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
• Názvy látek
• cytokiny MeSH
• TLR7 protein, human MeSH Prohlížeč
• TLR8 protein, human MeSH Prohlížeč
• toll-like receptor 7 MeSH
• toll-like receptor 8 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.

• Klíčová slova
• HSPCs, hematopoietic stem cells, innate immunity, myeloid cells, progenitor cells, trained immunity,
• 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
• Názvy látek
• cytokiny MeSH
• ligandy MeSH
• toll-like receptory 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.

• Klíčová slova
• NFAT signaling, calcineurin inbibitors, immunosuppression, neutrophil (PMN) function, pattern recognition receptor (PRR), sepsis,
• 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
• Názvy látek
• cytokiny MeSH
• kalcineurin MeSH
• mediátory zánětu MeSH
• receptory rozpoznávající vzory MeSH
• transkripční faktory NFATC 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.

• Klíčová slova
• COVID-19, mortality, principal-component analysis, respiratory severity, serum cytokines, type-I interferons,
• 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
• Názvy látek
• cytokiny 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.

• Klíčová slova
• COVID-19, HCoV-229E, SARS-CoV-2, prostate cancer, spike glycoprotein,
• 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
• Názvy látek
• cytokiny MeSH
• glykoprotein S, koronavirus MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč

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.

• Klíčová slova
• Ceratothoa oestroides, Dicentrarchus labrax, RNA-seq, aquaculture, cymothoidea, host-parasite interactions, immunoglobulin, isopoda,
• 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
• Názvy látek
• cytokiny MeSH

Phagocytosis is a complex process by which cells within most organ systems remove pathogens and cell debris. Phagocytosis is usually followed by inflammatory pathway activation, which promotes pathogen elimination and inhibits pathogen growth. Delayed pathogen elimination is the first step in sepsis development and a key factor in sepsis resolution. Phagocytosis thus has an important role during sepsis and likely contributes to all of its clinical stages. However, only a few studies have specifically explored and characterized phagocytic activity during sepsis. Here, we describe the phagocytic processes that occur as part of the immune response preceding sepsis onset and identify the elements of phagocytosis that might constitute a predictive marker of sepsis outcomes. First, we detail the key features of phagocytosis, including the main receptors and signaling hallmarks associated with different phagocytic processes. We then discuss how the initial events of phagosome formation and cytoskeletal remodeling might be associated with known sepsis features, such as a cytokine-driven hyperinflammatory response and immunosuppression. Finally, we highlight the unresolved mechanisms of sepsis development and progression and the need for cross-disciplinary approaches to link the clinical complexity of the disease with basic cellular and molecular mechanisms.

• MeSH
• cytokiny imunologie   MeSH
• fagocytóza * MeSH
• imunosupresivní léčba * MeSH
• lidé MeSH
• sepse imunologie   patologie   MeSH
• signální transdukce imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny 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.

• Klíčová slova
• Alemtuzumab, Chemokines, Cytokines, Immunotherapy effect, Intrathecal methotrexate, Lymphocyte subpopulations, Rasmussen encephalitis,
• 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
• Názvy látek
• cytokiny MeSH

Trichobilharzia regenti (Schistosomatidae) percutaneously infects birds and mammals and invades their central nervous system (CNS). Here, we characterized the peripheral immune response of infected mice and showed how it was influenced by the parasite-induced inflammation in the skin and the CNS. As revealed by flow cytometry, T cells expanded in the spleen and the CNS-draining lymph nodes 7-14 days post-infection. Both T-bet+ and GATA-3+ T cells were markedly elevated suggesting a mixed type 1/2 immune response. However, it dropped after 7 dpi most likely being unaffected by the neuroinflammation. Splenocytes from infected mice produced a high amount of IFN-γ and, to a lesser extent, IL-10, IL-4 and IL-17 after in vitro stimulation by cercarial homogenate. Nevertheless, it had only a limited capacity to alter the maturation status of bone marrow-derived dendritic cells (BMDCs), contrary to the recombinant T. regenti cathepsin B2, which also strongly augmented expression of Ccl5, Cxcl10, Il12a, Il33 and Il10 by BMDCs. Taken together, mice infected with T. regenti developed the mixed type 1/2 immune response, which was driven by the early skin inflammation rather than the late neuroinflammation. Parasite peptidases might play an active role in triggering the host immune response.

• Klíčová slova
• T lymphocytes, cathepsin B, central nervous system, dendritic cells, lymph nodes, skin, spleen,
• MeSH
• cerkárie imunologie   MeSH
• cytokiny imunologie   MeSH
• dendritické buňky imunologie   MeSH
• dermatitida imunologie   parazitologie   patologie   MeSH
• infekce červy třídy Trematoda imunologie   parazitologie   MeSH
• kathepsin B metabolismus   MeSH
• kůže imunologie   parazitologie   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• Schistosomatidae imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zánět parazitologie   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• kathepsin B MeSH

Psychological distress persisting for weeks or more promotes pro-inflammatory immune dysregulation, a risk factor for a range of chronic diseases. We have recently shown that mindfulness training reduces distress among university students. Here we present an exploratory trial to study immune dysregulation in a cohort of students who were exposed to progressively greater stress as the exam period approached, and to explore whether mindfulness training mitigated this dysregulation. Healthy University of Cambridge students were randomised to join an 8-week mindfulness course (N = 27), or to mental health support as usual (N = 27). Psychological distress, immune cell proportions, cytokines, CRP and serum cortisol were measured at baseline and during the exam period. Increased distress was associated with statistically significant increases in the proportion of B cells, regardless of trial arm (*p = 0.027). There were no other associations between any of the measured parameters, distress or mindfulness. Our finding that the proportion of B cells increases with psychological distress supports the findings of other studies. However, we found no evidence that mindfulness training is able to buffer the effects of psychological distress on healthy participants' immune system. In order to detect these effects, should they exist, larger randomised trials will be required.

• MeSH
• B-lymfocyty imunologie   MeSH
• cytokiny imunologie   MeSH
• dospělí MeSH
• duševní zdraví MeSH
• hydrokortison imunologie   MeSH
• imunitní systém imunologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• psychický stres imunologie   psychologie   MeSH
• studenti lékařství psychologie   MeSH
• všímavost metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• cytokiny MeSH
• hydrokortison MeSH