Omalizumab response correlates with reduced IFN-γ-, IL-10- and IL-31-secreting cells in chronic spontaneous urticaria.

BACKGROUND: The anti-IgE antibody omalizumab has been approved for the treatment of chronic spontaneous urticaria (CSU) in patients insufficiently responding to antihistamines. However, its mode of action in CSU is not clearly understood. OBJECTIVES: The aim of this study was to get a better insight in the immune mechanisms involved in clinical improvement of CSU patients treated with omalizumab. METHODS: Chronic spontaneous urticaria patients (n = 15) were followed for 5 months after initiation of omalizumab treatment. Clinical symptoms were assessed by UCT and CU-Q2 oL. Cell-bound IgE was quantified on both FcεRI- and FcεRII-expressing cell populations in peripheral blood. In addition, IgE and IgG as well as their receptors were measured on basophils, and basophil activation was assessed with different concentrations of anti-FcεRI and fMLP. Furthermore, the frequencies of different T-cell subsets secreting IL-5, IL-10, IL-31 or IFN-γ were analysed by ELISpot assay. RESULTS: Seven patients showed a full, five a partial and three no clinical response to omalizumab. Cell-bound IgE was reduced on FcεRI-bearing cells, but not on FcεRII-expressing cells. Likewise, the expression of FcεRI declined. Basophil activation increased upon FcεRI-stimulation while their sensitivity was not affected. Both basophil and T-cell frequencies remained unchanged. However, when comparing the individual response to omalizumab treatment with distinct T-cell subsets, a significant correlation was found between improved UCT and decreased frequencies of IL-10-, IL-31- and IFN-γ-secreting T cells. CONCLUSIONS: We here show that besides addressing IgE-dependent immune mechanisms, omalizumab treatment of CSU patients has effects on distinct T-cell subsets, which correlate with clinical improvement.

Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria.

BACKGROUND: Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE-mediated mechanisms also play an important role in CU. METHODS: Reactivity of CU patients' peripheral blood basophils (n=60) to specific anti-FcεRI and IgE-independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q2 oL. RESULTS: Stimulating CU patients' basophils via FcεRI, we identified three distinct immunologic phenotypes. One subgroup of patients' basophils reacted to FcεRI stimulation, whereas the others had anti-FcεRI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life. CONCLUSIONS: Patients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.