol. The intraassay and interassay CVs were 10
and 12%, respectively, for HRF. The sensitivity of the assay was
0.70 ng/mL. The minimum detectable dose of human HRF is typ-
ically <0.126 ng/mL. The sensitivity of this assay, i.e. the lower
limit of detection, was defined as the lowest protein concentration
that could be differentiated from zero.
Assay of HRF-Reactive IgE
ELISA polystyrene 96-well plates were coated overnight with
10 μg/mL of HRF (Uscn Life Science Inc.) in 0.1 M carbonate buff-
er (pH 9.5) as previously described [13]. The HRF-reactive IgE
concentration was determined by a specific IgE test kit (HOB Bio-
tech Group, Suzhou, China). The plates were washed and blocked
28 Int Arch Allergy Immunol 2017;172:27–32
DOI: 10.1159/000455099
with 10% fetal calf serum (FCS) or 1% bull serum albumin. The
patient and control sera (1: 100 dilution) were incubated in the
coated wells, after which the bound IgE was detected by incubation
with biotinylated anti-human IgE followed by HRP-conjugated
streptavidin. Color was developed using TMB substrate, and the
absorbance at 450 nm was measured. The intraassay and interassay
similarity was 100%. The sensitivity of the assay was 0.35 IU/mL.
LAD2 Cell Stimulation and β-Hexosaminidase Measurement
The human mast cell line LAD2 was kindly provided by Dr. A.S.
Kirshenbaum (NIAID, Bethesda, MD, USA). LAD2 cells were cen-
trifuged at 3,000 rpm (Hettich, Rotofix 32, swing-out rotor) and
resuspended in Tyrode buffer at 2 × 106 cells/mL. To analyze the
ability of HRF to form cross-links with receptor-bound, HRF-reac-
tive IgE on the surface of LAD2 mast cells, the cells were incubated
overnight with the appropriate concentration of patient sera. They
were activated the following morning with HRF and incubated for
1 h; the reaction was stopped by centrifuging the cells at 3,000 rpm
for 3 min [13, 14]. In the positive control, LAD2 cells were primed
overnight with 500 ng/mL of biotinylated human myeloma IgE (US
Biological, distributed by Europa Bioproducts Ltd) and activated
the following morning with 500 ng/mL of streptavidin [15]. The
β-hexosaminidase assay was carried out in a 96-well plate [13]. For
this assay, 100 μL of substrate (100 mM sodium citrate buffer, pH
4.5, 4 mM 4-nitrophenyl-n-acetyl-D-glucosamine) was added to
each well, followed by 80 μL of the sample to be assayed. The
reaction was stopped by the addition of 160 μL of stop buffer
(0.0167 M sodium carbonate, 0.0167 M sodium bicarbonate pH 10).
β-Hexosaminidase release was assessed by measuring the optical
density at 405 nm (OD405) using a microplate spectrophoto-
meter (Anthos Labtec) and was expressed as a percentage of total
cellular β-hexosaminidase with the following formula [13, 14]:
β-hexosaminidase release (%) = (OD405 of β-hexosaminidase release
from LAD2 stimulated – OD405 of spontaneous β-hexosaminidase
release)/(OD405 of total β-hexosaminidase release) ×100%. The
spontaneous levels of β-hexosaminidase release were measured in
cells incubated with release buffer only, and total β-hexosaminidase
release was determined by lysing the cells with Triton-X 100 (0.1%,
v/v) solution.
Statistical Analysis
Results are expressed as the median and interquartile ranges.
Because the data were not distributed normally, nonparametric
tests were used. The Kruskal-Wallis analysis of variance was used
to screen differences between the groups. The Mann-Whitney U
test was used to compare data between the patient groups and the
healthy controls. Wilcoxon’s paired test was used to evaluate dif-
ferences within the same group. Spearman’s rank test was used for
correlations. p < 0.05 was considered to be significant.
Results
Serum HRF Concentration and Its Correlation with
UAS
The serum concentration of HRF was significantly
higher in CU patients than in the healthy subjects (4.31 ±
2.13 vs. 8.81 ± 6.03 ng/mL, p < 0.001) (Fig. 1). In addition,
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 30 p < 0.001 2.5
p < 0.001
25
2.0

HRF-reactive IgE, IU/mL

20
HRF, ng/mL

1.5
15
1.0
10

0.5
5

0 0
Control CU Control CU

Fig. 1. Serum HRF concentrations in healthy subjects (control, Fig. 3. Serum HRF-reactive IgE concentrations in healthy subjects
n = 40) and CU patients (n = 40). (control, n = 40) and CU patients (n = 40).

20 1.5
* ++
HRF-reactive IgE, IU/mL

15 *+
1.0
*
HRF, ng/mL

10
+
* ++ 0.5
5

0 0
Control CU-mild Cu-moderate CU-severe Control CU-mild Cu-moderate CU-severe

Fig. 2. Serum HRF concentrations in healthy subjects (control, Fig. 4. Serum HRF-reactive IgE concentrations in healthy subjects
n = 40), and the mild (n = 14), moderate (n = 13), and severe (n = (control, n = 40), and the mild (n = 14), moderate (n = 13), and
13) CU groups. + p < 0.05 and ++ p < 0.01 vs. the CU-severe group. severe (n = 13) CU groups. * p < 0.01 vs. the control group. + p <
* p < 0.01 vs. the control group. 0.05 and ++ p < 0.01 vs. the CU-mild group.

the serum HRF concentration between the CU patients
with mild and severe symptoms showed significant dif-
ferences (5.64 ± 3.27 vs. 13.70 ± 7.42 ng/mL, p < 0.01). A
significant difference was also observed between the se-
rum HRF concentration in CU patients with moderate
and severe symptoms (7.34 ± 3.40 vs. 13.70 ± 7.42 ng/mL,
p < 0.05) (Fig. 2). Moreover, the serum HRF concentra-
tion showed a significant correlation with the disease ac-
tivity, which was assessed by calculating the cumulative
UAS during the 7 days before blood sampling (r = 0.696,
p < 0.0001).
Serum HRF-Reactive IgE Concentration and Its
Correlation with UAS
The serum HRF-reactive IgE concentration in CU pa-
tients was significantly higher than that in healthy sub-
jects (0.31 ± 0.15 vs. 1.04 ± 0.33 IU/mL, p < 0.001) (Fig. 3).
In addition, there were significant differences in the se-
rum HRF-reactive IgE concentrations between the CU
patients with mild, moderate, and severe symptoms (me-
dian 0.82 vs. 1.05 vs. 1.26 IU/mL, respectively; p < 0.05
and < 0.001) (Fig. 4). Similar to CU patients with moder-
ate or severe symptoms, the serum HRF-reactive IgE con-
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HRF and HRF-Reactive IgE in Chronic Int Arch Allergy Immunol 2017;172:27–32 29
Urticaria DOI: 10.1159/000455099
University of Hong Kong
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 2.0
HRF-reactive IgE, IU/mL
1.5
1.0
0.5
0
0 5 10 15 20 25 30
HRF, ng/mL
Fig. 5. Correlation between serum HRF-reactive IgE and HRF con-
centration in CU patients. r = 0859, p < 0.001.
centration in the mild CU group was higher than that in
the control group. Moreover, the HRF-reactive IgE con-
centration was significantly correlated with the disease
activity as assessed by weekly UAS (r = 0.693, p < 0.0001).
Correlation between HRF and Serum HRF-Reactive
IgE Concentration
There was a significant correlation between the circu-
lating concentration of HRF and HRF-reactive IgE (r =
0.859, p < 0.001) in the CU patients (Fig. 5).
Effects of HRF and the Patient Serum with the
Highest HRF-Reactive IgE Concentration upon
Mast Cell Activation
LAD2 cells were sensitized with either patient or
healthy sera and were then stimulated with 30 ng/mL of
HRF. HRF was able to significantly induce the β-hexos-
aminidase release of LAD2 cells sensitized with sera from
2 out of 12 CU patients with a higher HRF-reactive IgE
level, but not from normal subjects (Fig. 6 shows the re-
sults of 1 representative patient with CU, patient No. 24).
The β-hexosaminidase release level in LAD2 cells primed
by sera from patient No. 24 and then stimulated with HRF
was substantially higher than that in the PBS control
group (p < 0.01) (Fig.  6). Compared to the PBS group,
neither HRF alone nor the patient sera with the highest
IgE concentration alone could induce β-hexosaminidase
release from LAD2 cells (p > 0.05). It is suggested that
HRF is able to aggregate high-affinity IgE receptors, lead-
ing to the activation of mast cells in CU patients with a
higher serum level of HRF-reactive IgE.
30 Int Arch Allergy Immunol 2017;172:27–32
DOI: 10.1159/000455099
60
DŽ+H[RVDPLQLGDVHUHOHDVH
*
+
40
20
0
a b c d e
Fig. 6. β-Hexosaminidase release from LAD2 human mast cells.
LAD2 were sensitized with PBS overnight as a negative control
(PBS group) (a). The cells were washed and resuspended (2 × 106
cells/200 μL) in HEPES-Tyrode buffer and stimulated with 500 ng/
mL of streptavidin. Following this they were either: sensitized
overnight with 10% serum from patient No. 24 and stimulated
with 500 ng/mL of streptavidin (b); not sensitized overnight and
stimulated with 30 ng/mL of HRF (c); sensitized overnight with
10% serum from patient No. 24 and stimulated with 30 ng/mL of
HRF (d); or sensitized overnight with 500 ng/mL of biotinylated
human IgE and stimulated with 500 ng/mL of streptavidin as a
positive control (e). The cells were centrifuged and the percent re-
lease of β-hexosaminidase into the supernatant was calculated.
β-Hexosaminidase release (%) is expressed as the mean ± SEM for
3 separate experiments with LAD2 cells. * p > 0.05 and + p < 0.01
vs. the PBS group.
Discussion
Although mast cell degranulation induced by IgE and
histamine release is thought to play a pivotal role in CU,
the exact etiology of CU is still not completely under-
stood. In the present study, we demonstrated that the av-
erage serum concentration of HRF and HRF-reactive IgE
in CU patients was much higher than in the healthy con-
trols. We also found a significant linear correlation be-
tween HRF and HRF-reactive IgE. The levels of HRF and
HRF-reactive IgE in serum both correlated positively
with the CU activity score, which confirmed that HRF
and HRF-reactive IgE may play very important roles in
the pathogenesis of CU.
Autoreactive IgE and IgG levels against self-antigens
in patients with atopic dermatitis (AD; n = 28) and CU
(n = 85) were measured using enzyme-linked immuno-
sorbent assays by Hatada et al. [16]. DsDNA, thioredoxin,
peroxiredoxin, and thyroglobulin (5 μg/ml) were coated
in 96-well plates and left overnight at room temperature.
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The researchers found that the anti-dsDNA IgE levels
were significantly higher in patients with CU and AD
than in normal subjects, but no differences in the anti-
dsDNA IgG levels were observed. The levels of thiore-
doxin-, peroxiredoxin- and thyroglobulin-reactive IgE
and IgG were not significantly higher in the CU patients
than in the other 2 groups. In another report [13], recom-
binant HRF tagged with 6× histidine (10 μg/mL in PBS)
was coated in 96-well plates overnight at 4 ° C. After the
   
wells were blocked with 10% FCS-PBS, sera from AD pa-
tients were incubated in the well. Bound HRF-reactive
IgE molecules were detected by the ELISA method. It was
found that AD patients also had higher serum levels of
HRF than healthy controls. Two of these patients had ex-
tremely high IgE levels of 48.7 and 384 μg/mL. By con-
trast, none of the 25 healthy individuals had detectable
levels of anti-HRF IgE. In our study, the highest HRF-
reactive IgE level was observed in the serum of patient No.
24, at 2.008 IU/mL. All of the above-illustrated HRF-
reactive IgE can be examined in patients with enzyme-
linked immunosorbent assays, and some autoreactive IgE
is involved in the pathogenesis of certain CU or AD cases.
The reasons for the elevated HRF concentration in CU
patients have not been elucidated. Intracellular calcium
changes, cell growth factor, environmental pollutants,
and abnormal stimulus can all affect HRF expression [17–
20]. HRF was also found in parasites including Plasmo-
dium falciparum, Wuchereria bancrofti, Brugia malayi,
and Schistosoma mansoni [21–23]. All of these parasites
possess mast cell/basophil histamine-releasing activity.
The pathogenesis of CU has been reported to be related
to infection by viruses, parasites or Helicobacter pylori [1–
3]. Patients with infections and tumors were all excluded
in the present study. However, other factors that may
raise the serum concentration of HRF, including previous
diseases, subclinical infections, or other undiscovered
diseases, could not be entirely avoided in the present sub-
jects.
It was found that IgG autoantibodies that work direct-
ly against the subunit of the high-affinity IgE receptor
(FcεRI) may contribute to CU pathogenesis [3, 24]. Al-
though these antibodies were reportedly present in 30–
60% of the patients with CU, the pathogenic mechanism
in the residual CU patients with a lower level of IgG au-
toantibodies remains unknown [1–3]. It was reported
that both serum HRF and the HRF-reactive IgE concen-
tration were elevated in the patients with AD, and the
patients’ sera could stimulate mast cells to release cyto-
kines [25, 26]. In our study, we found that 30 ng/mL of
HRF could efficiently activate LAD2 cells only after prim-
HRF and HRF-Reactive IgE in Chronic
Urticaria
ing the cells with the highest HRF-reactive IgE concentra-
tion sera. These data indicate that synergistic actions of
HRF and HRF-reactive IgE are required to fully activate
mast cells.
In conclusion, our study demonstrated that the con-
centrations of HRF and HRF-reactive IgE in the sera of
CU patients were elevated and had a significant linear
correlation. More importantly, we found that the efficient
activation of mast cells by HRF required the synergistic
action of HRF-reactive IgE. Therefore, our study suggests
a novel potential pathogenesis of CU and indicates that
interrupting the synergistic activation of HRF and HRF-
reactive IgE may contribute to the development of novel
approaches to treating CU.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 81571569) and Research Project of Chi-
nese Medical Association-L’Oreal for Chinese Health Skin and
Hair (No. S2017140916).
Disclosure Statement
The authors have no conflicts of interest to declare.
Author Contributions
R.S. conceived and designed the experiments; X.H. and Z.L.
performed the experiments and analyzed the data; R.S. wrote the
paper.
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