Nanoparticles are commonly used in diagnostics and therapy. They are also increasingly being implemented in cancer immunotherapy because of their ability to deliver drugs and modulate the immune system. However, the effect of nanoparticles on immune cells involved in the anti-tumor immune response is not well understood. The study reported here showed that nickel-doped maghemite nanoparticles (FN NP) are differentially cytotoxic to cultured mouse and human cancer cell lines, causing their death without negatively impacting the subsequent anticancer immune response. It also found that FN NP induced cell death in the mouse colorectal cancer cell line CT26 and human prostate cancer cell line PC-3, but not in the human prostate cancer cell line LNCaP. The induced cancer cell death did not affect the phenotype and responsivity of the isolated mouse peritoneal macrophages, or ex vivo-generated mouse bone marrow-derived, or human monocyte-derived dendritic cells. Additionally, the induced cancer cell death did not prevent the ex vivo-generated mouse or human dendritic cells from stimulating lymphocytes and enriching cell cultures with cancer cell-reactive T-cells. In conclusion, this study shows that FN NP could be a valuable platform for targeting cancer cells without causing immunosuppressive effects on the subsequent anticancer immune response.

• MeSH
• buňky PC-3 MeSH
• dendritické buňky * imunologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty imunologie   terapie   MeSH
• nádory imunologie   terapie   MeSH
• nikl * chemie   imunologie   MeSH
• železité sloučeniny chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

CD8+ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen-presenting cells that induce their proliferation. Here, we show that thapsigargin-induced LAD2 mast cell (MC) line-released products can impair the ability of monocyte-derived DCs to induce CD8+ T-cell proliferation and the generation of Th1 cytokine-producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA-DR. However, thapsLAD2-matured DCs produced no detectable TNFα or IL-12 during the maturation. In addition, although their surface expression of PD-L1 was comparable with the immature or TLR7/8-agonist (R848)-matured DCs, their TIM-3 expression was significantly higher than in immature DCs and even much higher than in R848-matured DCs. In addition, contrary to R848-matured DCs, the thapsLAD2-matured DCs only tended to induce enhanced proliferation of CD4+ T cells than immature DCs. For CD8+ T cells, this tendency was not even detected because thapsLAD2-matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848-matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ- and IFNγ/TNFα-producing T cells. These findings show a novel mechanism of MC-mediated regulation of adaptive immune responses.

• MeSH
• aktivace lymfocytů * účinky léků   imunologie   MeSH
• buněčná diferenciace * účinky léků   MeSH
• buněčné linie MeSH
• buněčný receptor 2 viru hepatitidy A metabolismus   MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky * imunologie   účinky léků   metabolismus   MeSH
• imidazoly farmakologie   MeSH
• lidé MeSH
• mastocyty * imunologie   účinky léků   metabolismus   MeSH
• monocyty imunologie   účinky léků   metabolismus   MeSH
• proliferace buněk * účinky léků   MeSH
• thapsigargin * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Východiska: Histiocytózy jsou dle WHO klasifikace vzácné choroby charakterizované akumulací makrofágů a dendritických buněk nebo buněk odvozených z monocytů v různých orgánech a tkáních. Histiocytární choroby se vyskytují jak u dětí, tak u dospělých. Jejich klinická manifestace a morfologické formy jsou obvykle velmi divergentní. Histiocytózy je možné klasifikovat jak dle WHO klasifikace, poslední verze byla zveřejněna v roce 2022, tak dle klasifikace Histiocyte Society s poslední verzí z roku 2016. Cíl: V textu přikládáme přehled histiocytóz dle WHO klasifikace z roku 2022.

Background: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. Purpose: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

• MeSH
• Erdheimova-Chesterova nemoc farmakoterapie   patologie   MeSH
• histiocytární sarkom klasifikace   patologie   MeSH
• histiocytóza z Langerhansových buněk klasifikace   komplikace   patologie   terapie   MeSH
• histiocytóza * klasifikace   patologie   terapie   MeSH
• lidé MeSH
• lymfatické nemoci * klasifikace   patologie   terapie   MeSH
• lymfohistiocytóza hemofagocytární farmakoterapie   klasifikace   patofyziologie   patologie   MeSH
• pneumotorax etiologie   terapie   MeSH
• sinusová histiocytóza farmakoterapie   klasifikace   patologie   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

sou shrnuty biologické hypotézy Alzheimerovy nemoci (AD) založené na poznatcích o patofyziologii AD, které slouží jako východiska pro farmakoterapeutické strategie. Pokroky v poznání úlohy rizikových faktorů a biomarkerů AD v neurodegenerativních procesech umožňují jednak upřesnění stávajících hypotéz nebo tvorbu nových, jednak zlepšení diagnostiky onemocnění, sledování progrese onemocnění a nalezení molekulárních cílů nových léčiv. Kromě amyloidové a tau hypotézy, resp. patologie amyloidu beta a tau proteinu, se při vývoji nových léčiv a studiu mechanismů jejich účinků vychází především z hypotézy mitochondriální, metabolické, neurozánětlivé, oxidačního stresu, synaptoplastické a neurotransmiterové. Významné pro pochopení patofyziologie AD se jeví poznatky o vzájemném propojení, interakcích a synergiích buněčných patologických procesů považovaných za klíčové v hypotézách AD.

Biological hypotheses of Alzheimer ́s disease (AD) based on knowledge about the pathophysiology of AD are summarized, which serve as starting points for pharmacotherapeutic strategies. Advances in the knowledge of the role of risk factors and biomarkers of AD in neurodegenerative processes allow the refinement of existing hypotheses or the generation of new ones, as well as the improvement of disease diagnostics, the monitoring of disease progression, and the discovery of molecular targets for new drugs. In addition to the amyloid and tau hypothesis, respectively the pathology of amyloid beta and tau protein, the mitochondrial, metabolic, neuroinflammatory, oxidative stress, synaptoplastic, and neurotransmitter hypotheses are being used to develop new drugs and to study the mechanisms of their action. Important for the understanding of the pathophysiology of AD is the knowledge about the interrelationships, interactions, and synergies of the cellular pathological processes that are considered to be key in the various AD hypotheses.

• MeSH
• Alzheimerova nemoc * diagnóza   etiologie   patofyziologie   MeSH
• amyloidní beta-protein metabolismus   toxicita   MeSH
• biologické markery analýza   MeSH
• lidé MeSH
• mitochondrie metabolismus   patologie   MeSH
• nervový přenos fyziologie   MeSH
• neuroplasticita fyziologie   MeSH
• proteiny tau metabolismus   toxicita   MeSH
• rizikové faktory MeSH
• signální transdukce fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Anti-viral and anti-tumor vaccines aim to induce cytotoxic CD8+ T cells (CTL) and antibodies. Conserved protein antigens, such as p24 from human immunodeficiency virus, represent promising component for elicitation CTLs, nevertheless with suboptimal immunogenicity, if formulated as recombinant protein. To enhance immunogenicity and CTL response, recombinant proteins may be targeted to dendritic cells (DC) for cross presentation on MHCI, where mannose receptor and/or other lectin receptors could play an important role. Here, we constructed liposomal carrier-based vaccine composed of recombinant p24 antigen bound by metallochelating linkage onto surface of nanoliposomes with surface mannans coupled by aminooxy ligation. Generated mannosylated proteonanoliposomes were analyzed by dynamic light scattering, isothermal titration, and electron microscopy. Using murine DC line MutuDC and murine bone marrow derived DC (BMDC) we evaluated their immunogenicity and immunomodulatory activity. We show that p24 mannosylated proteonanoliposomes activate DC for enhanced MHCI, MHCII and CD40, CD80, and CD86 surface expression both on MutuDC and BMDC. p24 mannosylated liposomes were internalized by MutuDC with p24 intracellular localization within 1 to 3 h. The combination of metallochelating and aminooxy ligation could be used simultaneously to generate nanoliposomal adjuvanted recombinant protein-based vaccines versatile for combination of recombinant antigens relevant for antibody and CTL elicitation.

• MeSH
• antigeny MeSH
• dendritické buňky MeSH
• HIV-1 * MeSH
• lidé MeSH
• liposomy metabolismus   MeSH
• mannany metabolismus   MeSH
• myši MeSH
• rekombinantní proteiny metabolismus   MeSH
• vakcíny proti AIDS * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cannabinoid CB1 receptors have been shown to regulate wide array of functions ranging from homeostasis to the cognitive functioning but recent data support the hypothesis that astrocytes also operate as a mediator of synaptic plasticity and contribute to cognition and learning. The receptor heterogeneity plays a key role in understanding the molecular mechanisms underlying these processes. Despite the fact that the majority of CB1 receptors act on neurons, studies have revealed that cannabinoids have direct control over astrocytes, including energy generation and neuroprotection. The tripartite synapse connects astrocytes to neurons and allows them to interact with one another and the astrocytes are key players in synaptic plasticity, which is associated with cognitive functions. This review focuses on our growing understanding of the intricate functions of astroglial CB1 that underpin physiological brain function, and in Alzheimer's disease.

• MeSH
• Alzheimerova nemoc * MeSH
• astrocyty MeSH
• endokanabinoidy MeSH
• kognitivní dysfunkce * MeSH
• lidé MeSH
• neurony MeSH
• neuroplasticita fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

STAT1 gain-of-function (GOF) mutations underlie an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). Beyond the fungal susceptibility, attributed to Th17 failure, over half of the reported patients suffer from autoimmune manifestations, mechanism of which has not been explained yet. We hypothesized that the STAT1 mutations would affect dendritic cells' (DCs) properties and alter their inflammatory and tolerogenic functions. To test the hypothesis, we generated monocyte-derived DCs (moDCs) and tolerogenic DCs (tDCs). Functional and signaling studies, co-culture experiments and RNA sequencing demonstrated that STAT1 GOF DCs were profoundly altered in their phenotype and functions, characterized by loss of tolerogenic functions, proinflammatory skew and decreased capacity to induce Th17. Cytokine signaling, autophagy and metabolic processes were identified as the most prominently altered cellular processes. The results suggest that DCs are directly involved in STAT1 GOF-associated immune pathology, possibly contributing to both autoimmune manifestations and the failure of antifungal defense.

• MeSH
• aktivační mutace * MeSH
• autoimunita genetika   MeSH
• dendritické buňky metabolismus   MeSH
• kandidóza chronická mukokutánní * genetika   MeSH
• lidé MeSH
• mutace MeSH
• transkripční faktor STAT1 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines.

• MeSH
• kinetika MeSH
• kyselina glutamová * metabolismus   MeSH
• myši MeSH
• nervový přenos * MeSH
• neurony fyziologie   MeSH
• synapse fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Spitz tumors are melanocytic neoplasms characterized by specific, mutually exclusive driver molecular events, namely genomic rearrangements involving the threonine kinase BRAF and the tyrosine kinase receptors ALK , NTRK1 , NTRK2 , NTRK3 , MET , RET , ROS1 , and MAP3K8 or less commonly, mutations in HRAS or MAP2K1 . We hereby report 5 Spitz tumors with a SQSTM1::NTRK2 fusion. All patients were woman with the ages at diagnosis ranging from 30 to 50 years. Locations included the lower extremity (n = 3), forearm, and back (one each). All the neoplasms were superficial melanocytic proliferation with a flat to dome-shaped silhouette, in which junctional spindled and polygonal dendritic melanocytes were mainly arranged as horizontal nests associated with conspicuous lentiginous involvement of the follicular epithelium. Only one case showed heavily pigmented, vertically oriented melanocytic nests resembling Reed nevus. A superficial intradermal component observed in 2 cases appeared as small nests with a back-to-back configuration. In all lesions, next-generation sequencing analysis identified a SQSTM1::NTRK2 fusion. A single case studied with fluorescence in situ hybridization for copy number changes in melanoma-related genes proved negative. No further molecular alterations were detected, including TERT-p hotspot mutations.

• MeSH
• dospělí MeSH
• epiteloidní a vřetenobuněčný névus * genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory kůže * patologie   MeSH
• protoonkogenní proteiny genetika   MeSH
• sekvestosom 1 genetika   MeSH
• tyrosinkinasové receptory genetika   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH