Estudio de IL5RA como biomarcador genético en Poliposis Nasal

[ES] La IL-5 se caracteriza por su actividad en distintas células diana, entre las que se incluyen los linfocitos B, eosinófilos o basófilos. Es producida por linfocitos T, sobre todo Th2, ILC2 y mastocitos, y ejerce efectos en la proliferación y diferenciación, a través de su receptor (IL-5R), un heterodímero compuesto por una subunidad α específica de ligando (IL-5Rα) y otra subunidad β, común a otros receptores de citocinas. Debido a la relación de la poliposis nasal con la inflamación T2, la evolución de la poliposis nasal asociada al asma con eosinofilia se ha considerado un biomarcador para predecir la respuesta a los anticuerpos antiIL-5 en el asma. La terapia antagonista de IL-5 ha demostrado ser de utilidad en pacientes asmáticos con un fenotipo T2, siendo por lo tanto extensible el potencial de dicho tratamiento al de la inflamación en RSCcPN. La hipótesis principal de este estudio es que los pacientes con RSCcPN, asociados o no a otras patologías de vías respiratorias, atopia, hábitos tóxicos y a más variables clínicopatológicas, presentan una sobreexpresión del gen IL5RA respecto a los controles. La hipótesis secundaria se extrapola de la anterior, y es la posibilidad de considerar IL5RA como un biomarcador de poliposis nasal que pueda ser útil tanto en el diagnóstico, como en el seguimiento y el tratamiento, facilitando una terapia dirigida a determinados grupos de pacientes. En el estudio se plantearon los siguientes objetivos: 1. Determinar los niveles de expresión del gen IL5RA en sangre periférica en una población de pacientes con poliposis nasal frente a un grupo control. 2. Analizar las diferencias de expresión entre distintos fenotipos clínicos. 3. Determinar los niveles de expresión de IL5RA en tejido polipoideo y estudiar su relación con los niveles de expresión en sangre periférica. 4. Estudiar la posible correlación entre la expresión de IL5RA y otros genes que caracterizan grupos patológicos de rinosinusitis crónica, asma y otras enfermedades alérgicas

Interleukin 5 Receptor Subunit Alpha Expression as a Potential Biomarker in Patients with Nasal Polyposis

[EN]Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) affects the quality of life of patients suffering from it. The search for a suitable biomarker has been conducted over the last decades. Interleukin 5 receptor subunit alpha (IL-5Rα) involves the activation, maintenance, and survival of eosinophils, which are highly tied to chronic inflammatory processes of the airways, like asthma or CRSwNP. In this study, we evaluate the utility of IL5RA as a genetic biomarker in CRSwNP. IL5RA mRNA expression level was analyzed in different groups of patients by performing qPCR assays. A significant increase in IL5RA expression was observed in CRSwNP patients, especially those with asthma and atopy. We found differences in expression levels when comparing groups with or without polyposis or asthma, as well as some atypical cases related to eosinophil levels. That opens a path to future studies to further characterize groups of patients with common features in the context of pharmacogenetics and in an era towards developing a more precise personalized treatment with IL-5Rα as a therapeutic target for CRSwNP.Instituto de Salud Carlos III; European Union Next Generation EU; European Regional Development Fun

Molecular Analysis of IL-5 Receptor Subunit Alpha as a Possible Pharmacogenetic Biomarker in Asthma

[EN]Background: Asthma is a heterogeneous syndrome with a broad clinical spectrum and high drug response variability. The inflammatory response in asthma involves multiple effector cells and mediator molecules. Based on asthma immunopathogenesis, precision medicine can be a promising strategy for identifying biomarkers. Biologic therapies acting on the IL-5/IL-5 receptor axis have been developed. IL-5 promotes proliferation, differentiation and activation of eosinophils by binding to the IL-5 receptor, located on the surface of eosinophils and basophils. This study aimed to investigate the expression of IL5RA in patients with several types of asthma and its expression after treatment with benralizumab, a biologic directed against IL-5 receptor subunit alpha. Methods: Sixty peripheral blood samples, 30 from healthy controls and 30 from asthmatic patients, were selected for a transcriptomic RNAseq study. Differential expression analysis was performed by statistical assessment of fold changes and P-values. A validation study of IL5RA expression was developed using qPCR in 100 controls and 187 asthmatic patients. The effect of benralizumab on IL5RA expression was evaluated in five patients by comparing expression levels between pretreatment and after 3 months of treatment. The IL5RA mRNA levels were normalized to GAPDH and TBP expression values for each sample. Calculations were made by the comparative ΔΔCt method. All procedures followed the MIQE guidelines. Results: IL5RA was one of the most differentially overexpressed coding transcripts in the peripheral blood of asthmatic patients (P = 8.63E-08 and fold change of 2.22). In the qPCR validation study, IL5RA expression levels were significantly higher in asthmatic patients than in controls (P < 0.001). Significant expression differences were present in different asthmatic types. In the biological drug study, patients treated with benralizumab showed a significant decrease in IL5RA expression and blood eosinophil counts. A notable improvement in ACT and lung function was also observed in these patients. Conclusions: These results indicate that IL5RA is overexpressed in patients with different types of asthma. It could help identify which asthmatic patients will respond more efficiently to benralizumab, moving toward a more personalized asthma management. Although further studies are required, IL5RA could play a role as a biomarker and pharmacogenetic factor in asthma.Instituto de Salud Carlos III; European Regional Development Fund; Junta de Castilla y Leó