Soluble FcɛRI: A biomarker for IgE‐mediated diseases

Moñino-Romero, Sherezade; Lexmond, Willem S; Singer, Josef; Bannert, Christina; Amoah, Abena S; Yazdanbakhsh, Maria; Boakye, Daniel A; Jensen-Jarolim, Erika; Fiebiger, Edda; Szépfalusi, Zsolt; (2019) Soluble FcRI: a biomarker for IgE-mediated diseases. Allergy. ISSN 0105-4538 DOI: https://doi.org/10.1111/all.13734 Downloaded from: http://researchonline.lshtm.ac.uk/4653082/ DOI: https://doi.org/10.1111/all.13734

To the Editor, Soluble IgE receptors interact with IgE in the extracellular matrix and are important in the regulation of immune diseases. [1][2][3][4][5] Soluble FcεRII (sCD23) and galectin-3 (εBP) are currently used as biomarkers, 1 though correlation data on serum titers and severity of allergies are controversial. 1,6 FcεRI, the high-affinity IgE Fc receptor, is expressed on several innate cell types, 2 and a truncated version of the IgE-binding alpha subunit is found as a soluble isoform (sFcεRI) in human serum. In circulation, sFcεRI is mostly detected as a complex with IgE. 7 This observation raises the question of how sFcεRI affects detection of serum IgE titers.
Additionally, other sensitized groups and controls (n = 147) were included in the study (Table S1-S4).

SF CΕ RI IS ELEVATED IN SERUM OF ATOPIC
INDI VIDUALS AND IS MODULATED BY ALLERG EN EXPOSURE Serum samples were analyzed by ELISA to detect IgE-bound and total serum sFcεRI levels ( Figure S1). First, sFcεRI was ubiquitously detectable among controls (median 1.20 ng/mL) but titers were significantly higher in atopic individuals (median 2.88 ng/mL, Figure 1A and Table   S1). In line with previous studies, 7,8 IgE and sFcεRI levels correlated positively in all patients, and sFcεRI in circulation was almost uniquely detected as a complex with IgE ( Figure 1B,C). Next, we grouped the atopic individuals based on their main IgE-mediated disease (Table S2) as food allergy (FA), insect venom allergy (IV), allergic asthma (AA), or atopic dermatitis (AD). AD, AA, and FA groups presented with significantly higher sFcεRI levels than controls ( Figure 1D).
Since IgE-sensitization profiles toward food allergens are generally a poor measure of clinical symptoms, we compared sFcεRI titers in two food-sensitized nonallergic groups (FS and Ghana) with FA patients (Table S3). The Ghana cohort showed similar correlations as already described between IgE and sFcεRI, IgE-bound and total sFcεRI levels, and no correlation with peanut-specific IgE (sIgE) titers.
No significant difference was detected with regards to disease activity among food-sensitized individuals ( Figure S2).
We then investigated whether serum sFcεRI levels were different in patients diagnosed with atopic dermatitis or asthma, with (Pos sIgE) or without (Neg sIgE) a clinically relevant sIgE profile. sFcεRI titers did not differ based on the patients' sIgE profile. However, we found significantly higher titers in patients with elevated IgE ( Recently, we demonstrated that sFcεRI is released from dendritic cells and mast cells after antigen-specific FcεRI crosslinking. 5 Thus, we studied how sFcεRI levels in circulation are affected by allergen exposure. We compared sFcεRI levels in AA individuals (n = 14 pairs) during (In) and before/after (Out) season for their most clinically relevant allergen (Table S4) and observed that serum levels could significantly increase (50%) or decrease (50%) during season. This pattern was similarly observed with total IgE levels ( Figure S4). In order to better determine the role of allergen exposure, we analyzed foodsensitized individuals on allergen avoidance (n = 13) during an oral food challenge ( Figure S5). We observed a general trend of sFcεRI titers to decrease after allergen exposure ( Figure 1I).

IGE:SFCΕ RI COMPLEXES INTERFERE WITH IGE
DETECTION sFcεRI binds to the Fc portion of IgE and can potentially interfere with antibody binding to that region. We thus investigated whether sFcεRI affects antibody-based IgE detection. For this purpose, a recombinant IgE-binding protein (rsFcεRI) and a mutated version which cannot bind IgE (rsFcεRI m ) were generated. Prior to a commercial IgE ELISA, samples containing human cIgE were incubated with the recombinant proteins (Figure 2A-C). Our hypothesis was that IgE detection will be impaired and reflected in a decrease of IgE levels with increasing concentrations of rsFcεRI. In Figure 2D, we show an r = −0.867 with P = 0.005 which depicts a significant negative correlation in support of our hypothesis. On the contrary, as shown in Figure 2E, increasing concentrations of the mutant version of rsFcεRI which is unable to bind IgE do not show interference in IgE detection (r = 0.349, ns). This interference with IgE detection by rsFcεRI was confirmed with human IgE ( Figure 2F) and human serum (n = 2) from patients with elevated IgE levels ( Figure 2G). In addition, we observed that sFcεRI titers were significantly higher in serum than plasma ( Figure S6).
To the best of our knowledge, this is the first analysis of sFcεRI levels in a pediatric population of well-classified sensitized and allergic individuals. We show that sFcεRI is correlated with IgE levels, is significantly increased in IgE-sensitized individuals, and can be modulated by allergen exposure. We collected evidence that sFcεRI can

CONFLI CTS OF INTEREST
The authors declare that they have no conflicts of interest. Delayed drug hypersensitivity to bortezomib: Desensitization and tolerance to its analogue carfilzomib To the Editor, Bortezomib is a boronic acid dipeptide that selectively inhibits the proteasome and is currently used as standard of care in the treatment of patients with multiple myeloma (MM). 1,2 It has been shown to inhibit the expression of cell adhesion molecules, co-stimulatory molecules and NF-β activation, to deplete alloreactive T lymphocytes and to decrease Th1 cytokine production.
Cutaneous side effects related to bortezomib administration are frequent, as reported in a phase 3 randomized study, 3 in which 57% and 70% of patients experienced a grade 3 or higher skin toxicity with subcutaneous and intravenous administration, respectively. The severity of skin reactions described in the literature includes a wide range of manifestations, from local delayed flare reaction and perivascular dermatitis, to symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), 4 Nicolau syndrome, 5 sweet and sweet-like syndrome, 6 erythema multiforme-like, 7 drug reaction with eosinophilia and systemic symptoms (DRESS) 8 and fatal toxic epidermal necrolysis (TEN). 9 T cell-mediated immunopathology is central to these severe