RESUMO
BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is an effective treatment in chronic spontaneous urticaria (CSU). Predictors of fast and good response for omalizumab treatment have not yet been identified and characterized. OBJECTIVE: To evaluate whether soluble FcεRI (sFcεRI), a marker of IgE-mediated mast cell activation, predicts the time of response to omalizumab in CSU. METHODS: Sera of 67 CSU patients were obtained before omalizumab treatment and analysed for sFcεRI levels by ELISA (2 ng/mL was used as cut-off for elevated sFcÉRI). Treatment response during the first 4 weeks was assessed with the urticaria activity score (UAS7), urticaria control test (UCT) and the rolling UAS7 (rUAS7). RESULTS: Elevated pre-treatment sFcÉRI levels were detected in more than 70% of patients with completely controlled disease (UCT = 16) and well-controlled disease (UCT = 12-15) and were significantly associated with disease control (χ2 = 4.94, p < 0.05). More than half of the patients (14/25) with low levels had poor disease control (UCT < 12). Of the patients who achieved complete and marked UAS7 response, respectively, 75% and 63% had elevated baseline sFcÉRI levels. Post-treatment UAS7 scores were lower in patients with elevated sFcÉRI levels reaching statistical significance at Week 3 (p < 0.05). Patients with elevated baseline sFcÉRI levels achieved rUAS7 ≤ 6 and = 0 earlier than those with lower levels (Days 9 vs. 13 and Days 12 vs. 14, respectively). CONCLUSION: Elevated sFcεRI serum levels predict early and good response to treatment with omalizumab, which may help to better design treatment options for CSU patients.
Assuntos
Antialérgicos , Urticária Crônica , Omalizumab , Humanos , Antialérgicos/uso terapêutico , Urticária Crônica/tratamento farmacológico , Imunossupressores/uso terapêutico , Omalizumab/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: The soluble isoform of FcÉRI, the high-affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions. OBJECTIVE: To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions. METHODS: FcεRI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by FcεRI cross-linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal-associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE-dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild-type) and IgE-/- (IgE-deficient) mice. RESULTS: Antigen-specific cross-linking of IgE-loaded FcÉRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcÉRI activation induces sFcÉRI release. We demonstrated that generation of sFcÉRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcÉRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFcÉRI is an inhibitor of the human innate IgE effector axis, implying that sFcÉRI and omalizumab potentially inhibit each other in vivo. CONCLUSION: sFcÉRI is produced after antigen-specific IgE/FcÉRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcÉRI and IgE-mediated activation. Our results imply, therefore, that sFcÉRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.