sFcεRI as a potential biomarker for Endotypes of Chronic Urticaria (SECU)

• Applicant: Sherezade Moñino-Romero, Ph.D.
• Subject Area: Dermatology ; Clinical Immunology and Allergology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504179322

Chronic spontaneous or inducible urticaria (CSU or CIndU) is a common and debilitating disease characterized by recurrent episodes of itchy wheal and flare-type skin reactions, angioedema or both; due to the activation of skin mast cells (MCs). How MCs get activated and how this impac this impacts the treatment of patients is only partially understood.Two endotypes of CSU are proposed: type I (autoallergic) and type IIb (autoimmune). Both endotypes are difficult to identify, as appropriate tests are not available or cumbersome to perform. However, it is important to identify them, as they differ in clinical aspects. In this scenario, biomarkers would be of significant benefit, but as of now there is none allowing classification of endotypes, assignments to the course or severity of the disease or therapeutic responses.The high affinity IgE receptor FcεRI is constitutively present on immune cells of the innate IgE effector axis (MCs and basophils) and it is studied in immediate type allergies. During the acute phase of an immediate type immune response, FcεRI gets cross-linked and induces an activation cascade that results in the immediate release of mediators. Additionally, there is a soluble truncated version of the receptor: sFcεRI. The cellular signaling requirements for sFcεRI release comprise antigen-specific IgE-mediated cross-linking, Src kinase phosphorylation and receptor internalization. Released sFcεRI prevents IgE-binding and murine models of anaphylaxis. Serum sFcεRI is significantly elevated in atopic individuals and positively correlated with total IgE levels. Moreover, in cancer patients with confirmed drug allergy to platin chemotherapy undergoing desensitization, increased serum sFcεRI concentrations correlated with protection and served as a monitoring parameter. However, all these investigations and use as a biomarker were limited to allergic patients.As type I has been defined as autoallergic, we aim to study the role of sFcεRI in these patients. Preliminary analysis on CSU patients (n= 106) revealed that serum sFcεRI levels were significantly elevated in urticaria patients, showing a weak but significant correlation with total IgE serum levels. When CSU patients were subdivided, sFcεRI showed a difference for type I and type IIb patients.The first aim is the characterization of sFcεRI as a biomarker in CSU for the identification of type I and type IIb patients, and the effect of additional diseases or comorbidities (CIndU, atopy, autoimmune diseases). The second aim is to further elucidate systemic distribution of sFcεRI as well as the identification of endotypes in CIndU patients. For this, we will focus on selected CIndU patients where the trigger is known and easy to replicate during a challenge.There are many MC activation factors leading to symptoms but serum sFcεRI might be the first biomarker to distinguish between IgE- and non-IgE-mediated MC activation in CSU/CIndU thus improving patient care and treatment.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Martin Metz