BACKGROUND: Human leukocyte antigen G (HLA-G) belongs to non-classical MHC class I molecules that is involved in the suppression of immune response. As HLA-G plays important role in the maintenance of fetal tolerance, its overexpression has been associated with tumor progression. For the regulation of HLA-G levels, genetic variants within the 5' upstream regulatory region (5'URR) are of crucial importance. Our study aimed to analyze the association between 16 HLA-G 5'URR variants, sHLA-G level and clinical variables in glioma patients. METHODS: We investigated 59 patients with gliomas (mean age 54.70 ± 15.10 years) and 131 healthy controls (mean age 41.45 ± 9.75 years). Patient's blood was obtained on the day of surgical treatment. The HLA-G 5'URR polymorphisms were typed by direct sequencing and the plasma level of sHLA-G assessed by ELISA. RESULTS: Haploblock within HLA-G 5'URR consisting of -762T, -716G, -689G, -666T, -633A, followed by -486C and -201A alleles were significantly more frequent in patients with gliomas than in the controls (p < 0.05). No correlation of HLA-G 5'URR variants with sHLA-G plasma level was found. Analysis of HLA-G 5'URR variants with main clinical variables in patients with grade IV gliomas revealed that haploblock carriers of -762CT, -716TG, -689AG, -666GT, -633GA, -486AC, -477GC, -201GA followed by -369AC carriers tend to have lower age at onset as compared to other genotype carriers (p = 0.04). CONCLUSION: Our results suggest genetic association of HLA-G 5'URR variants with risk of developing gliomas and possible contribution of HLA-G to disease pathology.
- MeSH
- antikoncepce imunologická metody MeSH
- autoimunitní nemoci imunologie MeSH
- endometrióza imunologie patofyziologie MeSH
- fertilita imunologie MeSH
- fertilizace fyziologie imunologie MeSH
- HLA-G antigeny fyziologie klasifikace MeSH
- infertilita diagnóza imunologie MeSH
- klinické laboratorní techniky klasifikace MeSH
- lidé MeSH
- menstruační cyklus fyziologie imunologie MeSH
- porod fyziologie imunologie MeSH
- preeklampsie imunologie patofyziologie MeSH
- rozmnožování * fyziologie imunologie MeSH
- těhotenství imunologie MeSH
- zánět * imunologie patofyziologie MeSH
- Check Tag
- lidé MeSH
- těhotenství imunologie MeSH
- Publikační typ
- přehledy MeSH
INTRODUCTION: Crohn's disease (CD) is a disabling chronic enteropathy sustained by a harmful T-cell response toward antigens of the gut microbiota in genetically susceptible subjects. Growing evidence highlights the safety and possible efficacy of mesenchymal stem cells (MSCs) as a new therapeutic tool for this condition. Therefore, we aimed to investigate the effects of bone marrow-derived MSCs on pathogenic T cells with a view to clinical application. METHODS: T-cell lines from both inflamed and non-inflamed colonic mucosal specimens of CD patients and from healthy mucosa of control subjects were grown with the antigen muramyl-dipeptide in the absence or presence of donors' MSCs. The MSC effects were evaluated in terms of T-cell viability, apoptotic rate, proliferative response, immunophenotype, and cytokine profile. The role of the indoleamine 2,3-dioxygenase (IDO) was established by adding a specific inhibitor, the 1-methyl-DL-tryptophan, and by using MSCs transfected with the small interfering RNA (siRNA) targeting IDO. The relevance of cell-cell contact was evaluated by applying transwell membranes. RESULTS: A significant reduction in both cell viability and proliferative response to muramyl-dipeptide, with simultaneous increase in the apoptotic rate, was found in T cells from both inflamed and non-inflamed CD mucosa when co-cultured with MSCs and was reverted by inhibiting IDO activity and expression. A reduction of the activated CD4(+)CD25(+) subset and increase of the CD3(+)CD69(+) population were also observed when T-cell lines from CD mucosa were co-cultured with MSCs. In parallel, an inhibitory effect was evident on the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interferon-γ, interleukin-17A and -21, whereas that of the transforming growth factor-β and interleukin-6 were increased, and production of the tolerogenic molecule soluble HLA-G was high. These latter effects were almost completely eliminated by blocking the IDO, whose activity was upregulated in MSCs co-cultured with CD T cells. The use of a semipermeable membrane partially inhibited the MSC immunosuppressive effects. Finally, hardly any effects of MSCs were observed when T cells obtained from control subjects were used. CONCLUSION: MSCs exert potent immunomodulant effects on antigen-specific T cells in CD through a complex paracrine and cell-cell contact-mediated action, which may be exploited for widespread therapeutic use.
- MeSH
- acetylmuramyl-alanyl-isoglutamin farmakologie MeSH
- antigeny povrchové metabolismus MeSH
- apoptóza účinky léků MeSH
- buňky kostní dřeně cytologie MeSH
- časosběrné zobrazování MeSH
- Crohnova nemoc patologie MeSH
- cytokiny metabolismus MeSH
- dospělí MeSH
- HLA-G antigeny metabolismus MeSH
- imunofenotypizace MeSH
- indolamin-2,3,-dioxygenasa antagonisté a inhibitory genetika metabolismus MeSH
- kokultivační techniky MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- malá interferující RNA metabolismus MeSH
- mezenchymální kmenové buňky cytologie metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- proliferace buněk účinky léků MeSH
- RNA interference MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- střevní sliznice cytologie MeSH
- T-lymfocyty cytologie účinky léků imunologie MeSH
- tryptofan analogy a deriváty farmakologie MeSH
- viabilita buněk MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antigeny CD20 účinky léků MeSH
- dárci tkání MeSH
- desenzibilizace imunologická * ekonomika metody MeSH
- dialýza ledvin metody mortalita MeSH
- HLA-G antigeny imunologie MeSH
- isoantigeny účinky léků MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- přežívání štěpu účinky léků MeSH
- reakce příjemce proti štěpu účinky léků MeSH
- rejekce štěpu epidemiologie MeSH
- transplantace ledvin * metody mortalita MeSH
- Check Tag
- lidé MeSH
Asthma bronchiale je chronická zápalová choroba dýchacích ciest, ktorá sa klinicky prejavuje záchvatmi dýchavičnosti. Na vzniku astmy sa podiel'aju viaceré faktory, najma environmentálne a dědičné, avšak ich přesný mechanizmus pósobenia sa ešte stále študuje. V súvislosti s patogenézou astmy sa skúmajú aj geny umiestnené v HLA - genetickej oblasti. K takýmto génom sa nedávno zařadil aj gén kódujúci neklasickú molekulu HLA-G. Biologický význam HLA-G spočívá v potláčaní imunitnej odpovede a navodzovaní tolerancie. Na základe vyšetrenia sekvencie nukleotidov sa doteraz identifikovalo 47 róznych HLA-G aliel. Významný polymoďizmus zahřňa přítomnost' 14 nukleotidov na 3' konci genu HLA-G, ktorý ovplyvňuje stabilitu mRN A a pravděpodobné aj celkovú hladinu proteinu. V práci sme sa preto zamerali na analýzu přítomnosti tohto inzertu v gene HLA-G u pacientov s astmou. Celkovo sme vyšetřili 176 pacientov a 73 zdravých jedincov. Metodou PCR sme identifikovali jedincov s HLA-G genotypom „+14/+14" (19,89 % vs. 16,44 %), s genotypom „-14/-14" (29,55 % vs. 32,88 %) a heterozygotných jedincov s genotypom „+14/-14" (50,57 % vs. 50,68 %). V porovnaní s kontrolou, hladina preukaznosti/j nebola statisticky významná pri nijakej vyšetrovanej skupině, napriek tomu najváčší statistický rozdiel medzi skupinou pacientov a kontrolou sme zistili pri porovnávaní výskytu genotypu „+14/+14" (p = 0,5964).
Bronchial asthma is a chronic inflammatory disease of respiratory tract characterised by attacks of breathlessness. Many factors are involved in its development, including environmental and genetic factors; nevertheless the precise mechanisms of their contribution have not been completely elucidated until now. In relation to the pathogenesis of asthma, genes located in the HLA region have been intensively studied for many years, including HLA-G. The main biological function of HLA-G includes the participation in the tolerance induction. Similarly to other HLA genes, HLA-G is polymorphic too. By nucleotide sequence analysis 47 various HLA-G alleles have been identified until now. The most important polymorphism includes the presence of 14 bp sequence located in 3’ UTR region of HLA-G gene. It is proposed that this polymorphism is involved in mRNA stability which subsequently affects the levels of HLA-G molecules. The aim of our work was to analyse presence of 14 bp sequence in HLA-G gene in the group of patients suffering from bronchial asthma. Altogether we have analysed 176 asthma patients and 73 healthy individuals. Using PCR method we found individuals with HLA-G genotype „-14/-14“ (29,55% vs. 32,88%), with HLA-G genotype „+14/+14“ (19,89% vs. 16,44%) and those who are heterozygous „+14/-14“ (50,57% vs. 50,68%). No statistical significance has been observed by comparing any analysed group to healthy controls as revealed by parameter p counting, nevertheless, the most statistical difference were found between the „+14/+14“groups of patients and controls (p = 0,5964).
- Klíčová slova
- PCR-analýza,
- MeSH
- bronchiální astma etiologie genetika imunologie MeSH
- DNA analýza MeSH
- genetická predispozice k nemoci MeSH
- genetické testování MeSH
- genotyp MeSH
- HLA-G antigeny analýza MeSH
- lidé MeSH
- messenger RNA MeSH
- polymorfismus genetický MeSH
- statistika jako téma MeSH
- výběr pacientů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- MeSH
- biologické markery MeSH
- exprese genu MeSH
- faktory štěpení a polyadenylace mRNA MeSH
- HLA-G antigeny * diagnostické užití imunologie izolace a purifikace MeSH
- hodnotící studie jako téma MeSH
- lidé MeSH
- nádory ledvin * diagnóza imunologie terapie MeSH
- prediktivní hodnota testů MeSH
- reverzní transkripce MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Renal cell carcinoma (RCC) is characterized by its resistance to radiotherapy and/or chemotherapy. On the other hand, it is an immunogenic tumor - it is able to stimulate antitumor responses. A prognostic significance of HLA-G expression by neoplastic cells in RCC is not well characterized; significance HLA-E expression in RCC is not characterized at all. METHODS: In our study, we evaluated the expression of HLA-G and HLA-E specific mRNA transcripts produced by neoplastic cells in 38 cases of RCC and in 10 samples of normal kidney parenchyma. The results were statistically correlated with various clinico-pathological parameters. RESULTS: We confirmed that HLA-G is downregulated in normal kidney tissue; if it is up-regulated in RCC, then it is connected to worse prognosis. On the other hand, HLA-E mRNA transcripts were present in both normal kidney tissue and RCC and their increasing concentrations counterintuitively carried better prognosis, more favorable pT stage and lower nuclear Fuhrmann's grade. CONCLUSION: Considering the fact that there is known aberrant activation of HLA-G and HLA-E expression by interferons, identification of HLA-G and HLA-E status could contribute to better selection of RCC patients who could possibly benefit from more tailored neoadjuvant biological/immunological therapy. Thus, these molecules could represent useful prognostic biomarkers in RCC, and the expression of both these molecules in RCC deserves further study. THE VIRTUAL: Slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7383071387016614.
- MeSH
- dospělí MeSH
- HLA-G antigeny biosyntéza genetika MeSH
- imunohistochemie MeSH
- Kaplanův-Meierův odhad MeSH
- karcinom z renálních buněk imunologie metabolismus mortalita MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA analýza MeSH
- MHC antigeny I. třídy biosyntéza genetika MeSH
- nádorové biomarkery analýza MeSH
- nádory ledvin imunologie metabolismus mortalita MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- přežití bez známek nemoci MeSH
- prognóza MeSH
- regulace genové exprese u nádorů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The role of nonclassical human leukocyte antigens G and E (HLA-G and HLA-E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA-G and HLA-E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA-G and HLA-E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA-G and HLA-E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA-G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA-E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro-host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.
- MeSH
- čipová analýza tkání MeSH
- glioblastom metabolismus mortalita patologie MeSH
- HLA antigeny biosyntéza MeSH
- HLA-G antigeny MeSH
- imunohistochemie MeSH
- lidé MeSH
- MHC antigeny I. třídy biosyntéza MeSH
- nádorové biomarkery analýza MeSH
- nádorové buněčné linie MeSH
- nádory mozku metabolismus mortalita patologie MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia-glioblastoma cell interactions with respect to the expression of these molecules deserves further study.
- MeSH
- glioblastom imunologie patofyziologie MeSH
- glióza imunologie metabolismus patofyziologie MeSH
- HLA antigeny metabolismus MeSH
- HLA-G antigeny MeSH
- imunomodulace fyziologie MeSH
- lidé MeSH
- makrofágy imunologie metabolismus MeSH
- mezibuněčná komunikace imunologie MeSH
- MHC antigeny I. třídy metabolismus MeSH
- mikroglie imunologie metabolismus MeSH
- mozek imunologie metabolismus patofyziologie MeSH
- nádory mozku imunologie patofyziologie MeSH
- pohyb buněk imunologie MeSH
- přirozená imunita imunologie fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
