Patients with STAT1 gain-of-function (GOF) mutations suffer from an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). The pathogenesis behind this complex and heterogeneous disease is still incompletely understood. Beyond the well-recognized Th17 failure, linked to the STAT1/STAT3 dysbalance-driven abrogation of antifungal defense, only little is known about the consequences of augmented STAT1 signaling in other cells, including, interestingly, the innate immune cells. STAT1-mediated signaling was previously shown to be increased in STAT1 GOF CD14+ monocytes. Therefore, we hypothesized that monocytes might represent important co-orchestrators of antifungal defense failure, as well as various immunodysregulatory phenomena seen in patients with STAT1 GOF CMC, including autoimmunity. In this article, we demonstrate that human STAT1 GOF monocytes are characterized by proinflammatory phenotypes and a strong inflammatory skew of their secretory cytokine profile. Moreover, they exhibit diminished CD16 expression, and reduction of classical (CD14++C16-) and expansion of intermediate (CD14++16+) subpopulations. Amongst the functional aberrations, a selectively enhanced responsiveness to TLR7/8 stimulation, but not to other TLR ligands, was noted, which might represent a contributing mechanism in the pathogenesis of STAT1 GOF-associated autoimmunity. Importantly, some of these features extend to STAT1 GOF monocyte-derived dendritic cells and to STAT1 GOF peripheral myeloid dendritic cells, suggesting that the alterations observed in monocytes are, in fact, intrinsic due to STAT1 mutation, and not mere bystanders of chronic inflammatory environment. Lastly, we observe that the proinflammatory bias of STAT1 GOF monocytes may be ameliorated with JAK inhibition. Taken together, we show that monocytes likely play an active role in both the microbial susceptibility and autoimmunity in STAT1 GOF CMC.
- MeSH
- aktivační mutace MeSH
- antifungální látky MeSH
- cytokiny metabolismus MeSH
- kandidóza chronická mukokutánní * genetika MeSH
- lidé MeSH
- monocyty metabolismus MeSH
- toll-like receptor 7 metabolismus MeSH
- transkripční faktor STAT1 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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
Challenges with various TLR ligands (TLRLs)in combination with D-galactosamine (GalN) in rodents may mimic diverse conditions of acute inflammation and organ failure. Here, we report that CpG (ODN1826, TLR9 agonist)/GalN induced a liver-specific injury with modest systemic effects, whereas R848 (resiquimod, TLR7/8 agonist)/GalN exhibited systemic and liver toxicity. We also observed the protective effect of Gr-1+ cells (the population containing neutrophils) against liver injury in both the R848/GalN and CpG/GalN models. In cytokine measurements, the intraperitoneal administration of antibodies showed a non-specific tolerance induction effect, which was more pronounced in the CpG/GalN than in the R848/GalN model. Cytokine analyses also suggested that the TLR9 agonist/GalN induced a limited degree of systemic inflammation compared to TLR7/8 agonist/GalN models. The relevance of this finding to the TLR9-mediated induction of stress tolerance (protective effect) in non-immune cells is discussed.
- MeSH
- galaktosamin toxicita MeSH
- imidazoly toxicita MeSH
- lékové postižení jater etiologie metabolismus patologie MeSH
- lipopolysacharidy toxicita MeSH
- membránové glykoproteiny agonisté MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- stupeň závažnosti nemoci MeSH
- toll-like receptor 7 agonisté MeSH
- toll-like receptor 8 agonisté MeSH
- toll-like receptor 9 agonisté MeSH
- zánět chemicky indukované metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
- MeSH
- adjuvancia imunologická chemie MeSH
- antigeny nádorové imunologie MeSH
- CD8-pozitivní T-lymfocyty metabolismus MeSH
- individualizovaná medicína MeSH
- melanom experimentální farmakoterapie imunologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanočástice MeSH
- primáti MeSH
- protinádorové vakcíny aplikace a dávkování imunologie MeSH
- toll-like receptor 7 imunologie MeSH
- toll-like receptor 8 imunologie MeSH
- vakcinace MeSH
- vakcíny konjugované MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Small molecule Toll-like receptor-7 and -8 agonists (TLR-7/8a) can be used as vaccine adjuvants to induce CD8 T cell immunity but require formulations that prevent systemic toxicity and focus adjuvant activity in lymphoid tissues. Here, we covalently attached TLR-7/8a to polymers of varying composition, chain architecture and hydrodynamic behavior (∼300 nm submicrometer particles, ∼10 nm micelles and ∼4 nm flexible random coils) and evaluated how these parameters of polymer-TLR-7/8a conjugates impact adjuvant activity in vivo. Attachment of TLR-7/8a to any of the polymer compositions resulted in a nearly 10-fold reduction in systemic cytokines (toxicity). Moreover, both lymph node cytokine production and the magnitude of CD8 T cells induced against protein antigen increased with increasing polymer-TLR-7/8a hydrodynamic radius, with the submicrometer particle inducing the highest magnitude responses. Notably, CD8 T cell responses induced by polymer-TLR-7/8a were dependent on CCR2+ monocytes and IL-12, whereas responses by a small molecule TLR-7/8a that unexpectedly persisted in vaccine-site draining lymph nodes (T1/2 = 15 h) had less dependence on monocytes and IL-12 but required Type I IFNs. This study shows how modular properties of synthetic adjuvants can be chemically programmed to alter immunity in vivo through distinct immunological mechanisms.
