Roa, S. (Sergio)
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- Age-dependent nasal immune responses in non-hospitalized bronchiolitis children(Frontiers, 2022-12-06) López, V. (Victoria); Solís, B. (Beatriz); Rodriguez, J. (Javier); García-Vao, C. (Carlos); Andrés, B. (Belén) de; Rodríguez, M. (Mercedes); Roa, S. (Sergio); Díaz, J. (Juncal); Gaspar, M.L. (María Luisa); Cortegano, I. (Isabel); Zaballos, A. (Ángel); Arrabal, A. (Alejandro); Arribas-Sánchez, C. (Cristina); Fernández, S. (Sandra); Rosa, B. (Belén) de la; Hernangómez, S. (Susana); Garrido-Martínez-de-Salazar, F. (Felipe)Bronchiolitis in children is associated with significant rates of morbidity and mortality. Many studies have been performed using samples from hospitalized bronchiolitis patients, but little is known about the immunological responses from infants suffering from mild/moderate bronchiolitis that do not require hospitalization. We have studied a collection of nasal lavage fluid (NLF) samples from outpatient bronchiolitis children as a novel strategy to unravel local humoral and cellular responses, which are not fully characterized. The children were age-stratified in three groups, two of them (GI under 2-months, GII between 2-4 months) presenting a first episode of bronchiolitis, and GIII (between 4 months and 2 years) with recurrent respiratory infections. Here we show that elevated levels of pro-inflammatory cytokines (IL1β, IL6, TNFα, IL18, IL23), regulatory cytokines (IL10, IL17A) and IFNγ were found in the three bronchiolitis cohorts. However, little or no change was observed for IL33 and MCP1, at difference to previous results from bronchiolitis hospitalized patients. Furthermore, our results show a tendency to IL1β, IL6, IL18 and TNFα increased levels in children with mild pattern of symptom severity and in those in which non RSV respiratory virus were detected compared to RSV+ samples. By contrast, no such differences were found based on gender distribution. Bronchiolitis NLFs contained more IgM, IgG1, IgG3 IgG4 and IgA than NLF from their age-matched healthy controls. NLF from bronchiolitis children predominantly contained neutrophils, and also low frequency of monocytes and few CD4+ and CD8+ T cells. NLF from infants older than 4-months contained more intermediate monocytes and B cell subsets, including naïve and memory cells. BCR repertoire analysis of NLF samples showed a biased VH1 usage in IgM repertoires, with low levels of somatic hypermutation. Strikingly, algorithmic studies of the mutation profiles, denoted antigenic selection on IgA-NLF repertoires. Our results support the use of NLF samples to analyze immune responses and may have therapeutic implications.
- YRNAs overexpression and potential implications in allergy(Elsevier BV, 2019) Marcos-Vadillo, E. (Elena); Estravís, M. (Miguel); Isidoro-García, M (María); Pascual, M. (Marien); García-Sánchez, A. (Asunción); Roa, S. (Sergio); Davila, I. (I.); Trivino, J.C. (Juan Carlos); Sanz, C. (C.); Marques-García, F. (Fernando)Small non-coding RNAs (snRNAs) develop important functions related to epigenetic regulation. YRNAs are snRNAs involved in the initiation of DNA replication and RNA stability that regulate gene expression. They have been related to autoimmune, cancer and inflammatory diseases but never before to allergy. In this work we described for the first time in allergic patients the differential expression profile of YRNAs, their regulatory mechanisms and their potential as new diagnostic and therapeutic targets. Methods: From a previous whole RNAseq study in B cells of allergic patients, differential expression profiles of coding and non-coding transcripts were obtained. To select the most differentially expressed non coding transcripts, fold change and p-values were analyzed. A validation of the expression differences detected was developed in an independent cohort of 304 individuals, 208 allergic patients and 96 controls by using qPCR. Potential binding and retrotransponibility capacity were characterized by in silico structural analysis. Using a novel bioinformatics approach, RNA targets identification, functional enrichment and network analyses were performed. Results: We found that almost 70% of overexpressed non-coding transcripts in allergic patients corresponded to YRNAs. From the three more differentially overexpressed candidates, increased expression was independently confirmed in the peripheral blood of allergic patients. Structural analysis suggested a protein binding capacity decrease and an increase in retrotransponibility. Studies of RNA targets allowed the identification of sequences related to the immune mechanisms underlying allergy. Conclusions: Overexpression of YRNAs is observed for the first time in allergic patients. Structural and functional information points to their implication on regulatory mechanisms of the disease.
- Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma(2023) Perez, C. (Cristina); Fresquet, V. (Vicente); Maia, C. (Catarina); Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Celay, J. (Jon); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Roncador, G. (Giovanna); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Walensky, L.D. (Loren D.); Panizo, C. (Carlos); Lasater, E.A. (Elisabeth A.); Katz, S.G. (Samuel G.); Larrayoz, M. (Marta); Roa, S. (Sergio); Bergsagel, P.L. (P. Leif); Gonzalez, P. (Patricia); Botta, C. (Cirino); Ordóñez-Ciriza, R. (Raquel); Takahashi, S. (Satoru); Aguirre-Ena, X. (Xabier); Kurilovich, A. (Anna); Amann, M. (Maria); Rodriguez-Otero, P. (Paula); Llopiz, D. (Diana); Paiva, B. (Bruno); Sarobe, P. (Pablo); Campos-Sanchez, E. (Elena); Ruppert, S.M. (Shannon M.); Martínez-Cano, J. (Jorge); Larrayoz, M.J. (María J.); Revuelta, M.V. (Maria V.); Cobaleda, C. (César); Prosper-Cardoso, F. (Felipe); Etxebeste-Mitxeltorena, A. (Amaia); Calasanz-Abinzano, M.J. (Maria Jose); San-Miguel, J.F. (Jesús F.); Cerchietti, L. (Leandro); Planell, N. (Núria); Jiménez-Andrés, M. (Maddalen); Kudryashova, O. (Olga); Chesi, M. (Marta); Lasarte, J.J. (Juan José)The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-kappaB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of 500 mice and 1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.