Nejčastější imunitně podmíněná zánětlivá revmatická onemocnění – revmatoidní artritida, psoriatická artritida a axiální spondyloartritida – zaznamenala v posledních letech významný pokrok se zavedením biologické léčby proti cytokinům a imunitním buňkám, ale také proti nitrobuněčným enzymům, konkrétně Janusovým kinázám (JAK). Nitrobuněčná signa- lizace JAK se aktivuje navázáním různých cytokinů nebo růstových faktorů na příslušné buněčné receptory, umožní se aktivace transkripčních faktorů STAT (Signal Transducers and Activators of Transcription) a finálně transkripce genů s dů- ležitým postavením v průběhu vrozené a získané imunitní odpovědi. Popsány jsou čtyři Janusovy kinázy: JAK1, JAK2, JAK3 a tyrosin kináza-2 (TYK2). V současnosti jsou schválené čtyři JAK inhibitory (tofacitinib, baricitinib, upadacitinib a filgoti- nib) pro léčbu revmatoidní artritidy, některé pro léčbu psoriatické artritidy a axiální spondyloartritidy. JAK inhibitory mají různou selektivitu proti jednotlivým kinázám. Některé JAK inhibitory jsou zkoušeny u dalších vzácnějších systémových onemocnění pojiva. Obecnou výhodou JAK inhibitorů je perorální podávání, rychlý nástup účinku a účinnost v monoterapii. Bezpečnostní profil JAK inhibitorů v porovnání s biologickou léčbou se zdá být srovnatelný, častěji se vyskytuje herpes zoster, diskutuje se zvýšený výskyt závažných kardiovaskulárních onemocnění, tromboembolických komplikací a nádorů u rizikových pacientů. Cílem této práce bude shrnout nejnovější poznatky o JAK inhibitorech ve schválených indikacích nejčastějších revmatických onemocnění.
The most common immune-mediated inflammatory rheumatic diseases, rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis and have reached significant advances in recent years with the introduction of biological therapies against cytokines and immune cells, but also against intracellular enzymes, specifically Janus kinases (JAKs). Intracellular JAK signalling is activated by binding of various cytokines or growth factors to the respective cellular receptors, allowing the activation of STAT (Signal Transducers and Activators of Transcription) transcription factors and ultimately the transcription of genes with important roles during the innate and adaptive immune response. Four Janus kinases have been described: JAK1, JAK2, JAK3 and tyrosine kinase-2 (TYK2). Four JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) are currently approved for the treatment of rheumatoid arthritis, and some for the treatment of psoriatic arthritis and axial spondyloarthritis. JAK inhibitors have varying selectivity against individual kinases. Some JAK inhibitors are being tested in other rarer systemic connective tissue diseases. The general advantages of JAK inhibitors are oral administration, rapid onset of action, and efficacy in monotherapy. The safety profile of JAK inhibitors compared with biologic therapy appears to be comparable, with a higher incidence of herpes zoster, and an increased incidence of major cardiovascular disease, thromboembolic complications, and cancer in at-risk patients is discussed. The aim of this paper will be to summarize the latest findings on JAK inhibitors in approved indications for the most common rheumatic diseases.
- MeSH
- axiální spondyloartritida farmakoterapie MeSH
- biologická terapie metody MeSH
- cytokiny imunologie MeSH
- inhibitory Janus kinas * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- psoriatická artritida farmakoterapie MeSH
- revmatické nemoci farmakoterapie MeSH
- revmatoidní artritida farmakoterapie MeSH
- Check Tag
- lidé MeSH
- MeSH
- cvičení * fyziologie imunologie MeSH
- cytokiny * imunologie MeSH
- imunitní systém MeSH
- interleukin-6 imunologie metabolismus MeSH
- lidé MeSH
- muskuloskeletální systém imunologie patologie MeSH
- osteoartróza imunologie terapie MeSH
- psoriatická artritida imunologie terapie MeSH
- revmatoidní artritida imunologie terapie MeSH
- syndrom přetrénování imunologie metabolismus MeSH
- tendinopatie imunologie terapie MeSH
- terapie cvičením * MeSH
- Check Tag
- lidé MeSH
Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.
- MeSH
- autoimunitní hemolytická anemie genetika imunologie MeSH
- cytokiny genetika imunologie MeSH
- dvojčata monozygotní MeSH
- HEK293 buňky MeSH
- lidé MeSH
- mutace * MeSH
- posouzení stavu pacienta MeSH
- toll-like receptor 7 genetika imunologie MeSH
- toll-like receptor 8 genetika imunologie MeSH
- zánět genetika imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- studie na dvojčatech MeSH
Recent evidence shows that innate immune cells, in addition to B and T cells, can retain immunological memory of their encounters and afford long-term resistance against infections in a process known as 'trained immunity'. However, the duration of the unspecific protection observed in vivo is poorly compatible with the average lifespan of innate immune cells, suggesting the involvement of long-lived cells. Accordingly, recent studies demonstrate that hematopoietic stem and progenitor cells (HSPCs) lay at the foundation of trained immunity, retaining immunological memory of infections and giving rise to a "trained" myeloid progeny for a long time. In this review, we discuss the research demonstrating the involvement of HSPCs in the onset of long-lasting trained immunity. We highlight the roles of specific cytokines and Toll-like receptor ligands in influencing HSPC memory phenotypes and the molecular mechanisms underlying trained immunity HSPCs. Finally, we discuss the potential benefits and drawbacks of the long-lasting trained immune responses, and describe the challenges that the field is facing.
- MeSH
- cytokiny imunologie MeSH
- hematopoetické kmenové buňky imunologie MeSH
- imunologická paměť imunologie MeSH
- lidé MeSH
- ligandy MeSH
- přirozená imunita imunologie MeSH
- toll-like receptory imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Neutrophils are innate immune cells with important roles in antimicrobial defense. However, impaired or dysregulated neutrophil function can result in host tissue damage, loss of homeostasis, hyperinflammation or pathological immunosuppression. A central link between neutrophil activation and immune outcomes is emerging to be the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, which is activated by neutrophil detection of a microbial threat via pattern recognition receptors and results in inflammatory cytokine production. This potent pro-inflammatory pathway is also the target of several immunosuppressive drugs used for the treatment of autoimmune disorders, during solid organ and hematopoietic cell transplantations, and as a part of anti-cancer therapy: but what effects these drugs have on neutrophil function, and their broader consequences for immune homeostasis and microbial defense are not yet known. Here, we bring together the emerging literature describing pathology- and drug- induced neutrophil impairment, with particular focus on their effects on calcineurin-NFAT signaling in the innate immune compartment.
- MeSH
- cytokiny imunologie metabolismus MeSH
- homeostáza imunologie MeSH
- imunologická tolerance imunologie MeSH
- kalcineurin imunologie metabolismus MeSH
- lidé MeSH
- mediátory zánětu imunologie metabolismus MeSH
- neutrofily imunologie metabolismus MeSH
- přirozená imunita imunologie MeSH
- receptory rozpoznávající vzory imunologie metabolismus MeSH
- signální transdukce imunologie MeSH
- transkripční faktory NFATC imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The adaptive immune response to severe acute respiratory coronavirus 2 (SARS-CoV-2) is important for vaccine development and in the recovery from coronavirus disease 2019 (COVID-19). Men and cancer patients have been reported to be at higher risks of contracting the virus and developing the more severe forms of COVID-19. Prostate cancer (PCa) may be associated with both of these risks. We show that CD4+ T cells of SARS-CoV-2-unexposed patients with hormone-refractory (HR) metastatic PCa had decreased CD4+ T cell immune responses to antigens from SARS-CoV-2 spike glycoprotein but not from the spiked glycoprotein of the 'common cold'-associated human coronavirus 229E (HCoV-229E) as compared with healthy male volunteers who responded comparably to both HCoV-229E- and SARS-CoV-2-derived antigens. Moreover, the HCoV-229E spike glycoprotein antigen-elicited CD4+ T cell immune responses cross-reacted with the SARS-CoV-2 spiked glycoprotein antigens. PCa patients may have impaired responses to the vaccination, and the cross-reactivity can mediate antibody-dependent enhancement (ADE) of COVID-19. These findings highlight the potential for increased vulnerability of PCa patients to COVID-19.
- MeSH
- adaptivní imunita MeSH
- CD4-pozitivní T-lymfocyty imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- COVID-19 imunologie virologie MeSH
- cytokiny imunologie MeSH
- glykoprotein S, koronavirus imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský koronavirus 229E imunologie MeSH
- nádory prostaty imunologie patologie MeSH
- SARS-CoV-2 imunologie MeSH
- senioři MeSH
- zkřížené reakce MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Markedly elevated levels of proinflammatory cytokines and defective type-I interferon responses were reported in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. METHODS: Cytokine concentrations and severe acute respiratory syndrome coronavirus 2 antigen were measured at hospital admission in serum of symptomatic patients with COVID-19 (N = 115), classified at hospitalization into 3 respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS), and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal-component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N = 86). RESULTS: At time of hospitalization, ECMO patients presented a dominant proinflammatory response with elevated levels of TNF-α, IL-6, IL-8, and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at 1 month was associated with higher levels of proinflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients, and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (risk ratio, 24.3; P < .0001). Severe acute respiratory syndrome coronavirus 2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with proinflammatory response or severity. CONCLUSIONS: Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.
- MeSH
- COVID-19 * imunologie mortalita terapie MeSH
- cytokiny imunologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- SARS-CoV-2 imunologie MeSH
- senioři MeSH
- stupeň závažnosti nemoci * MeSH
- umělé dýchání * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
Ceratothoa oestroides (Cymothoidea, Isopoda) is a generalist crustacean parasite that negatively affects the economic sustainability of European sea bass (Dicentrarchus labrax) aquaculture in the North-East Mediterranean. While mortalities are observed in fry and fingerlings, infection in juvenile and adult fish result in approximately 20% growth delay. A transcriptomic analysis (PCR array, RNA-Seq) was performed on organs (tongue, spleen, head kidney, and liver) from infected vs. Ceratothoa-free sea bass fingerlings. Activation of local and systemic immune responses was detected, particularly in the spleen, characterized by the upregulation of cytokines (also in the tongue), a general reshaping of the immunoglobulin (Ig) response and suppression of T-cell mediated responses. Interestingly, starvation and iron transport and metabolism genes were strongly downregulated, suggesting that the parasite feeding strategy is not likely hematophagous. The regulation of genes related to growth impairment and starvation supported the growth delay observed in infected animals. Most differentially expressed (DE) transcripts were exclusive of a specific organ; however, only in the tongue, the difference between infected and uninfected fish was significant. At the attachment/feeding site, the pathways involved in muscle contraction and intercellular junction were the most upregulated, whereas the pathways involved in fibrosis (extracellular matrix organization, collagen formation, and biosynthesis) were downregulated. These results suggest that parasite-inflicted damage is successfully mitigated by the host and characterized by regenerative processes that prevail over the reparative ones.
- MeSH
- cytokiny imunologie MeSH
- hlavová ledvina * imunologie parazitologie MeSH
- Isopoda imunologie MeSH
- játra * imunologie parazitologie MeSH
- nemoci ryb * imunologie parazitologie MeSH
- parazitární nemoci u zvířat * imunologie parazitologie MeSH
- Percoidea * imunologie parazitologie MeSH
- stanovení celkové genové exprese MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Středozemní moře MeSH
BACKGROUND: Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. METHODS: Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. RESULTS: Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. CONCLUSIONS: We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.
- MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- cytokiny imunologie MeSH
- dítě MeSH
- ELISA MeSH
- encefalitida patologie terapie MeSH
- imunoterapie metody MeSH
- lidé MeSH
- mozek patologie MeSH
- předškolní dítě MeSH
- zánět terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
