INTRODUCTION: Idiopathic inflammatory myopathies (IIM) are a group of rare systemic autoimmune diseases characterized by muscle weakness, histopathological signs of inflammation in muscle tissues, elevated serum levels of muscle-associated enzymes, inflammatory mononuclear cells infiltrating muscle tissue and progressive symmetrical proximal muscle weakness. The current view is that they begin by immune activation in response to environmental factors in genetically predisposed people, but despite the number of investigations into the genetic background, the detailed etiopathogenesis remains unknown. The aim of this study was to examine the relationship between select polymorphisms located in the human major histocompatibility complex (MHC) and IIM. These genetic markers may take part in the onset of the autoimmune process, and their identification could aid in the diagnosis and classification of IIM subtypes. MATERIAL AND METHODS: One hundred and fifty-two adult patients suffering from IIM (82 dermatomyositis and 70 polymyositis) and 150 healthy controls were analyzed in this study. All were from the Czech Republic. SNPs of the HSP70 genes HSPA1A (rs1008438, rs1043618), HSPA1B (rs1061581, rs539689, pentanucleotide tandem duplication rs9281590) and HSPA1L (rs2227956) were analyzed in all patients and controls. For the detection of HLA polymorphisms, we used commercial kits from CareDx. Haplotypes were created using Arlequin 3.5. RESULTS: Our results confirm the association of IIM with the ancestral haplotype HLA-DRB1*03-DQB1*02. The most important MHC haplotype related to IIM and covering all polymorphisms was HLA-DQB1*02-DRB1*03:01-T-C-C-G-C-INS (p < 0.05, OR = 1.90, 95% CI: 1.15-3.13). This haplotype is associated with the risk of IIM development. CONCLUSIONS: Our results show that polymorphism typing within the MHC might be a very strong tool for recognition of IIM.

• Publikační typ
• časopisecké články MeSH

The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi-square test, Fisher's exact test, Pearson's goodness-of-fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA-1 or EQCA-2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible.

• MeSH
• alely MeSH
• chov MeSH
• hlavní histokompatibilní komplex * genetika   MeSH
• koně genetika   MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• receptory buněk NK genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• biologie MeSH
• lékařská genetika MeSH
• molekulární medicína MeSH

• Konspekt
• Lékařské vědy. Lékařství
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• biologie
• NLK Publikační typ
• učebnice vysokých škol

INTRODUCTION: This study aimed to identify the phytochemical constituents that could target gastric cancer in Kangai injection using a network pharmacology-based approach. METHODS: Protein-protein interactions (PPI), Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted utilizing String and OmicShare tools. In the in vitro experiments, the related mRNA and protein levels were assessed via real-time quantitative polymerase chain reaction and Western blotting, respectively. Cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. RESULTS: Kangai injection comprises several compounds, which target multiple substrates and pathways related to gastric cancer. The PPI and Gene Ontology analyses revealed that tumor necrosis factor (TNF) was a hub gene. KEGG pathway enrichment analysis indicated that the the TNF pathway was significantly enriched. Kangai injection decreased the mRNA levels of TNFR2, TRAF2, PI3K, AKT, and IκBα and inhibited the phosphorylation of PI3K, AKT, and IκBα phosphorylations. Kangai injection inhibited cell proliferation, while TNFR2 overexpression or treatment with the PI3K activator 740 Y-P partially restored it. CONCLUSION: Kangai injection operates through multiple targets and pathways in gastric cancer, with the TNFR2/PI3K/AKT/NF-κB pathway playing a crucial role in its mechanism against gastric cancer.

• MeSH
• fosfatidylinositol-3-kinasy MeSH
• lidé MeSH
• nádory žaludku * farmakoterapie   genetika   MeSH
• NFKB inhibitor alfa MeSH
• protoonkogenní proteiny c-akt MeSH
• receptory TNF - typ II MeSH
• síťová farmakologie MeSH
• TNF-alfa genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: T-cell receptor (TCR) recognition of foreign peptides presented by the major histocompatibility complex (MHC) initiates the adaptive immune response against pathogens. While a large number of TCR sequences specific to different antigenic peptides are known to date, the structural data describing the conformation and contacting residues for TCR-peptide-MHC complexes is relatively limited. In the present study we aim to extend and analyze the set of available structures by performing highly accurate template-based modeling of these complexes using TCR sequences with known specificity. METHODS: Identification of CDR3 sequences and their further clustering, based on available spatial structures, V- and J-genes of corresponding T-cell receptors, and epitopes, was performed using the VDJdb database. Modeling of the selected CDR3 loops was conducted using a stepwise introduction of single amino acid substitutions to the template PDB structures, followed by optimization of the TCR-peptide-MHC contacting interface using the Rosetta package applications. Statistical analysis and recursive feature elimination procedures were carried out on computed energy values and properties of contacting amino acid residues between CDR3 loops and peptides, using R. RESULTS: Using the set of 29 complex templates (including a template with SARS-CoV-2 antigen) and 732 specificity records, we built a database of 1585 model structures carrying substitutions in either TCRα or TCRβ chains with some models representing the result of different mutation pathways for the same final structure. This database allowed us to analyze features of amino acid contacts in TCR - peptide interfaces that govern antigen recognition preferences and interpret these interactions in terms of physicochemical properties of interacting residues. CONCLUSION: Our results provide a methodology for creating high-quality TCR-peptide-MHC models for antigens of interest that can be utilized to predict TCR specificity.

• MeSH
• aminokyseliny MeSH
• antigenní specifita receptorů T-buněk MeSH
• COVID-19 * MeSH
• komplement MeSH
• lidé MeSH
• SARS-CoV-2 MeSH
• specificita protilátek MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Protilátkami zprostředkovaná (humorální) rejekce je závažná komplikace, která je asociována se zhoršenou prognózou přežití transplantovaných orgánů. Její diagnostika byla dlouho zaměřena na detekci protilátek specifických proti HLA antigenům, nicméně se v posledních letech ukázalo, že při rozvoji této rejekce mohou hrát roli i protilátky proti antigenům, které jsou kódovány geny mimo HLA komplex. Non HLA antigeny jsou polymorfní molekuly, a proto mohou být rozpoznány imunitním systémem příjemců orgánů. Tyto antigeny se vyskytují na povrchu endoteliálních a epiteliálních buněk, ale mohou být lokalizovány i intracelulárně a uvolňovat se v případě buněčné lýze. Mezi non HLA antigeny patří molekuly MICA – major-histocompatibility-complex (MHC) class I-related chain A, receptor angiotensinu II-R1, kolagen, K-α1 tubulin, srdeční myosin, vimentin a další. Non HLA protilátky se mohou vyskytovat před transplantací, ale rovněž mohou být produkovány i de novo. Diagnostika non HLA protilátek se provádí za využití xMap technologie (Luminex) nebo endoteliálním crossmatch (křížová zkouška) a dalšími technikami. Nicméně všechny metodiky i interpretace výsledků non HLA má svá úskalí.

Antibody-mediated (humoral) rejection (AMR) is a serious complication that is associated with a worse prognosis of survival of transplanted organs. The diagnosis of AMR has been long time focused on the detection of antibodies specific to HLA antigens, however, in recent years it has become clear that antibodies against antigens encoded by genes outside the HLA complex can also play a role in the development of AMR. Non-HLA antigens are polymorphic molecules and therefore can be recognised by the immune system of organ transplant recipients. These antigens are expressed on the surface of endothelial and epithelial cells, but can also be localised intracellularly and released in case of cell lysis. Non-HLA antigens include molecules MICA – major-histocompatibility-complex (MHC) class I-related chain A, angiotensin II-R1 receptor (ATR1), collagen, K-α1 tubulin, cardiac myosin, vimentin and others. Non-HLA antibodies can occur before transplantation, but may also be produced de novo. The diagnosis of non-HLA antibodies is carried out using xMap technology (Luminex), the so-called endothelial crossmatch and other techniques, however, all methodologies and interpretation of results have their pitfalls.

• Klíčová slova
• non HLA protilátky, technologie Luminex,
• MeSH
• autoprotilátky klasifikace   škodlivé účinky   toxicita   MeSH
• HLA antigeny * imunologie   MeSH
• lidé MeSH
• rejekce štěpu diagnóza   etiologie   komplikace   MeSH
• testování histokompatibility metody   MeSH
• transplantace orgánů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The major histocompatibility complex (MHC) with its class I and II genes plays a crucial role in the immune response to pathogens by presenting oligopeptide antigens to various immune response effector cells. In order to counteract the vast variability of infectious agents, MHC class I and II genes usually retain high levels of SNPs mainly concentrated in the exons encoding the antigen binding sites. The aim of the study was to reveal new variability of selected MHC genes with a special focus on MHC class I physical haplotypes. Long-range NGS to was used to identify exon 2-exon 3 alleles in three genetically distinct horse breeds. A total of 116 allelic variants were found in the MHC class I genes Eqca-1, Eqca-2, Eqca-7 and Eqca-Ψ, 112 of which were novel. The MHC class II DRA locus was confirmed to comprise five exon 2 alleles, and no new sequences were observed. Additional variability in terms of 15 novel exon 2 alleles was identified in the DQA1 locus. Extensive overall variability across the entire MHC region was confirmed by an analysis of MHC-linked microsatellite loci. Both diversifying and purifying selection were detected within the MHC class I and II loci analyzed.

• MeSH
• alely MeSH
• exony genetika   MeSH
• geny MHC třídy II * MeSH
• hlavní histokompatibilní komplex MeSH
• koně genetika   MeSH
• MHC antigeny I. třídy * MeSH
• MHC antigeny II. třídy genetika   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• buněčná imunita MeSH
• lymfocyty MeSH
• nemoci imunitního systému MeSH
• tvorba protilátek MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• alergologie a imunologie
• NLK Publikační typ
• učebnice vysokých škol

Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.

• MeSH
• alanin MeSH
• fosfoproteiny MeSH
• glycin MeSH
• infekce virem Epsteina-Barrové * MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• peptidy genetika   MeSH
• proteinové agregáty MeSH
• proteiny vázající RNA metabolismus   MeSH
• virus Epsteinův-Barrové - jaderné antigeny metabolismus   MeSH
• virus Epsteinův-Barrové * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

• MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární * genetika   MeSH
• duševní poruchy * genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• pokus o sebevraždu MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH