Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.
- MeSH
- Anaplasma phagocytophilum imunologie MeSH
- dinoproston imunologie MeSH
- ehrlichióza imunologie MeSH
- ELISA MeSH
- imunoblotting MeSH
- inflamasomy imunologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- proteiny regulující apoptózu imunologie MeSH
- proteiny vázající vápník imunologie MeSH
- receptory prostaglandinů E - podtyp EP3 imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1β (IL-1β) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod.
- MeSH
- Anaplasma phagocytophilum genetika imunologie MeSH
- annexin A2 chemie genetika imunologie MeSH
- arachnida jako vektory chemie genetika imunologie MeSH
- cystatiny chemie genetika imunologie MeSH
- ehrlichióza imunologie mikrobiologie patologie MeSH
- Escherichia coli genetika metabolismus MeSH
- imunitní únik * MeSH
- inflamasomy genetika imunologie MeSH
- interleukin-18 genetika imunologie MeSH
- interleukin-1beta genetika imunologie MeSH
- kaspasa 1 genetika imunologie MeSH
- kaspasy genetika imunologie MeSH
- klíště chemie genetika imunologie MeSH
- lidé MeSH
- makrofágy imunologie mikrobiologie MeSH
- molekulární modely MeSH
- myši MeSH
- protein - isoformy chemie genetika imunologie MeSH
- proteiny regulující apoptózu chemie genetika imunologie MeSH
- proteiny vázající vápník chemie genetika imunologie MeSH
- regulace genové exprese MeSH
- rekombinantní proteiny chemie genetika imunologie MeSH
- sekvence aminokyselin MeSH
- signální transdukce MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Maligní lymfomy představují klinicky, biologicky a geneticky velmi pestrou skupinu neoplazií. Poslední dekáda navíc přinesla do moderní hemato-onkologie řadu nových biologicky aktivních léčiv, která rozšířila terapeutické možnosti a změnila osud nemocných. Éra personalizované medicíny klade na rozhodovací proces lékaře nové nároky. Kvalifikovaná předpověď osudu nemocných je nyní nezbytným nástrojem volby léčebné strategie. Prediktivní nástroje – tedy prognostické faktory, prodělaly ruku v ruce s vývojem terapie dramatický rozvoj. Původní klinická schémata a prognostické indexy postulovaná v éře před zavedením imunoterapie a intenzivních protokolů léčby mají v dnešní době limitovanou výpovědní schopnost. Nové prognostické faktory více reflektují povahu samotného nádoru, umožňují odhadnout efektivitu chemoimunoterapie a zohledňují imunitní interakci mezi nádorem a organismem pacienta. Použití moderních molekulárně-cytogenetických a imunohistochemických metod přináší mnoho důležitých přídatných prognostických informací. Cílem sdělení je poskytnout přehled současně používaných prediktivních nástrojů od klasických skórovacích systémů až po nové poznatky na poli cytogenetiky a imunogenomiky nádorů.
Malignant lymphomas represent a clinically, biologically and genetically varied group of neoplasms. Moreover, the last decade has provided modern haemato-oncology with numerous novel biologically active drugs that have extended therapeutic options and changed our patients' lives. The era of personalized medicine places new demands on physicians' decision-making processes. A confident prediction of the patient's outlook is now an indispensable tool for selecting treatment strategy. Predictive tools, or predictive factors, hand in hand with changes in therapy, have undergone dramatic development. Previous clinical schemes and prognostic indices postulated in the era prior to the introduction of immunotherapy and intensive treatment protocols have limited information value today. Novel prognostic factors are better at reflecting the nature of tumours themselves, allowing estimation of chemo-immunotherapy effectiveness and take into consideration the immune interaction between a tumour and the patient's organism. Modern molecular cytogenetic and immunohistochemical methods yield important additional prognostic information. The article aims at providing a review of currently used predictive tools, from traditional scores to novel findings in the field of tumour cytogenetics and immunogenomics.
- Klíčová slova
- imunogenomika, klinické prognostické faktory,
- MeSH
- antigeny CD20 imunologie MeSH
- antigeny CD279 imunologie MeSH
- cytogenetické vyšetření metody MeSH
- cytogenetika MeSH
- difúzní velkobuněčný B-lymfom diagnóza genetika klasifikace MeSH
- folikulární lymfom diagnóza genetika MeSH
- imunohistochemie metody MeSH
- imunoterapie MeSH
- lidé MeSH
- lymfom z plášťových buněk diagnóza genetika MeSH
- lymfom * diagnóza genetika MeSH
- monoklonální protilátky terapeutické užití MeSH
- nádorové biomarkery * analýza genetika imunologie MeSH
- počet lymfocytů MeSH
- prognóza * MeSH
- proteiny regulující apoptózu imunologie MeSH
- receptory Fc imunologie MeSH
- rituximab MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND AIMS: Microvesicles (MV) shed from the plasma membrane of eukaryotic cells, including human embryonic stem cells (hESC), contain proteins, lipids and RNA and serve as mediators of cell-to-cell communication. However, they may also contain immunogenic membrane domains and infectious particles acquired from xenogenic components of the culture milieu. Therefore, MV represent a potential risk for clinical application of cell therapy. METHODS: We tested the ability of hESC and their most commonly used feeder cells, mouse embryonic fibroblasts (MEF), to produce MV. We found that hESC are potent producers of MV, whereas mitotically inactivated MEF do not produce any detectable MV. We therefore employed a combined proteomic approach to identify the molecules that constitute the major components of MV from hESC maintained in a standard culture setting with xenogenic feeder cells. RESULTS: In purified MV fractions, we identified a total of 22 proteins, including five unique protein species that are known to be highly expressed in invasive cancers and participate in cellular activation, metastasis and inhibition of apoptosis. Moreover, we found that hESC-derived MV contained the immunogenic agents apolipoprotein and transferrin, a source of Neu5Gc, as well as mouse retroviral Gag protein. CONCLUSIONS: These findings indicate that MV represent a mechanism by which hESC communicate; however, they also serve as potential carriers of immunogenic and pathogenic compounds acquired from environment. Our results highlight a potential danger regarding the use of hESC that have previously been exposed to animal proteins and cells.
- MeSH
- antigeny heterofilní imunologie MeSH
- antigeny nádorové imunologie metabolismus MeSH
- apolipoproteiny imunologie metabolismus MeSH
- buněčné linie MeSH
- elektronová mikroskopie MeSH
- embryonální kmenové buňky cytologie imunologie metabolismus MeSH
- fibroblasty cytologie imunologie metabolismus MeSH
- genové produkty gag imunologie metabolismus MeSH
- kokultivační techniky MeSH
- lidé MeSH
- mikropartikule imunologie metabolismus MeSH
- myši MeSH
- proteiny regulující apoptózu imunologie metabolismus MeSH
- proteomika MeSH
- riskování MeSH
- skot MeSH
- tandemová hmotnostní spektrometrie MeSH
- tkáňová terapie - dějiny škodlivé účinky MeSH
- transferin imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
