Person: Fernández-Cruz Pérez, Eduardo
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First Name
Eduardo
Last Name
Fernández-Cruz Pérez
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Area
Inmunología
Identifiers
3 results
Search Results
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Item 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, AntonioHLA-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.Item Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes(Cellular and Molecular Life Sciences, 2022) Suarez-Trujillo, Fabio; Juarez, Ignacio; Rodríguez-Sainz, Carmen; Palacio-Gruber, José; Vaquero-Yuste, Christian; Molina-Alejandre, Marta; Fernández-Cruz, Eduardo; Martin-Villa, José Manuel; Arnaiz Villena, Antonio; Juárez Martín-Delgado, Ignacio; Fernández-Cruz Pérez, Eduardo; Martín Villa, José ManuelAbstractClassicalHLA(Human Leukocyte Antigen) is the Major Histocompatibility Complex (MHC) in man. HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been established yet.HLA-Gimmune modulation gene (and also-Eand-F) are starting the same arduous way: statistics and allele association are the trending subjects with the same few results obtained byHLAclassical genes, i.e., no pathogenesis may be discovered after many years of a great amount of researchers’ effort. Thus, we believe that it is necessary to follow different research methodologies: (1) to approach this problem, based on how evolution has worked maintaining together a cluster of immune-related genes (the MHC) in a relatively short chromosome area since amniotes to human at least, i.e., immune regulatory genes (MHC-G, -E and -F), adaptive immune classical class I and II genes, non-adaptive immune genes like (C2, C4 and Bf) (2); in addition to using new in vitro models which explain pathogenetics ofHLAand disease associations. In fact, this evolution may be quite reliably studied during about 40 million years by analyzing the evolution ofMHC-G, -E, -F, and their receptors (KIR—killer-cell immunoglobulin-like receptor, NKG2—natural killer group 2-, or TCR-T-cell receptor—among others) in the primate evolutionary lineage, where orthology of these molecules is apparently established, although cladistic studies show thatMHC-GandMHC-Bgenes are the ancestral class I genes, and that New World apesMHC-Gis paralogous and not orthologous to all other apes and manMHC-Ggenes. In the present review, we outline past and possible future research topics: co-evolution of adaptiveMHCclassical (class I and II), non-adaptive (i.e., complement) and modulation (i.e., non-classical class I) immune genes may imply that the study of full or part of MHC haplotypes involving several loci/alleles instead of single alleles is important for uncovering HLA and disease pathogenesis. It would mainly apply to starting research on HLA-G extended haplotypes and disease association and not only using single HLA-G genetic markers.Item HLA-G: Too Much or Too Little? Role in Cancer and Autoimmune Disease(Frontiers in Immunology, 2022) Martín Villa, José Manuel; Juárez Martín-Delgado, Ignacio; Fernández-Cruz Pérez, Eduardo; Arnaiz Villena, Antonio; Christian Vaquero-Yuste; Marta Molina-Alejandre; Fabio Suárez-Trujillo; Adrián López-Nares; José Palacio‐Gruber; Luis Barrera-Gutiérrez; Carmen Rodríguez-SainzHLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3’UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.