Low Responsiveness of Basophils via FcεRI Reflects Disease Activity in Chronic Spontaneous Urticaria

doi:10.1016/j.jaip.2019.05.020

The Journal of Allergy and Clinical Immunology: In Practice

Volume 7, Issue 8, November–December 2019, Pages 2835-2844.e7

https://doi.org/10.1016/j.jaip.2019.05.020 Get rights and content

Background

The insufficient effect of H1-antihistamine in some patients with chronic spontaneous urticaria (CSU) suggests that factors other than histamine are involved in the pathophysiology of CSU. Moreover, a central role for basophils in the pathophysiology of CSU has been hypothesized. However, few studies have focused on the relationship between basophil reactivity via FcεRI and clinical features in patients with CSU.

Objective

To assess basophil reactivity via FcεRI against anti-IgE and FcεRI stimulation in patients with CSU, and its association with disease activity in CSU. FcεRI expression and IgE binding on basophils from patients with CSU were also investigated.

Methods

We analyzed 38 patients with CSU, 8 patients with atopic dermatitis (AD), and 11 healthy controls (HCs). The surface CD203c expression with or without anti-IgE or FcεRI stimulation, and IgE and FcεRI (CRA1, CRA2) expression on blood basophils were evaluated. Patients with CSU were also evaluated and classified by disease activity and the above parameters were compared.

Results

The proportion of CD203c^high basophils after anti-IgE or anti-FcεRI stimulation was lower in patients with CSU compared with HCs and patients with AD. It was lowest in the CSU group with severe disease. Basophils from patients with CSU had higher FcεRI (CRA1) expression, although it was not closely related to the severity of CSU. Subgroup analysis revealed that patients with CSU showing low responsiveness of basophils via FcεRI exhibited a short duration of disease but severe disease activity.

Conclusions

Low reactivity of basophils via FcεRI is characteristic of patients with CSU. This attenuated reactivity is associated with severe clinical activity in patients with CSU (250 of 250).

Section snippets

Study population

Patients with CSU and AD who agreed to participate in this study were enrolled at the Dermatological Institute of Kobe University Hospital. CSU was defined as recurrent wheals occurring for more than 6 weeks without an identifiable cause. HCs were enrolled from healthy adult volunteers who are currently without symptoms of urticaria and no history of urticaria. Disease activity in patients with CSU was assessed both in clinical care and trials with the urticaria activity score 7 (UAS7). The UAS

Study population

The characteristics of patients with CSU are described in Table I. Thirty-eight patients with CSU (14 male and 24 female patients) were enrolled in the study. The mean age was 46.3 ± 16.2 years and the median duration of disease was 4.0 years. Median serum total IgE was 139.5 IU/mL. The ASST was performed in 17 patients, with the result being positive in 41.1% (7 of 17). Only 1 patient had concomitant angioedema.

In this study, the patients with CSU were categorized into 3 subgroups based on the

Discussion

This study focused on the fluctuation of CD203c expression as an activation marker on basophils in CSU pathogenesis. Previous studies have noted the unique features of peripheral blood basophils in patients with CSU. Some reports documented that basophils in patients with CSU have reduced histamine release in response to anti-IgE or CD63 induction in response to anti-FcεRI.12, 13 In contrast, other studies found that basophils of patients with CSU exhibit high response to anti-IgE based on

Acknowledgments

We thank Simon Teteris, PhD, from the Edanz Group (www.edanzediting.com/ac) and Tatsuya Horikawa, for editing the English text of a draft of this manuscript.

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Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.
Activated steady status and distinctive FcεRI-mediated responsiveness in basophils of atopic dermatitis
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Citation Excerpt :
This antibody can bind receptors directly, unlike anti-IgE antibody which binds to receptors indirectly via IgE. In this study, the CD203c response ratio of anti-FcεRI/baseline was lower than that of anti-IgE/baseline in HCs, consistent with a previous report.29 This means that the anti-IgE antibody under our experimental conditions could increase the HC basophil responsiveness more efficiently than the anti-FcεRI antibody.
Although basophils are considered to play an important role for maintenance of type 2 inflammation in atopic dermatitis (AD), studies on basophils in AD patients are limited. Some studies have reported the activation status, including CD203c and CD63, of peripheral blood basophils in AD patients.
We examined the features of circulating basophils in AD patients, assessed cell surface marker expressions and total serum IgE, and compared basophil responsiveness to stimulation between AD patients and healthy controls (HCs). In addition, the correlations among AD severity, laboratory factors, and features of basophils were examined. Blood samples from 38 AD patients and 21 HCs were analyzed. Basophil response markers CD203c and CD63, and expression of surface-bound IgE and FcεRI on basophils were measured. CD203c and CD63 expressions induced by stimulation with anti-IgE and anti-FcεRI antibodies were measured. Clinical/laboratory factors including total serum IgE were examined for correlations with these basophil parameters.
Baseline CD203c and CD63 expression on basophils were significantly higher in AD patients compared with HCs. The CD203c/CD63 response ratio to anti-FcεRI stimulation was higher than that to anti-IgE stimulation in AD patients, but not HCs. FcεRI expression on basophils was higher in AD patients than in HCs, although surface-bound IgE on basophils was equivalent. Total serum IgE had negative correlations with surface-bound IgE and CD63 responsiveness to anti-IgE stimulation.
Basophils were spontaneously activated under steady-state conditions in AD patients and responsiveness to anti-IgE stimulation was lower than in HCs. Despite high serum IgE and high basophil FcεRI expression, surface-bound IgE on basophils remained relatively low. Basophils might be suppressed or exhausted regarding FcεRI signaling via IgE in severe AD.
The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells
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Citation Excerpt :
The cause of the increased phosphatases is unknown, but its importance is highlighted by the changes observed during symptom reversal. Whether improvement is spontaneous, that is, remission, or induced by therapy such as use of omalizumab, the basopenia reverses and the basophils become more responsive to anti-IgE.101,108 Although these changes are coincidental with improvement, it is perhaps paradoxical that basophil histamine release (using circulating basophils) increases at a time that urticarial lesions in the skin quiet down.
Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the T helper (Th)2 subtype but also Th1 cells, with Th17 cell–derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. Although the role of the cellular infiltrate has not previously been addressed, each constituent can contribute to the overall pathogenesis. It is of interest that CSU responds to corticosteroid, yet, short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review, we address each cell's contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products.
Improved FcεRI-Mediated CD203c Basophil Responsiveness Reflects Rapid Responses to Omalizumab in Chronic Spontaneous Urticaria
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Whole blood was taken just before the first and second omalizumab administration using blood collection tubes containing ethylenediaminetetraacetic acid (EDTA), and assays were performed within 24 hours of blood sampling. The Allergenicity Kit (Beckman Coulter, Fullerton, CA) was modified and used for the quantification of basophil CD203c expression as previously described.7 Basophils were stimulated with anti-IgE antibody (clone: E124-2-8D) (0.1 μg/mL) (Beckman Coulter), VioBlue-conjugated anti-IgE antibody (clone: MB10-5C4) (1.1 μg/mL) (Miltenyi Biotec, Bergisch Gladbach, Germany), or biotinylated anti-FcεRI antibody (clone: CRA1) (16 μg/mL) (BioAcademia, Osaka, Japan).
Omalizumab is effective in patients with chronic spontaneous urticaria (CSU) although its mechanism of action is poorly understood. Several studies reported that decreased high-affinity IgE receptor (FcεRI)-mediated histamine release and/or responsiveness was characteristic of basophils in patients with CSU. However, few studies have focused on the relationship between changes in basophil responsiveness via FcεRI after omalizumab treatment and the therapeutic effect in patients with CSU.
To assess basophil responsiveness via FcεRI stimulation, as well as FcεRI expression and IgE binding on blood basophils from patients with CSU before and after omalizumab treatment and its possible association with the clinical response.
We analyzed 34 patients with CSU treated with omalizumab who were categorized as fast responders (FRs) (n = 20) and non or slow responders (N/SRs) (n = 14). CD203c expression induced by FcεRI stimulation, and IgE and FcεRI expressions on blood basophils from patients with CSU before and after omalizumab treatment were analyzed. Basophil responsiveness via FcεRI stimulation was observed in vitro using basophils pretreated with omalizumab.
FRs had increased CD203c responsiveness after treatment with omalizumab compared with N/SRs. This improvement of basophil responsiveness via FcεRI stimulation in FRs was not observed in peripheral blood basophils preincubated with omalizumab in vitro, suggesting that omalizumab does not directly affect circulating pre-existing abnormal basophils.
Increased basophil responsiveness via FcεRI after omalizumab treatment is associated with the therapeutic effect and mechanism of action of omalizumab.
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This article provides highlights of the clinically impactful original studies and reviews published in The Journal of Allergy and Clinical Immunology: In Practice in 2019 on the subjects of anaphylaxis, asthma, dermatitis, drug allergy, food allergy, immunodeficiency, immunotherapy, rhinitis/sinusitis, and urticaria/angioedema/mast cell disorders. Within each topic, practical aspects of diagnosis and management are emphasized. Treatments discussed include lifestyle modifications, allergen avoidance therapy, positive and negative effects of pharmacologic therapy, and various forms of immunologic and desensitization management. We designed this review to help readers consolidate and use this extensive and practical knowledge for the benefit of their patients.

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: This work was supported in part by a Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI Grant Numbers 15K09742 and 16K19722) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to A.F. and K.W.).

: Conflicts of interest: The authors declare that they have no relevant conflicts of interest.

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Original ArticleLow Responsiveness of Basophils via FcεRI Reflects Disease Activity in Chronic Spontaneous Urticaria

Background

Objective

Methods

Results

Conclusions

Section snippets

Study population

Study population

Discussion

Acknowledgments

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

Ann Allergy Asthma Immunol

J Invest Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol Pract

J Allergy Clin Immunol

The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

Allergy

Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: an expert opinion

Eur J Dermatol

Original Article
Low Responsiveness of Basophils via FcεRI Reflects Disease Activity in Chronic Spontaneous Urticaria

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria