Screening for tuberculosis infections (TBI) using the tuberculin skin test or interferon-gamma release assays (IGRA) is crucial in controlling the global TB burden. This study evaluates the performance of a new IGRA for the detection of T-cell responses against Mycobacterium tuberculosis. Blood samples from 34 adults with tuberculosis disease (TB) and from 30 children with TB, TBI or without TB were analyzed using the prototype Quan-T-Cell TB (EUROIMMUN). The pediatric samples were additionally measured using the established QuantiFERON-TB Gold Plus assay (Qiagen). Clinical performance and inter-assay concordance were analyzed. The prototype Quan-T-Cell TB yielded positivity rates of 88.2% and 100% in adults with TB and children with TBI, respectively, at a specificity of 93.8%. Comparison between the two IGRAs showed positive, negative and overall agreement rates of 100%, 93.8% and 96.3%, respectively, with a kappa score of 0.924 indicating almost perfect agreement. Our study shows promising results of the new prototype Quan-T-Cell TB, as reflected by high concordance with the final diagnosis in adults and children and performance comparable to that of the QuantiFERON IGRA. In individual cases, the data suggest that the prototype Quan-T-Cell TB may be even more consistent with TBI-related clinical findings. Unlike the QuantiFERON assay, the Quan-T-Cell TB has a predefined borderline range, which is advantageous as it may help to differentiate non-specific variation near the cut-off, and fewer sample tubes are required per analysis. The new Quan-T-Cell TB may therefore be a good alternative to the established QuantiFERON IGRA for TBI screening. Further assay optimization is underway, including evaluation studies based on larger patient and control cohorts.

• MeSH
• dítě MeSH
• dospělí MeSH
• interferon gama MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Mycobacterium tuberculosis * imunologie   MeSH
• předškolní dítě MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• T-lymfocyty * imunologie   MeSH
• test pomocí interferonu gama * metody   MeSH
• tuberkulóza * diagnóza   imunologie   mikrobiologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH

BACKGROUND: Cognitive impairment is a well-recognized symptom of multiple sclerosis (MS) that can manifest early in the disease course. Deficits in cognitive function can have a major impact on daily life. However, cognitive decline is often under-examined in clinical trials and clinical practice due to lack of adequate data. The objective of this study was to examine the longitudinal effect of ocrelizumab vs interferon beta (IFNβ)-1a on cognitive impairment in 2 phase 3 studies in relapsing MS (RMS). METHODS: The pooled population of participants with RMS (n = 1656) from the OPERA I/II clinical trials received subcutaneous IFNβ-1a (44 μg; n = 829) 3 times weekly or intravenous ocrelizumab (600 mg; n = 827) every 24 weeks. Cognition was assessed with a Symbol Digit Modalities Test (SDMT), administered in written or oral form according to each site investigator's choice, that primarily measured cognitive processing speed at baseline and every 12 weeks until the end of the double-blind treatment (96 weeks). Treatment effects were investigated based on longitudinal linear models for the change from baseline in SDMT and Cox regression for the time to 12- or 24-week confirmed decline of ≥4 points. RESULTS: Among the participants with an SDMT assessment at baseline and ≥1 postbaseline time point (IFNβ-1a, n = 749; ocrelizumab, n = 766), ocrelizumab treatment was associated with a greater mean SDMT improvement over 96 weeks than IFNβ-1a treatment (5.4 [95 % CI, 4.4-6.5] vs 4.0 [95 % CI, 3.0-5.1]; adjusted mean difference, 1.4 [95 % CI, 0.05-2.72]; P = 0.042). The risk of a clinically meaningful SDMT decline (≥4 points) was lower for those treated with ocrelizumab for both ≥12 weeks (IFNβ-1a, 18.4 %; ocrelizumab, 12.7 %; hazard ratio, 0.63 [95 % CI, 0.47-0.85]; P = 0.003) and ≥24 weeks (IFNβ-1a, 12.9 %; ocrelizumab, 7.9 %; HR, 0.57 [95 % CI, 0.39-0.82]; P = 0.003). CONCLUSION: Ocrelizumab treatment resulted in better cognitive outcomes as measured by SDMT in participants with RMS compared with IFNβ-1a treatment. However, methodological limitations need to be considered when interpreting these data. CLINICALTRIALS: gov: NCT01247324, NCT01412333.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• imunologické faktory * aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• interferon beta 1a * aplikace a dávkování   farmakologie   MeSH
• kognitivní dysfunkce etiologie   farmakoterapie   chemicky indukované   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS). METHODS: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period. RESULTS: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time. DISCUSSION: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• imunologické faktory * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• interferon beta 1a terapeutické užití   aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• progrese nemoci MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   diagnostické zobrazování   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: The longitudinal study was conducted over the initial 2 years of the COVID-19 pandemic, spanning from June 2020 to December 2022, in healthcare workers (HCWs) of the Thomayer University Hospital. A total of 3892 blood samples were collected and analyzed for total nucleocapsid (N) antibodies. The aim of the study was to evaluate the dynamics of N antibodies, their relationship to the PCR test, spike (S) antibodies, interferon-gamma, and prediction of reinfection with SARS-CoV-2. METHODS: Blood collections were performed in three rounds, along with questionnaires addressing clinical symptoms of past infection, PCR testing, and vaccination. Antibody measurements included total N antibodies (Roche Diagnostics) and postvaccination S antibodies (Euroimmun). Cellular immunity was tested by interferon-gamma release assay (Euroimmun). RESULTS: At the end of the study, 35.9% of HCWs were positive for N antibodies, and 39.5% of HCWs had either known PCR positivity or N antibodies or both. Ten percent of participants had no knowledge of a COVID-19 infection and 35% of positive individuals exhibited no symptoms. The values of positive antibodies decrease over a period of 6 months to 1 year, depending on the initial value, and their dynamics are highly variable. The study also demonstrated that the highest levels of spike antibodies and interferon-gamma occur during so-called hybrid immunity. CONCLUSION: Nucleocapsid antibodies proved valuable in monitoring SARS-CoV-2 infection dynamics, and they may detect cases of SARS-CoV-2 infection missed by PCR tests. The study identified distinct patterns in antibody dynamics and protection of hybrid immunity during reinfection.

• MeSH
• biologické markery krev   MeSH
• COVID-19 * imunologie   krev   diagnóza   epidemiologie   MeSH
• dospělí MeSH
• fosfoproteiny MeSH
• glykoprotein S, koronavirus imunologie   MeSH
• interferon gama krev   MeSH
• koronavirové nukleokapsidové proteiny imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• nemocnice univerzitní MeSH
• nukleokapsida imunologie   MeSH
• protilátky virové * krev   MeSH
• SARS-CoV-2 * imunologie   MeSH
• sérologické testování na COVID-19 metody   MeSH
• zdravotnický personál * statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Účinnost interferonu alfa v terapii Ph negativních myeloproliferativních onemocnění je známá již několik desetiletí, nicméně až nové pegylované formy s lepšími farmakokinetickými vlastnostmi vedly k jeho rozšíření do běžné klinické praxe. Interferon alfa prokazatelně vede u vysokého procenta nemocných s pravou polycytemií k dosažení nejenom hematologické, ale i molekulární odpovědi a tím snižuje riziko přechodu do myelofibrózy. Jednotlivé přípravky pegylovaných interferonů se od sebe liší způsobem pegylace, což má za následek rozdíly nejenom v četnosti frekvence aplikace, ale také v toleranci léčby.

Efficiency of interferon alpha in treatment of Ph-negative myeloproliferative neoplasms is well known for many decades, however only recently new pegylated forms of interferon with better pharmacokinetic profile led to its widespread use in routine clinical practice. Interferon alpha has shown in multiple studies in substantial proportion of patients with polycythemia vera its potential to achieve not only hematological but also molecular response important for reducing risk of progression to myelofibrosis. In the Czech Republic, there are two pegylated interferon forms with different pegylation, which causes differences in dosing intervals and safety profile.

• Klíčová slova
• Ropeg-IFN, Peg-IFN,
• MeSH
• interferon alfa * farmakologie   klasifikace   terapeutické užití   MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• polycythaemia vera * diagnóza   farmakoterapie   MeSH
• tolerance léku MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The RNA editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) is essential for correct functioning of innate immune responses. The ADAR1p110 isoform is mainly nuclear and ADAR1p150, which is interferon (IFN) inducible, is predominately cytoplasmic. Using three different methods - co-immunoprecipitation (co-IP) of endogenous ADAR1, Strep-tag co-IP and BioID with individual ADAR1 isoforms - a comprehensive interactome was generated during both homeostasis and the IFN response. Both known and novel interactors as well as editing regulators were identified. Nuclear proteins were detected as stable interactors with both ADAR1 isoforms. In contrast, BioID identified distinct protein networks for each ADAR1 isoform, with nuclear components observed with ADAR1p110 and components of cytoplasmic cellular condensates with ADAR1p150. RNase A digestion distinguished between distal and proximal interactors, as did a double-stranded RNA (dsRNA)-binding mutant of ADAR1 which demonstrated the importance of dsRNA binding for ADAR1 interactions. IFN treatment did not affect the core ADAR1 interactomes but resulted in novel interactions, the majority of which are proximal interactions retained after RNase A treatment. Short treatment with high molecular weight poly(I:C) during the IFN response resulted in dsRNA-binding-dependent changes in the proximal protein network of ADAR1p110 and association of the ADAR1p150 proximal protein network with some components of antiviral stress granules.

• MeSH
• adenosindeaminasa * metabolismus   genetika   MeSH
• buněčné jádro * metabolismus   MeSH
• cytoplazma * metabolismus   MeSH
• dvouvláknová RNA metabolismus   genetika   MeSH
• editace RNA MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• interferony metabolismus   genetika   MeSH
• lidé MeSH
• mapy interakcí proteinů MeSH
• poly I-C farmakologie   MeSH
• protein - isoformy * metabolismus   genetika   MeSH
• proteiny vázající RNA * metabolismus   genetika   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.

• MeSH
• autoprotilátky * imunologie   MeSH
• dospělí MeSH
• interferon typ I * imunologie   MeSH
• klíšťová encefalitida * imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neutralizující protilátky * imunologie   MeSH
• senioři MeSH
• viry klíšťové encefalitidy imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Rakousko MeSH

• MeSH
• cytokiny * farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• erythropoetin analogy a deriváty   farmakologie   klasifikace   terapeutické užití   MeSH
• faktor stimulující kolonie granulocytů farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• interferony farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• interleukin-1 farmakologie   imunologie   terapeutické užití   MeSH
• interleukin-2 farmakologie   imunologie   terapeutické užití   MeSH
• receptory cytokinové imunologie   klasifikace   MeSH
• thrombopoetin agonisté   farmakologie   klasifikace   terapeutické užití   MeSH
• TNF-alfa farmakologie   terapeutické užití   MeSH
• Publikační typ
• přehledy MeSH

Type I interferon (IFN) is a class of proinflammatory cytokines with a dual role on malignant transformation, tumor progression, and response to therapy. On the one hand, robust, acute, and resolving type I IFN responses have been shown to mediate prominent anticancer effects, reflecting not only their direct cytostatic/cytotoxic activity on (at least some) malignant cells, but also their pronounced immunostimulatory functions. In line with this notion, type I IFN signaling has been implicated in the antineoplastic effects of various immunogenic therapeutics, including (but not limited to) immunogenic cell death (ICD)-inducing agents and immune checkpoint inhibitors (ICIs). On the other hand, weak, indolent, and non-resolving type I IFN responses have been demonstrated to support tumor progression and resistance to therapy, reflecting the ability of suboptimal type I IFN signaling to mediate cytoprotective activity, promote stemness, favor tolerance to chromosomal instability, and facilitate the establishment of an immunologically exhausted tumor microenvironment. Here, we review fundamental aspects of type I IFN signaling and their context-dependent impact on malignant transformation, tumor progression, and response to therapy.

• MeSH
• cytokiny MeSH
• interferon typ I * MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.

• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• interferon beta * terapeutické užití   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• proteomika * MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   imunologie   krev   MeSH
• roztroušená skleróza farmakoterapie   imunologie   krev   MeSH
• stupeň závažnosti nemoci MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH