Gimeno Arias, Lourdes

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Gimeno Arias, Lourdes

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Anatomía Humana y Psicobiología

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Estudio de los genes Fgf15 y Fgf19 en el desarrollo del tubo neural de vertebrados / Lourdes Gimeno Arias ; dirección Salvador Martínez Pérez.
(Murcia : Universidad de Murcia, Departamento de Anatomía Humana y Psicobiología,, 2005) Gimeno Arias, Lourdes
Open Access
NKG2D Polymorphism in Melanoma Patients from Southeastern Spain
(MDPI, 2019-03-28) Martínez-Banaclocha, H; Bernardo, MV; Bolarin, JM; Marín, L; López-Hernández, R; López-Alvarez, MR; Moya-Quiles, MR; Muro, M; Frias-Iniesta, JF; Martínez-Escribano, J; Alvarez-López, MR; Minguela, A; Campillo, JA; Gimeno Arias, Lourdes; Anatomía Humana y Psicobiología
Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and CD8+ T cells. An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described. The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain. Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5' Nuclease Assay in 233 melanoma patients and 200 matched healthy controls. Results: A linkage disequilibrium analysis of the SNPs performed in the NKC region revealed two blocks of haplotypes (Hb-1 and Hb-2) with 14 and seven different haplotype subtypes, respectively. The third most frequent haplotype from the block Hb-2-NK3 (CAT haplotype)-was significantly more frequent on melanoma patients than on healthy controls (p = 0.00009, Pc = 0.0006). No further associations were found when NKC SNPs were considered independently. Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma. Keywords: Melanoma; NK cell; NKG2A; NKG2D; gene polymorphism.
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KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury
(Lippincott, Williams & Wilkins, 2013-04-27) López Álvarez, María R.; Campillo, José A.; Moya Quiles, María Rosa; Bolarín, José Miguel; Peña, Jesús de la; Salgado, Gema; García Alonso, Ana M.; Muro, Manuel; Miras, Manuel; Alonso, Clara; Álvarez López, María Rocio; Minguela, Alfredo; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Background. Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial. Methods. KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups. Results. KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3+ and KIR2DS1+ exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4+ significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3+ recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107–0.962; P=0.042), whereas KIR2DS1+ and KIR2DS4+ recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156–27.369; P=0.002 for KIR2DS1+; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267–11.365; P=0.017 for KIR2DS4). Conclusions. This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4+/C ligands also influence short-term graft survival.
Open Access
Activating Killer-cell Immunoglobulin-like Receptors are associated with the severity of COVID-19
(Oxford University Press, 2021-04-30) Bernal, Enrique; Alcaraz, María J.; Quadee, Ahmed A.; Moreno, Marta; Martínez-Sánchez, María V.; Campillo, José A.; Gómez, Jose M.; Peláez, Ana; García-Vázquez, Elisa; Herranz, Maite; Hernández-Olivo, Marta; Martínez-Alfaro, Elisa; Alcaraz, Antonia; Muñoz, Ángeles; Cano, Alfredo; McKay, Matthew R.; Muro, Manuel; Minguela, Alfredo; Murcian COVID19 Study group; Gimeno Arias, Lourdes; Medicina
Background: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. Here we investigate the role of Killer-cell Immunoglobulin-like receptor (KIR)/Human Leukocyte Antigen Class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. Methods: KIR and HLA-I genotyping and NK cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 non-infected controls. Results: NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe than mild/moderate patients and controls (83.7%, 55.7% and 36.2%, p<7.7x10-9). In mild/moderate patients HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared to patients with other HLA-B*15 subtypes and non-infected controls (90.9%, 42.9% and 47.3%, p<0.002, Pc=0.022). This strongly suggests that HLA-B*15:01 specifically presenting SARS-CoV-2 peptides could form a neo-ligand interacting with KIR3DS1. Similarly, a putative neo-ligand for KIR2DS4 could arise from other HLA-I molecules presenting SARS-CoV-2 peptides expressed on infected/activated lung antigen presenting cells. Conclusions: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/Ligand interactions associated to disease severity.
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Epidemiology, evolution, and long-term survival of alcoholic cirrhosis patients submitted to liver transplantation in southeastern Spain
(Wiley, 2016-04) Navarro Noguera, Elena; Bolarín, Jose M.; García Alonso, Ana M.; Luna Maldonado, Aurelio; Mrowiec, Anna; Campillo, José Antonio; Moya Quiles, Rosa; Álvarez López, María del Rocio; Minguela Puras, Alfredo; Miras, Manuel; Sánchez Bueno, Francisco; Muro, Manuel; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Background Alcoholic cirrhosis (AC) is a common cause of death among individuals abusing alcohol. In the last resort, liver transplantation (LT) is considered the only solution to save the patient's life, generating socioeconomic and public health problems. Clinical and sociodemographic characteristics, rejection frequency, and short- and long-term graft survival are not well known in end-term AC patients undergoing LT. The aim was to determine the sociodemographic and clinical characteristics, their incidence in LT, main pre- and posttransplant complications, and short- and long-term post-transplant graft survival in AC patients in southeastern Spain. Methods The medical records of 1,026 patients who underwent LT over the last 23 years were retrospectively reviewed, and demographic data and posttransplant survivals were analyzed and compared. Biochemical characteristics, major pre- and posttransplant complications and short- and long-term survivals were analyzed in a total of 398 male patients with AC undergoing LT. Results AC and viral cirrhosis are the main indications for LT in our study. Mostly represented in our study are AC men without associated viral infections with a mean age of 53.06 years. Main pretransplant complications in AC patients are ascites (78.3%) and encephalopathy (43.5%), while acute graft rejection is the most common liver posttransplant complication (26.6%), nevertheless with low graft loss frequency (1.1%). AC and autoimmune cirrhosis show the best posttransplant survival in both the short and long term. Patients with AC included on the waiting list for LT were Child-Pugh class B (52.1%) and Model for End-Stage Liver Disease score of 10 to 19 (71.2%). The highest percentage of AC patient survival was observed at 1 year posttransplant (81.2%) and progressively decreased over time up to 10 years posttransplant (69.6%). Pretransplant complications such as ascites and encephalopathy did not have an influence on the percentage of posttransplant survivals, although better survival rates were observed in nonviral AC patients. Conclusions AC without viral infections is the main indication for LT in southeastern Spain although its frequency has decreased in last decade. AC is a good indication for LT for its high survival rate and few posttransplant complications. Despite having a high percentage of pretransplant complications (ascites and encephalopathy) but does not appear to influence survivals being observed posttransplant survival rates above those expected. Conversely, viral infections in the patient with AC decrease patient survivals. The main future goals are design new strategies to detect, treat, and reduce AC frequency in our population and know alcoholic recidivism rate posttransplant in our population.
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Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance
(American Association for Cancer Research, 2019-08-01) Guillamón, Concepción F.; Martínez Sánchez, María V.; Campillo, José A.; Server Pastor, Gerardo; Martínez García, Jerónimo; Martínez Escribano, Jorge; Torroba, Amparo; Ferri, Belén; Abellán, Daniel J.; López Álvarez, María R.; Moya Quiles, María R.; Muro, Manuel; Minguela, Alfredo; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Therapies using NK cells (NKc) expanded/activated ex vivo or stimulated in vivo with new immunostimulatory agents offer alternative opportunities for patients with recurrent/refractory tumors, but relevant biomarkers to guide the selection of patients are required for optimum results. Overall survival of 249 solid cancer patients was evaluated in relation to the genetics and/or the expression on peripheral blood NKcs of inhibitory and activating killer-cell immunoglobulin-like receptors (iKIR and aKIR, respectively), HLA class I ligands, CD226 (also known as DNAM-1), and NKG2A. Compared with patients with higher expression, patients with low expression of CD226 on total NKcs showed shorter mean overall survival (60.7 vs. 98.0 months, P < 0.001), which was further reduced in presence of telomeric aKIRs (KIR2DS1-DS5 and/or KIR3DS1, 31.6 vs. 96.8 months, P < 0.001). KIR2DL2/S2+, KIR3DL1+, KIR2DL1+, and KIR2DL3+ NKc subsets in the presence of their cognate ligands primarily contributed to shortening patients’ overall survival by increasing the sensitivity to CD226 downmodulation in aKIR-rich telomeric genotypes. In patients with high tumor burden who died during the follow-up period, aKIR-rich telomeric genotypes were associated with: (i) specific downmodulation of CD226 on educated NKcs but not on CD8+ T cells or uneducated NKcs, (ii) lower expression of CD226 and higher expression of NKG2A on aKIR+ NKcs, and (iii) lower numbers of total CD56dim NKcs. The reduced expression of CD226 on NKcs with aKIR-rich genotypes may be a biomarker indicative of NKc hyporesponsiveness in patients that could benefit from new NKc immune-stimulatory therapies.
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Expression of IZUMO1 and JUNO in the gonads of domestic cats (Felis catus)
(Elsevier, 2024-05) Sanguansook, P; Rodprasert, W; Sawangmake, C; Ferrán, JL; Soria-Monzó, P; Chatdarong, K; Gimeno Arias, Lourdes; Izquierdo Rico, María José; Avilés Sánchez, Manuel; Biología Celular e Histología
Because of the time-consuming nature of surgical neutering and the rapid rate of reproduction among domestic cats, it is crucial to investigate alternative, nonsurgical methods of contraception for this species. Sperm protein IZUMO1 and its oocyte receptor JUNO have been proposed as potential targets for nonsurgical contraceptives. This study aimed to demonstrate (1) the protein coding sequence of feline IZUMO1 and JUNO, (2) gene expression in specific organs by measuring mRNA levels in different visceral tissues, and (3) the expression of IZUMO1 and JUNO during sperm maturation and folliculogenesis, respectively. Amplification for sequencing of feline IZUMO1 and JUNO was performed using the RT-PCR method. Levels of gene expression in different tissues were evaluated using real-time PCR. In situ hybridization was performed to localize JUNO mRNA in ovarian tissues. The complete coding sequences of IZUMO1 and JUNO were obtained and analyzed. A comparison between protein orthologs demonstrated the conservation of IZUMO1 and JUNO in Felidae. The real-time PCR results from various visceral organs indicated that IZUMO1 was significantly higher in the testis than in other organs, whereas JUNO was significantly higher in the ovary than in other organs. Expression of IZUMO1 was found to be higher in the testes than in the caput, corpus, and cauda of epididymides. In situ hybridization revealed that JUNO mRNA was in the ooplasm and nucleus of the primordial, primary, secondary, and antral follicles. Importantly, this was the first study to demonstrate the IZUMO1 and JUNO genes in the testis and ovary of cats. The results are useful for future research related to these genes and for developing contraceptives against these targets.
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Divergences in KIR2D+ natural killer and KIR2D+CD8+ T-cell reconstitution following liver transplantation
(Elsevier, 2011-03) López Álvarez, M.R.; Campillo, J.A.; Blanco García, R.M.; Salgado Cecilia, G.; Bolarín, J.M.; Gil, J.; García Alonso, A.M.; Muro, M.; Álvarez López, M.R.; Miras, M.; Minguela, A.; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Natural killer (NK) and CD8+ T cells may be active elements in the allograft response, but little is known about their role in liver transplantation. Some of these cells express killer immunoglobulin-like receptors (KIRs), which after binding specific ligands may transmit inhibitory/activating signals. In this study, circulating NK and CD8+ T cells expressing CD158a/h (KIR2DL1/S1) or CD158b/j (KIR2DL2/3/S2) receptors were analyzed in 142 liver recipients by flow cytometry. They were underrepresented in patients before transplantation, but following transplantation, whereas the KIR2D+ NK subsets experienced a late recuperation (day 365) mainly in C2-homozygous patients developing early acute rejection, recovery of the 2 CD8+KIR2D+ T cells started earlier, showing significant differences on day 365 between patients without acute rejection and those suffering from it (p = 0.004 and p < 0.0001, respectively). These differences were also evident when the human leukocute antigen-C genotypes of the recipient were considered. In conclusion, whereas the late recovery of KIR2D+ NK cells in C2/C2 patients appears to be linked to acute rejection, the increase in early CD8+KIR2D+ T cells in overall liver recipients correlates with a most successful early graft outcome. Therefore, monitoring of KIR2D+ cells appears to be a useful tool for liver transplant follow-up.
Open Access
Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing
(Taylor and Francis Group, 2016-04-08) Martínez Sánchez, María V.; Periago, Adela; Mrowiec, Anna; Montes Baqueros, Natividad R.; Campillo, Jose Antonio; Bolarin, José M.; Bernardo, María V.; López Álvarez, María R.; González, Consuelo; García Caray, María C.; Muro, Manuel; Cabañas Perianes, Valentín; Fuster, Jose L.; García Alonso, Ana M.; Moraleda, José M.; Álvarez López, María Rocio; Minguela, Alfredo; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Missing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands. The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls. Compared to controls, myeloma accumulates KIR2DL1−L2+L3− genotypes (2.8% vs. 13.2%, p < 0.01, OR = 5.29) and less diverse peripheral repertoires of NKc clones. Less diverse and weaker-affinity repertoires of iKIR2D/HLA-C licensing interactions increased myeloma susceptibility. Thus, the complete absence of conventional iKIR2D/HLA-C licensing interactions (KIR2DL1−L2+L3−/C2C2, 2.56% vs. 0.35%; p < 0.05; OR = 15.014), single-KIR2DL3+/C1+ (20.51% vs. 10.84%; p < 0.05; OR = 2.795) and single-KIR2DL2+/C1+ (12.82% vs. 4.9%; p < 0.01; OR = 5.18) interactions were over-represented in myeloma, compared to controls. Additionally, KIR2DL1−L2+L3− (20% vs. 83%, p < 0.00001) as well as KIR3DL1− (23% vs. 82%, p < 0.00001) genotypes had a dramatic negative impact on the 3-y progression-free survival (PFS), particularly in patients with low-tumor burden. Remarkably, myeloma-PCs, compared to K562 and other hematological cancers, showed substantial over-expression of HLA-I (“increasing-self” instead of missing-self), including HLA-C, and mild expression of ligands for NKc activating receptors (aRec) CD112, CD155, ULBP-1 and MICA/B, which apparently renders myeloma-PCs susceptible to lysis mainly by licensed NKc. KIR2DL1−L2+L3−/C2C2 patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myeloma-PCs (4% vs. 15%; p < 0.05, compared to controls). These results support a model where immunosurveillance of no-missing-self cancers, e.g., myeloma, mainly depends on NKc licensing.
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NK Cell Education in Tumor Immune Surveillance: DNAM-1/KIR Receptor Ratios as Predictive Biomarkers for Solid Tumor Outcome
(American Association for Cancer Research, 2018-12-03) Guillamón, Concepción F.; Martínez Sánchez, María V.; Mrowiec, Anna; Martínez García, Jerónimo; Server Pastor, Gerardo; Martínez Escribano, Jorge; Torroba, Amparo; Ferri, Belén; Abellán, Daniel; López Álvarez, Maria R.; Moya Quiles, María Rosa; Muro, Manuel; Minguela, Alfredo; Campillo, José A.; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
Natural killer cell (NKc)-based therapies offer promising outcomes in patients with tumors, but they could improve with appropriate selection of donors and optimization of methods to expand NKcs in vitro. Education through licensing interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) and NKG2A with their cognate HLA class-I ligands optimizes NKc functional competence. This work has evaluated the role of licensing interactions in NKc differentiation and the survival of cancer patients. We have analyzed KIR and KIR-ligand genes, and the expression of activating (CD16 and DNAM-1/CD226) and inhibitory (NKG2A and iKIRs) receptors on peripheral blood NKcs in 621 healthy controls and 249 solid cancer patients (80 melanoma, 80 bladder, and 89 ovarian). Licensing interactions upregulated the expression of activating CD226, reduced that of iKIR receptors, and shifted the CD226/iKIR receptor ratio on NKc membranes to activating receptors. A high tumor burden decreased CD226 expression, reduced the ratio of CD226/iKIR, and negatively affected patient survival. The progression-free survival (38.1 vs. 67.0 months, P < 0.002) and overall survival (56.3 vs. 99.6 months, P < 0.00001) were significantly shorter in patients with lower expression of CD226 on NKcs. Hence, transformed cells can downmodulate these licensing-driven receptor rearrangements as a specific mechanism to escape NKc immune surveillance. Our results suggest the importance of the CD226/iKIR receptor ratio of NKcs induced by licensing interactions as critical determinants for solid cancer immune surveillance, and may provide predictive biomarkers for patient survival that may also improve the selection of donors for NKc immunotherapy.