Person:
Juárez Martín-Delgado, Ignacio

First Name

Ignacio

Last Name

Juárez Martín-Delgado

URI

https://hdl.handle.net/20.500.14352/86394

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Inmunología, Oftalmología y ORL

Area

Inmunología

Identifiers

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Now showing 1 - 10 of 21

Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus
(Rheumatology, 2020) Katsuyama, Takayuki; Juárez Martín-Delgado, Ignacio; Krishfield, Suzanne M; Kyttaris, Vasileios C; Moulton, Vaishali R
Objective: Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. Methods: We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. Results: We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. Conclusion: Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.
A Reliable and Standardizable Differential PCR and qPCR Methodology Assesses HER2 Gene Amplification in Gastric Cancer
(Biology, 2021) Juárez Martín-Delgado, Ignacio; Toro Fernandez, Juan Francisco; Vaquero Yuste, Christian; Molina Alejandre, Marta; Lasa, Inmaculada; Gomez, Remedios; Lopez, Adela; Martín Villa, José Manuel; Gutierrez, Alberto
We have applied two PCR techniques, differential PCR (diffPCR) and qPCR for the identification of HER2 gene amplifications in genomic DNA of tumor and distal gastric samples from patients with gastric cancer. The diffPCR technique consists of the simultaneous amplification of the HER2 gene and a housekeeping gene by conventional PCR and the densitometric analysis of the bands obtained. We established a cut-off point based on the mean and standard deviation analyzing the DNA of 30 gastric tissues from patients undergoing non-cancer gastrectomy. diffPCR and qPCR yielded consistent results. HER2-overexpression was detected in 25% of patients and was further confirmed by immunohistochemistry and immunofluorescence. The approaches herein described may serve as complementary and reliable methods to assess HER2 amplification.
Project number: PIMCD112/23-24
Aplicación de la citometría de flujo como herramienta para el estudio de la Inmunología Molecular
(2024) Cruz Adalia, Aranzazu; Lamana Domínguez, Amalia; Peláez Prestel, Héctor Fernando; González García, Sara; Juárez Martín-Delgado, Ignacio; Cabañas Gutiérrez, Carlos; Reche Gallardo, Pedro Antonio; Lafuente Duarte, María Esther; Recio Hoyas, María José; Sancho Temiño, Lucía; Osuna Perez, Jesus; Castillo Gonzalez, Raquel Ana; Cruz Adalia, Aranzazu
HLA study in Mexico Nahua/Aztec Amerindians: Close relatedness to the ancient Central America ethnic groups
(Human Immunology, 2023) Suarez Trujillo, Fabio; Vargas Alarcon, Gilberto; Juárez Martín-Delgado, Ignacio; Gil Martin, Roberto; Granados, Julio; Vaquero Yuste, Christian; Martín Villa, José Manuel; Arnaiz Villena, Antonio
Nahua population (also named Aztec or Mexica) was studied for HLA class II genes in a Mexican rural city (Santo Domingo Ocotitlan, Morelos State) belonging to the nowadays Náhuatl speaking areas in Mexico. The most frequent HLA class II alleles were typical Amerindian (HLA-DRB1*04:07, DQB1*03:01 DRB1*04:03 or DRB1*04:04) and also were some calculated extended haplotypes (HLA-DRB1*04:07-DQB1*03:02,DRB1*08:02-DQB1*04:02, or DRB1*10:01-DQB1*05:01 among others). When using HLA-DRB1 Neís genetic distances, our isolated Nahua population was found to be close to other Central America Amerindians like the ancient-established Mayans or Mixe. This may suggest that Nahuas origin was also from Central America. It contrasts to legend that assumes they came from the North, and they built the Aztec Empire after submitting Central America neighbouring ethnic groups before 1519 CE when Spaniards led by Hernán Cortés arrived to Mexico
Major histocompatibility complex complement (MHC) Bf alleles show trans species evolution between man and chimpanzee
(Scientific Reports, 2023) Arnaiz Villena, Antonio; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Ignacio Juarez; Alejandro Sánchez-Orta; José Manuel Martín-Villa; Fabio Suarez-Trujillo
AbstractHLA and disease studies by using single allele statistics have been fruitless during the last 40 years for explaining association pathogenesis of the associated diseases.Other approaches are necessary to untangle this puzzle. We aim to revisit complement alleleism in humans and primates for both studying MHC and disease association to complotypes and extended MHC haplotypes in order to also explain the positive directional selection of maintaining immune response genes (complement, MHC adaptive and MHC non-specific genes) that keeps these three type of genes together in a short chromosome stretch (MHC) for million years. These genes may be linked to conjointly avoid microbes attack and autoimmunity. In the present paper, it is obtained a new Bf chimpanzee allele, provisionaly named Patr-Bf*A:01,that differs from other Bf alleles by having CTG at eleventh codon of exon 2 in order to start the newly suggested methodology and explain functional and evolutionary MHC obscure aspects. Exons 1 to 6 of Ba fragment of Bf gene were obtained from chimpanzee. This new chimpanzee Factor B allele (Patr-Bf*A:01) is to be identical to a infrequent human Bf allele (SNP rs641153); it stresses the strong evolutive pressure upon certain alleles that are trans specific. It also may apply to MHC extended haplotipes which may conjointly act to start an adequate immune response. It is the first time that a complement MHC class III allele is described to undergo trans species evolution,in contrast to class I and class II alleles which had already been reported . Allelism of complement factors are again proposed for studying MHC complement genes, complotypes, and extended MHC haplotypes which may be more informative that single MHC marker studies.
An Experimental DUAL Model of Advanced Liver Damage
(Hepatology Communications, 2021) Benede Ubieto, Raquel; Estévez Vázquez, Olga; Guo, Feifei; Chen, Chaobo; Gómez Del Moral Martín-Consuegra, Manuel María; Lamas Paz, Aranzazu; Morán, Laura; López Alcántara, Nuria; S. Mazariegos, Marina; Zheng, Kang; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Asensio, Iris; Vaquero Martín, Francisco Javier; Peligros Gómez, María Isabel; Romero Gómez, Manuel; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, Yulia
Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
HLA genetic study in Iran Saqqez-Baneh Kurds: no genetic trace of Aryan invasions in Anatolian Turks and Kurds is found
(Human Immunology, 2022) Suarez Trujillo, Fabio; Juárez Martín-Delgado, Ignacio; Palacio Grüber, José Manuel de; Martin Villa, Jose Manuel; Amirzargar, Ali; Arnaiz Villena, Antonio
Kurds are living at Middle East region comprising several countries (38 million people) and also have emigrated to Asia, Europe and America. Kurds from Iran have been HLA typed in the present work from Saqqez and Baneh towns, Kordestan province, Iran. Origin of Kurds is considered autochthonous from Anatolia and surrounding mountains :they have been referred as “the mountain people” by classic Persian, Greek and Roman authors. Present day Turks are also autochthonous from Anatolia, but they were not recognized by classical authors as living in the mountains and they speak a language of Asian origin that was imposed to Anatolia by a “elite” invasion without a noticeable high Asian gene input. Most frequent class I and class II HLA alleles found in Iranian Kurds population are: HLA‐A*24:02, A*02:01 and HLA‐B*35:01, and HLA‐DRB1*11:01, DRB1*03:02 and HLA‐DQB1*03:01; also, most frequent HLA extended haplotypes from this Iran Kurdish sample are not shared with Iranians but with Mediterranean, Turkish and Caucasus people. This is confirmed by Neighbour‐Joining and correspondence analysis studied together with the corresponding populations. Finally, our studies show that both Kurds and Turks are genetically original from Anatolian Peninsula and surrounding countries and that an apparent Asian genetic or Aryan invasion does not exist in the area.
HLA-G 3’UTR Polymorphisms Are Linked to Susceptibility and Survival in Spanish Gastric Adenocarcinoma Patients
(Frontiers in Immunology, 2021) Vaquero Yuste, Christian; Juárez Martín-Delgado, Ignacio; Molina Alejandre, Marta; Molanes López, Elisa María; López Nares, Adrián; Suárez Trujillo, Fabio; Gutiérrez Calvo, Alberto; Fernández-Cruz Pérez, Eduardo; Rodríguez Sainz, Carmen; Martín Villa, José Manuel; Arnaiz Villena, Antonio
HLA-G is a non-classical class I HLA molecule that induces tolerance by acting on receptors of both innate and adaptive immune cells. When overexpressed in tumors, limits surveillance by the immune system. The HLA-G gene shows several polymorphisms involved in mRNA and protein levels. We decided to study the implication of two polymorphisms (rs371194629; 14bp INS/DEL and rs1063320; +3142 C/G) in paired tissue samples (tumoral and non-tumoral) from 107 Spanish patients with gastric adenocarcinoma and 58 healthy control individuals, to assess the possible association of the HLA-G gene with gastric adenocarcinoma susceptibility, disease progression and survival. The presence of somatic mutations involving these polymorphisms was also analyzed. The frequency of the 14bp DEL allele was increased in patients (70.0%) compared to controls (57.0%, p=0.025). In addition, the haplotype formed by the combination of the 14bp DEL/+3142 C variants is also increased in patients (54.1% vs 44.4%, p=0.034, OR=1.74 CI95% 1.05-2.89). Kaplan-Meier analysis revealed that 14bp DEL/DEL patients showed lower 5-year life-expectancy than INS/DEL or INS/INS (p=0.041). Adjusting for TNM staging (Cox regression analysis) disclosed a significant difference in death risk (p=0.03) with an expected hazard 2.6 times higher. Finally, no somatic mutations were found when comparing these polymorphisms in tumoral vs non-tumoral tissues, which indicates that this is a preexisting condition in patients and not a de novo, tumor-restricted, event. In conclusion, the variants predominant in patients were those increasing HLA-G mRNA stability and HLA-G expression, clearly involving this molecule in gastric adenocarcinoma susceptibility, disease progression and survival and making it a potential target for immunotherapeutic approaches.
Estudio de marcadores genéticos e inmunitarios relacionados con inmunoterapia en cáncer gástrico
(2021) Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Tsokos, George C.
El cáncer es una enfermedad multifactorial con una serie de características definitorias: mantenimiento de las señales de proliferación, resistencia a la muerte celular, inmortalidad replicativa, inducción de angiogénesis, motilidad y metástasis, inestabilidad genómica y mutación, inflamación pro-tumoral, reprogramación del metabolismo energético y evasión de la respuesta inmunitaria antitumoral. Como parte de esta última característica, destaca la implicación del sistema inmunitario en la respuesta antitumoral, siguiendo un proceso denominado inmunoedición, que se compone de tres fases: eliminación del tumor por parte del sistema inmunitario, equilibrio entre la respuesta inmunitaria y los mecanismos supresores del tumor y, finalmente, escape del tumor e invasión de tejidos adyacentes y distales. El cáncer gástrico es el quinto tipo de tumor más frecuente en la población mundial, con más de un millón de muertes anuales en todo el mundo. Es uno de los tumores con mayor prevalencia de mutaciones somáticas, lo que facilita la formación de neo-antígenos tumorales y hace susceptible estos tumores para su tratamiento con diversos tipos de inmunoterapia. La inmunoterapia comprende una serie de tratamientos que promueven la estimulación del sistema inmunitario tendentes a la prevención o tratamiento de una enfermedad. La inmunoterapia contra el cáncer tiene como objetivo el bloqueo de vías de señalización protumorales, así como la estimulación (directa o indirecta) de la respuesta inmunitaria contra los tumores. En el caso concreto del cáncer gástrico, el tratamiento con anticuerpos bloqueantes de HER2 (trastuzumab) se emplea en emplea en pacientes HER+, mientras que los inhibidores de puntos del control del sistema inmunitaria únicamente están aprobados para el tratamiento de pacientes en estadios muy avanzados de la enfermedad, con enfermedad diseminada, y refractarios a quimio y radioterapia. La dificultad para el tratamiento de estos pacientes radica en la correcta determinación de biomarcadores que identifiquen a pacientes susceptibles de recibir inmunoterapia...
TGFB1 polymorphisms and TGF‐β1 plasma levels identify gastric adenocarcinoma patients with lower survival rate and disseminated disease
(Cellular and Molecular Life Sciences, 2020) Alberto Gutierrez; Christian Vaquero‐Yuste; Adela López; Inmaculada Lasa; Remedios Gómez; Juárez Martín-Delgado, Ignacio; Molanes López, Elisa María; Martín Villa, José Manuel
AbstractTGF‐β1 is involved in tumour growth. Four TGFB1 SNPs and TGF‐β1 production by stimulated PBMC were determined in seventy‐eight gastric adenocarcinoma patients. In addition, TGF‐β1 levels were measured in the plasma of further thirty patients. rs1800471‐G/C genotype was prevalent in patients (20.7%) compared to controls (8.4%), as it also was the rs1800468 SNP‐G/A genotype in stage IV patients (20.7%) compared to stage I, II and III patients, combined (10.3%). Conversely, the T/T rs1800469 SNP‐T/T genotype was absent in the former group and present in 19.0% in the latter. Furthermore, the rs1800469‐C/rs1800470‐T (CT) haplotype was found in 15.0% of stage IV patients as compared to 3.0% of the remaining patients (3.0%) and also identifies patients with worse five‐year life expectancy (P = .03). TGF‐β1 synthesis by stimulated PBMCs was significantly lower in patients with the risk SNPs or haplotype, compared to the alternative genotype. Finally, TGF‐β1 plasma levels were lower in patients with worse life expectancy. Analysis of TGFB1 SNPs and measurement of plasma TGF‐β1 levels serves to identify patients at risk of developing a more aggressive disease.