- MeSH
- adjuvancia imunologická aplikace a dávkování chemie farmakologie MeSH
- aktivace lymfocytů * MeSH
- buněčné linie MeSH
- CD8-pozitivní T-lymfocyty účinky léků imunologie MeSH
- cytokiny metabolismus MeSH
- hydrodynamika MeSH
- kultivované buňky MeSH
- micely * MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- toll-like receptor 7 agonisté MeSH
- toll-like receptor 8 agonisté MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28-treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma.
- MeSH
- alergeny toxicita MeSH
- Ascaris suum chemie imunologie MeSH
- bronchiální astma * chemicky indukované imunologie patologie MeSH
- interleukin-13 imunologie MeSH
- interleukin-5 imunologie MeSH
- Macaca fascicularis MeSH
- proteiny červů toxicita MeSH
- toll-like receptor 7 * agonisté imunologie MeSH
- toll-like receptor 8 * agonisté imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Morbilliviruses, such as Cetacean morbillivirus (CeMV) or Phocine distemper virus (PDV), represent a growing threat for marine mammals on both hemispheres. Because free-ranging animal populations strongly rely on natural resistance mechanisms, innate immunity-related genes and virus cell entry receptor genes may represent key factors involved in susceptibility to CeMV in Cetaceans. Using the next generation sequencing technology, we have sequenced 11 candidate genes in two model species, Stenella coeruleoalba and Phocoena phocoena. Suitable single nucleotide polymorphism markers of potential functional importance, located in genes coding for basigin (BSG, CD147), the signaling lymphocyte activating molecule (SLAMF1), the poliovirus-related receptor-4 (NECTIN4, PVRL4), toll-like receptors 3, 7, 8 (TLR3, TLR7, TLR8), natural resistance-associated macrophage protein (SLC11A1) and natural cytotoxicity triggering receptor 1 (NCR1), were identified in each model species, along with MHC-DQB haplotypes unique for each species. This set of molecular markers represents a potentially useful tool for studying host genetic variation and susceptibility to morbillivirus infection in Cetaceans as well as for studying functionally important genetic diversity of selected Cetacean populations.
- MeSH
- basigin genetika imunologie MeSH
- biologické markery metabolismus MeSH
- delfíni rodu Stenella genetika imunologie virologie MeSH
- exprese genu MeSH
- genetická predispozice k nemoci * MeSH
- infekce viry z rodu Morbillivirus genetika imunologie virologie MeSH
- jednonukleotidový polymorfismus * MeSH
- MHC antigeny II. třídy genetika imunologie MeSH
- molekuly buněčné adheze genetika imunologie MeSH
- Morbillivirus imunologie patogenita MeSH
- Phocoena genetika imunologie virologie MeSH
- proteiny přenášející kationty genetika imunologie MeSH
- receptor 1 spouštějící přirozenou cytotoxicitu genetika imunologie MeSH
- SLAMF1 protein genetika imunologie MeSH
- toll-like receptor 3 genetika imunologie MeSH
- toll-like receptor 7 genetika imunologie MeSH
- toll-like receptor 8 genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, TH1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.
- MeSH
- adjuvancia imunologická aplikace a dávkování MeSH
- inbrední kmeny myší MeSH
- lékové transportní systémy metody MeSH
- nanočástice aplikace a dávkování chemie MeSH
- neutralizující protilátky MeSH
- polymery chemie MeSH
- proteiny virové fúze aplikace a dávkování chemie MeSH
- syntetické vakcíny aplikace a dávkování chemie MeSH
- techniky syntetické chemie MeSH
- toll-like receptor 7 agonisté MeSH
- toll-like receptor 8 agonisté MeSH
- vakcíny proti respiračnímu syncyciálnímu viru aplikace a dávkování imunologie farmakologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Celiac disease (CD) is an organ-specific autoimmune disease, and both adaptive and innate immunity are involved in its development. OBJECTIVES: The aim of the study was to determine whether the markers of intestinal mucosal inflammation in CD can be detected in peripheral blood monocytes (PBMs), and whether the immune properties of PBMs change as the clinical signs and symptoms of CD improve after the introduction of a gluten-free diet (GFD). The focus was on changes in mRNA expression of selected toll-like receptors (TLR2, TLR4, TLR7), stress cytokine prolactin (PRL), and proand anti-inflammatory cytokines (TNF-α, IL-6, IL-12, IL-10) in PBMs. MATERIAL AND METHODS: The study involved 20 CD patients diagnosed according to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria and Marsh criteria: 10 recently-diagnosed cases (rCD) and 10 on a GFD for a minimum of one year. The control group comprised 10 ageand sex-matched healthy volunteers. PBMs from peripheral blood specimens were separated using immunomagnetic CD14+ beads. Total RNA was isolated using a standard commercial kit. Cytokine and TLR mRNA levels were quantified by relative qPCR with PGK1 as a reference gene. RESULTS: Significantly higher expression of TLR4 and TLR7 mRNA was observed in PBMs from rCD patients compared to the healthy controls (1.63 times higher; p < 0.05). TLR7 mRNA levels in rCDs were also significantly elevated in comparison to the CD-GFD patients (2.11 times higher; p < 0.01). TNF-α mRNA expression tended to be higher in both groups of patients; by contrast, in IL-6 mRNA, a trend to a fourfold decrease was detected in PBMs from the CD-GFD subjects. IL-10, IL-12 and PRL levels did not differ among the groups. CONCLUSIONS: The data suggest that the inflammatory process in rCD intestinal mucosa and submucosa reflecting enterocyte damage can be detected in PBMs in peripheral blood. Further, the cytokine and TLR expression profile in PBMs alters after one year of GFD treatment.
- MeSH
- celiakie krev genetika MeSH
- dospělí MeSH
- interleukin-6 genetika metabolismus MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé MeSH
- messenger RNA MeSH
- prolaktin krev genetika metabolismus MeSH
- TNF-alfa genetika metabolismus MeSH
- toll-like receptor 4 krev genetika MeSH
- toll-like receptor 7 krev genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Bazaliom je maligní epidermální nádor vycházející z buněk bazální vrstvy. Roste pomalu, ale destruuje kůži i okolní tkáně v daném místě. Má však extrémně nízké riziko metastazování. Bazaliom má charakteristický klinický a histologický obraz. Mezi terapeutické možnosti patří chirurgická excize, kyretáž, kryoterapie, diatermokoagulace, lokální imunoterapie, fotodynamická terapie, cílená systémová léčba a radioterapie. V článku jsou některé z nich probrány detailně.
Basal cell carcinoma is a malignant epidermal tumour arising from the basal cell layer. It grows slowly, but destroys the skin as well as surrounding tissue in the site area. However, it has an extremely low risk of metastasis. Basal cell carcinoma has a characteristic clinical and histological presentation. Treatment options include surgical resection, curettage, cryotherapy, diathermocoagulation, local immunotherapy, photodynamic therapy, targeted systemic therapy, and radiotherapy. Some of them are discussed in detail in the present article.
- MeSH
- anilidy aplikace a dávkování terapeutické užití MeSH
- bazocelulární karcinom * diagnóza etiologie terapie MeSH
- chirurgie operační * metody trendy využití MeSH
- cílená molekulární terapie metody využití MeSH
- diklofenak aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- fluoruracil aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- fotochemoterapie metody využití MeSH
- imunomodulace imunologie účinky léků MeSH
- klinický obraz nemoci * MeSH
- kryoterapie metody využití MeSH
- lidé MeSH
- protinádorové látky terapeutické užití MeSH
- pyridiny aplikace a dávkování terapeutické užití MeSH
- radioterapie metody využití MeSH
- toll-like receptor 7 antagonisté a inhibitory aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH