Lin^-CD117⁺CD34⁺FcεRI⁺ progenitor cells are increased in chronic spontaneous urticaria and predict clinical responsiveness to anti-IgE therapy.

Abstract

Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage^-CD34^hiCD117^int/hiFcεRI⁺ cells in blood have previously been shown to represent a mast cell precursor. We enumerated FcεRI^-, FcεRI⁺ and FcεRI^hi lineage^-CD34⁺CD117⁺ cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage^-CD34^hiCD117^hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4). CSU patients had more lineage^-CD34⁺CD117⁺FcεRI⁺ blood cells than controls. Lineage^-CD34⁺CD117⁺FcεRI⁺ cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage^-CD34⁺CD117⁺FcεRI⁺ cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI^- and FcεRI⁺ myeloid progenitors. Increased blood CD34⁺CD117⁺FcεRI⁺ cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab.