Avances en el manejo del asma difícil de tratar y asma grave

págs.: 177-188Capítulo incluido en el libro: Optimizando el abordaje del asma bronquial. Manuel Alcántara Villar (coordinador). Sevilla: Universidad Internacional de Andalucía, 2023. ISBN: 978-84-7993-396-8. Enlace: http://hdl.handle.net/10334/7376 . En los últimos tiempos se han realizado notables avances en el tratamiento del asma, particularmente desde la introducción de los biológicos. Existen datos que indican que se está avanzando de modo exponencial en la investigación de nue vos compuestos, con la introducción de nuevos biológicos, como el tezepelumab (en investigación también su administración por vía inhalatoria), que abre la era de inhibición de las alarminas. Se están estudiando también compuestos que in hiben la IL-33 o su receptor y otros. También se está explorando la introducción de moléculas pequeñas, como los inhibidores duales de fosofodiesterasas, de c-kit, moduladores del receptor de glucocorticoides o agonistas de TLR9. Todo ello contribuirá a la mejoría de una enfermedad que, en un porcentaje importante de pacientes, no está controlada, particularmente en el asma T2 baja

Molecular Analysis of Activation-Induced Cytidine Deaminase Gene in Immunoglobulin-E Deficient Patients

[EN]Understanding how class switch recombination (CSR) is regulated to produce immunoglobulin E (IgE) has become fundamental because of the dramatic increase in the prevalence of IgE-mediated hypersensitivity reactions. CSR requires the induction of the enzyme AICDA in B cells. Mutations in AICDA have been linked to Hyper-IgM syndrome (HIGM2), which shows absence of switching to IgE as well as to IgG and IgA. Although isolated IgE deficiency is a rare entity, here we show some individuals with normal serum IgM, IgG, and IgA levels that had undetectable total serum IgE levels. We have analyzed the AICDA gene in these individuals to determine if there are mutations in AICDA that could lead to selective IgE deficiency. Conformational sensitive gel electrophoresis (CSGE) and sequencing analysis of AICDA coding sequences demonstrated sequence heterogeneity due to 5923A/G and 7888C/T polymorphisms, but did not reveal any novel mutation that might explain the selective IgE deficit

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

[EN]Asthma is a multifactorial pathology influenced by environmental and genetic factors. Glucocorticoid treatment decreases symptoms by regulating genes involved in the inflammatory process through binding to specific DNA sequences. Polymorphisms located in the promoter region of the Prostaglandin D Receptor (PTGDR) gene have been related to asthma. We aimed to analyze the effect of PTGDR promoter haplotypes on gene expression and response to corticosteroid therapy. A549 lung epithelial cells were transfected with vectors carrying four different PTGDR haplotypes (CTCT, CCCC, CCCT and TCCT), and treated with dexamethasone. Different approaches to study the promoter activity (Dual Luciferase Reporter System), gene expression levels (qPCR) and cytokine secretion (Multiplexed Bead-based Flow Cytometric) were used. In addition, in silico analysis was also performed. Cells carrying the TCCT haplotype showed the lowest promoter activity (p-value<0.05) and mRNA expression levels in basal conditions. After dexamethasone treatment, cells carrying the wild-type variant CTCT showed the highest response, and those carrying the TCCT variant the lowest (p-value<0.05) in luciferase assays. Different transcription factor binding patterns were identified in silico. Moreover, differences in cytokine secretion were also found among different promoter haplotypes. Polymorphisms of PTGDR gene influence basal promoter activity and gene expression, as well as the cytokine secretory pattern. Furthermore, an association between these positions and response to corticoid treatment was observed

Quantitative and qualitative methods of evaluating response to biologics in severe asthma patients: Results from a real-world study

[EN] Asthma is a complex major noncommunicable disease affecting around 333 million people worldwide, both children and adults.New biological therapies for treating severe asthma have remarkably improved disease management. Notwith-standing, one remaining crucial problem is evaluating the response to these treatments. Therefore, adequate measurement of the response to biologics in a holistic manner that integrates clinical variables of interest and quality of life is needed, particularly in identifying super-responder patients (SR). Menzies-Gow et al went more profound in the concept and proposed a consensus to evaluate remission.Instituto de Salud Carlos III (ISCIII); European Union -Next Generation EU; Junta de Castilla y Leó

Effects of Therapeutic Antibodies on Gene and Protein Signatures in Asthma Patients: A Comparative Systematic Review

[EN]Several biologic therapies that target inflammatory modulators are now used for treating patients with uncontrolled, severe asthma. Knowledge about how this type of treatment modifies the molecular milieu is rapidly increasing. Thus, this systematic review aimed to compile the reported effects of therapeutic antibodies on the transcriptome or proteome of asthma patients. Studies of asthmatic patients under biological treatment describing transcriptomic or proteomic changes upon treatment were included. Preclinical or single gene/protein studies were not considered. PubMed and Scopus search was performed in August and September 2021. Following PRISMA guidelines and GRADE recommendations, we selected 12 studies on gene or protein expression changes in patients treated with the antibodies currently approved by EMA and the FDA. All studies were at low risk of bias as per the RoB2 tool. Different gene clusters have been identified to change upon omalizumab treatment, found a reduction in eosinophil-associated gene signatures after benralizumab treatment, and protein profiles were different in patients treated with mepolizumab and in those treated with benralizumab. The main potential biomarkers proposed by the selected studies are shown. These results may contribute to discovering biomarkers of response and selecting the best therapy for each patient.Instituto de Salud Carlos III; Junta de Castilla y León; Sociedad Española de Alergia e Inmunología Clínic

Filaggrin gene mutations and new SNPs in asthmatic patients: a cross-sectional study in a Spanish population

[EN] Background: Several null-mutations in the FLG gene that produce a decrease or absence of filaggrin in the skin and predispose to atopic dermatitis and ichthyosis vulgaris have been described. The relationship with asthma is less clear and may be due to the influence of atopy in patients with associated asthma. Methods: Four hundred individuals were included, 300 patients diagnosed with asthma divided into two groups according to their phenotype (allergic and non-allergic asthma) and 100 strictly characterized controls. The coding region and flanking regions of the FLG gene were amplified by PCR. We proceeded to the characterization of potential gene variants in that region by RFLP and sequencing and analysed their association with lung function parameters, asthma control and severity, and quality of life. Results: We identified two null-mutations (R501X and 2282del4), seven SNPs previously described in databases and three SNPs that had not been previously described. One of the SNP identified in this study (1741A > T) was more frequently detected in patients with non-allergic asthma, worse FVC, FEV1 and PEF values and a higher treatment step. In addition, lowered spirometric values were observed in the non-allergic group carrying any of the nonsynonymous SNPs. Conclusions: In the association study of genetic variants of the FLG gene in our population the 1741A > T polymorphism seems to be associated with non-allergic asthma

Genome-wide association studies (GWAS) and their importance in asthma

[EN] Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease.FEDER funds; Junta de Castilla y León; Fundación Botín-Universidad de Salamanca; Sociedad Española de Alergología e Inmunología Clínica; Fundación Salud 200

Genome-wide expression profiling of B lymphocytes reveals IL4R increase in allergic asthma

[EN] Allergic asthma is a multifactorial disorder in which activation and differentiation of B lymphocytes toward the production of IgE play an essential role. In these B cells, molecular mechanisms to generate IgE antibodies from IgM depend on a complex network of molecules that trigger class-switch recombination specifically at the Sε region of the IgH locus. Several trans-membrane receptors and activating signaling cascades are known to physiologically participate in these processes, including the IL4R signaling pathway. In this regard, our group has studied in the past genetic polymorphisms in the IL4/IL4R pathway that might hold clinical correlations with atopy and asthma.Spanish Ministry of Health (FIS - Fondo de Investigación Sanitaria); Instituto de Salud Carlos III; FEDER - Fondo Europeo de Desarrollo Regional funds; Spanish Society of Allergology and Clinical Immunolog

Retinoic Acid Modulates PTGDR Promoter Activity

[EN] Background and objective: Vitamin A has been linked to the development of allergic diseases although its role is not fully understood, Retinoic acid (RA), a metabolite of Vitamin A, has been previously associated with the prostaglandin pathway, and PTGDR, a receptor of PGD2, has been proposed as a candidate gene in allergy and asthma. Considering the role of PTGDR in allergy, the goal of this study was to analyze the effect of RA on the activation of the promoter region of the PTGDR gene. Methods: A549 lung epithelial cells were transfected with 4 combinations of genetic variants of the PTGDR promoter and stimulated with all-trans RA (ATRA); luciferase assays were performed using the Dual Luciferase Reporter System, and real-time quantitative polymerase chain reaction was used to measure the expression of PTGDR, CYP26A1, RARA, RARB, RARG, and RXRA in basal A549 cell cultures and after ATRA treatment. We also performed an in silico analysis. Results: After ATRA treatment increased expression of CYP26A1 (12-fold) and RARB (4-fold) was detected. ATRA activated PTGDR promoter activity in transfected cells (P<.001) and RA response element sequences were identified in silico in this promoter region. Conclusions: RA modulated PTGDR promoter activity. Differential response to RA and to new treatments based on PTGDR modulation could depend on genetic background in allergic asthmatic patients.Instituto de Salud Carlos III; European Regional Development Fund (ERDF); Junta de Castilla y León; Fundación Botín-Universidad de Salamanca; Sociedad Española de Alergología e Inmunología Clínica; Fundación Salud 200

Genetic association study in nasal polyposis.

[EN] Nasal polyposis (NP) is a chronic inflammatory disease of the upper airways with a variable clinical course and unknown pathogenesis that often coexists with other conditions. Considering the possibility of genetic predisposition, we decided to analyze whether polymorphisms in LTC4S, CYSLTR1, PTGDR, and NOS2A were associated with NP. The study population comprised 486 Caucasian individuals. Polyposis and aspirin intolerance were diagnosed following the recommendations of the European Position Paper on Rhinosinusitis and Nasal Polyps. Genotypes were determined using polymerase chain reaction amplification and direct sequencing. The -444A > C LTC4S polymorphism was significantly associated with NP and atopy (P = .033) and with NP and atopic asthma, (P =.012). In addition, a significant association was found when the (CCTTT) repetition of the NOS2A gene was present more than 14 times in patients with NP and asthma (P = .034), in patients with polyposis and intolerance to nonsteroidal anti-inflammatory drugs (P = .009), and in patients with the aspirin triad (P = .005). The PTGDR diplotype CCCT/CCCC (-613CC, -549CC, -441CC and -197TC) was more frequent in patients with NP (P = .043), NP with asthma (P = .013), and the aspirin triad (P = .041). NP was associated with specific polymorphisms only when it occurred with related phenotypes. Our results suggest that this genetic background plays a more relevant role in the development of the associated clinical features of nasal polyposis than in simple polyposis.Junta de Castilla y León; Merck Sharpe Dohme; Mutua Madrileñ