DOI: 10.1111/all.13734
L E T T E R TO TH E E D I T O R
Soluble FcɛRI: A biomarker for IgE‐mediated diseases
To the Editor, in two food‐sensitized nonallergic groups (FS and Ghana) with FA
Soluble IgE receptors interact with IgE in the extracellular matrix and patients (Table S3). The Ghana cohort showed similar correlations as
are important in the regulation of immune diseases.1-5 Soluble FcεRII already described between IgE and sFcεRI, IgE‐bound and total
(sCD23) and galectin‐3 (εBP) are currently used as biomarkers,1 sFcεRI levels, and no correlation with peanut‐specific IgE (sIgE) titers.
though correlation data on serum titers and severity of allergies are No significant difference was detected with regards to disease activ-
controversial.1,6 ity among food‐sensitized individuals (Figure S2).
FcεRI, the high‐affinity IgE Fc receptor, is expressed on several We then investigated whether serum sFcεRI levels were different
innate cell types,2 and a truncated version of the IgE‐binding alpha in patients diagnosed with atopic dermatitis or asthma, with (Pos
subunit is found as a soluble isoform (sFcεRI) in human serum. In cir- sIgE) or without (Neg sIgE) a clinically relevant sIgE profile. sFcεRI
culation, sFcεRI is mostly detected as a complex with IgE.7 This titers did not differ based on the patients’ sIgE profile. However, we
observation raises the question of how sFcεRI affects detection of found significantly higher titers in patients with elevated IgE (Fig-
serum IgE titers. ure S3) in both AD and AA groups (Figure 1E‐H).
In order to assign clinical implications of sFcεRI, we assessed Recently, we demonstrated that sFcεRI is released from dendritic
serum titers in its total and IgE‐bound forms in different IgE‐ cells and mast cells after antigen‐specific FcεRI crosslinking.5 Thus,
mediated diseases in 312 individuals. We compared pediatric popula- we studied how sFcεRI levels in circulation are affected by allergen
tions with primary food allergies (n = 59), insect venom allergies exposure. We compared sFcεRI levels in AA individuals (n = 14 pairs)
(n = 9), allergic asthma (n = 24), atopic dermatitis (n = 25), food‐sen- during (In) and before/after (Out) season for their most clinically rele-
sitized nonallergic children (n = 31), and nonallergic controls (n = 17). vant allergen (Table S4) and observed that serum levels could signifi-
Additionally, other sensitized groups and controls (n = 147) were cantly increase (50%) or decrease (50%) during season. This pattern
included in the study (Table S1-S4). was similarly observed with total IgE levels (Figure S4). In order to
better determine the role of allergen exposure, we analyzed food‐
sensitized individuals on allergen avoidance (n = 13) during an oral
SFCΕRI IS ELEVATED IN SERUM OF ATOPIC
food challenge (Figure S5). We observed a general trend of sFcεRI
INDIVIDUALS AND IS MODULATED BY ALLERGEN
titers to decrease after allergen exposure (Figure 1I).
EXPOSURE
Serum samples were analyzed by ELISA to detect IgE‐bound and total
IGE:SFCΕRI COMPLEXES INTERFERE WITH IGE
serum sFcεRI levels (Figure S1). First, sFcεRI was ubiquitously detect-
DETECTION
able among controls (median 1.20 ng/mL) but titers were significantly
higher in atopic individuals (median 2.88 ng/mL, Figure 1A and Table sFcεRI binds to the Fc portion of IgE and can potentially interfere
S1). In line with previous studies,7,8 IgE and sFcεRI levels correlated with antibody binding to that region. We thus investigated whether
positively in all patients, and sFcεRI in circulation was almost uniquely sFcεRI affects antibody‐based IgE detection. For this purpose, a
detected as a complex with IgE (Figure 1B,C). Next, we grouped the recombinant IgE‐binding protein (rsFcεRI) and a mutated version
atopic individuals based on their main IgE‐mediated disease (Table S2) which cannot bind IgE (rsFcεRIm) were generated. Prior to a commer-
as food allergy (FA), insect venom allergy (IV), allergic asthma (AA), or cial IgE ELISA, samples containing human cIgE were incubated with
atopic dermatitis (AD). AD, AA, and FA groups presented with signifi- the recombinant proteins (Figure 2A‐C). Our hypothesis was that IgE
cantly higher sFcεRI levels than controls (Figure 1D). detection will be impaired and reflected in a decrease of IgE levels
Since IgE‐sensitization profiles toward food allergens are gener- with increasing concentrations of rsFcεRI. In Figure 2D, we show an
ally a poor measure of clinical symptoms, we compared sFcεRI titers r = −0.867 with P = 0.005 which depicts a significant negative corre-
lation in support of our hypothesis. On the contrary, as shown in
Abbreviations: cIgE, chimeric humanized anti-NIP immunoglobulin E; DC, dendritic cell; Figure 2E, increasing concentrations of the mutant version of rsFcεRI
FcεRI, Fc epsilon Receptor I, high-affinity IgE Fc receptor; IgE, Immunoglobulin E; IQR,
interquartile range; MC, mast cell; OFC, oral food challenge; rsFcεRIm, mutant recombinant which is unable to bind IgE do not show interference in IgE detec-
human sFcεRI; rsFcεRI, recombinant human sFcεRI; sCD23, soluble isoform of CD23, tion (r = 0.349, ns). This interference with IgE detection by rsFcεRI
low-affinity IgE Fc receptor; sFcεRI, soluble isoform of FcεRI; sIgE, allergen-specific
was confirmed with human IgE (Figure 2F) and human serum (n = 2)
immunoglobulin E; SPT, skin prick test; εBP, epsilon binding protein.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.
Allergy. 2019;1–4. wileyonlinelibrary.com/journal/all | 1
2 | LETTER TO THE EDITOR
(A) (B) (C)
30 **** Atopy 40 Atopy30
r = 0.3327 r = 0.9751
P < 0.0001 P < 0.0001
30
20
20
20
10 10 10
0 0 0
Co Atopy 0 2000 4000 6000 0 10 20 30 40
IgE (kU/L) IgE-bound sFcɛRI (ng/mL)
(D)
30 IgE-mediated diseases (E) 15 Atopic Dermatitis (F) Atopic Dermatitis** 15
P = 0.4049 **
20 10 10
****
**
10 5 5
0 0 0
Co IV AD AA FA Pos sIgE Neg sIgE Elevated IgE Normal IgE
(G) Asthma (H) Asthma (I)30 30 12 OFC Time course
P = 0.9737
* OFC positive
10 OFC negative
20 20 8
6
10 410
2
0 00
Pos sIgE Neg sIgE Elevated IgE Normal IgE Before 0 +30 +90 +120
minutes after reaction/last dose
F IGURE 1 sFcεRI is highly expressed in allergic individuals and it is modulated by allergen exposure. Detection of total and IgE‐bound
sFcεRI levels by ELISA. Total sFcεRI levels in control and atopic (n = 148) groups (A). Correlation between total sFcεRI and total IgE levels in
atopic group (B). Total and IgE‐bound sFcεRI levels in atopic group (C). Total sFcεRI levels in control and IgE diseases groups (D). Total sFcεRI
levels with and without sIgE sensitizations, and normal and elevated IgE levels in AD (E‐F) and AA (G‐H). Total sFcεRI levels during OFC (I).
Graphs represent individuals with median plus IQR. Mann‐Whitney test (A, E‐H), Kruskal‐Wallis test plus Dunn's multiple correction (C), and
Spearman r coefficient ranks (B, D) were performed, where *P < 0.05, **P < 0.01, and ****P < 0.0001. Co: control (n = 17); IV: insect venom
(n = 9); AD: atopic dermatitis (n = 45); AA: allergic asthma (n = 69); FA: food allergy (n = 59); Pos: positive; Neg: negative; IQR: interquartile
range; OFC: oral food challenge (n = 13) [Color figure can be viewed at wileyonlinelibrary.com]
from patients with elevated IgE levels (Figure 2G). In addition, we To the best of our knowledge, this is the first analysis of sFcεRI
observed that sFcεRI titers were significantly higher in serum than levels in a pediatric population of well‐classified sensitized and aller-
plasma (Figure S6). gic individuals. We show that sFcεRI is correlated with IgE levels, is
sFcɛRI (ng/mL) sFcɛRI (ng/mL) sFcɛRI (ng/mL)
sFcɛRI (ng/mL)
sFcɛRI (ng/mL)
sFcɛRI (ng/mL)
sFcɛRI (ng/mL)
Total sFcɛRI (ng/mL)
sFcɛRI (ng/mL)
LETTER TO THE EDITOR | 3
(A) (B) (C)
KDa KDa
130 130
100 100
70 70
55 55
rsFcεRI rsFcεRIm
35 35triple-flag point mutation
(D) (E)
2.0 cIgE 2.0 cIgE
1.8 1.8
1.6 1.6
1.4 1.4
F IGURE 2 sFcεRI interferes with IgE 1.2 r = –0.867P = 0.005 1.2
r = 0.349
detection ELISA. Detection of IgE and ns
sFcεRI levels by ELISA and Western Blot. 1.0 1.0
Representation of rsFcεRI and rsFcεRIm 2 4 8 16 32 64 128 256 512 2 4 8 16 32 64 128 256 512
m
proteins (A). Detection of rsFcεRI and rsFcεRI (ng/mL) rsFcεRI  (ng/mL)
rsFcεRIm proteins by Western Blot analysis (F) Human IgE (G) Human serum
in nonreducing and reducing conditions (B‐ 12000 ****
C). Detection of IgE pre‐incubated with 10000 3500
rsFcεRI and rsFcεRIm proteins in a 500 ng/
mL cIgE solution (D‐E). Detection of IgE 8000 3000
pre‐incubated with rsFcεRI in human IgE 800 Patient A
(1:10‐ 25001:100) or human serum (3202 and Patient B
903 ng/mL) solutions (F‐G). Graphs 600 2000
represent assay triplicates of a
representative experiment (D‐E), or assay 400 1500
duplicates of biological triplicates (F) or 1000
two individuals (G). Spearman coefficient 200
rank analysis or 1‐way ANOVA test plus 500
Tukey's multiple correction was performed, 0
where *P < 0.05 and ****P < 0.0001 IgE 1:10 1:10 1:100 1:100 0rsFcεRI - 0.8 2.5 - 0.8 2.5
[Color figure can be viewed at rsFcεRI - 8.3 - 8.3
(ng/μL) (ng/μL)wileyonlinelibrary.com]
significantly increased in IgE‐sensitized individuals, and can be modu- Bannert, and Dr. Susanne C. Diesner for their contribution in patient
lated by allergen exposure. We collected evidence that sFcεRI can recruitment. Special thanks to Alexandra C. Graf from the Center for
interfere with IgE detection in serum, which might be of importance Medical Statistics, Informatics, and Intelligent Systems, Medical
in regard to interference in sIgE detection and diagnosis. Although University of Vienna, for her assistance on the statistical analysis.
further research on the modulation by allergen exposure and inter- This work was supported by the Austrian Science Fund (FWF):
ference with sIgE molecules is needed, sFcεRI represents an addi- DK MCCA W 1248‐B13 (ZS), W 1205‐B09 (EJJ), SFB F4606‐B28
tional biomarker for IgE‐mediated diseases and its use could be a (EJJ), and by the Harvard Digestive Diseases Center Grant
valuable tool in clinical practice. P30DK034854, Core B (EF). EF is supported by a Bridge Grant from
the Research Council of Boston Children's Hospital, an Emerging
Investigator Award from FARE, a Senior research grant of the CCF
ACKNOWLEDGMENTS
and an unrestricted gift from the Mead Johnson Nutrition Company.
We thank all the members of the Szépfalusi, Fiebiger, and Yazdan- The Ghana study was supported by European Commission grants;
bakhsh laboratories for discussions and technical assistance. We EuroPrevall (grant no. FOOD‐CT‐2005‐514000) and GLOFAL (grant
thank Klara Schmidthaler, Dr. Eleonora Dehlink, Dr. Christina no. FOOD‐CT‐2005‐517812).
IgE (ng/mL) Average OD 450
IgE (ng/mL) Average OD 450
4 | LETTER TO THE EDITOR
CONFLICTS OF INTEREST 7Department of Parasitology, Leiden University Medical Center, Leiden,
The Netherlands
The authors declare that they have no conflicts of interest.
8Department of Parasitology, Noguchi Memorial Institute for Medical
Research, College of Health Sciences, University of Ghana, Legon-Accra,
ORCID Ghana
Sherezade Moñino-Romero https://orcid.org/0000-0003-3775- Correspondence
2989 Zsolt Szépfalusi, Department of Pediatrics and Adolescent Medicine,
Josef Singer https://orcid.org/0000-0002-8701-2412 Medical University of Vienna, Vienna, Austria.
Erika Jensen-Jarolim https://orcid.org/0000-0003-4019-5765 Email: zsolt.szepfalusi@meduniwien.ac.at
Edda Fiebiger https://orcid.org/0000-0003-3385-0100
Zsolt Szépfalusi https://orcid.org/0000-0003-4852-3102 REFERENCES
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