Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.
Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.
Bakteriální lyzáty nespecificky stimulují celkovou imunitu organismu. Působí na nespecifické obranné mechanismy, což vede ke zvýšení IgA na sliznicích, fagocytární aktivitě a produkci interferonu gama. Mohou také stimulovat tvorbu specifických protilátek proti bakteriálním antigenům, které tvoří přípravek. V mnoha klinických studiích bylo prokázáno, že perorální bakteriální lyzáty snižují četnost opakovaných respiračních infekcí u dětí i dospělých a snižují potřebu podávání antibiotik.
Bacterial lysates stimulate the general immunity of the body in a non-specific way. They act on non-specific defense mechanisms, leading to an increase IgA in mucous membranes, phagocytic activity and interferon gamma production. They can also stimulate the production of specific antibodies against the bacterial antigens that make up the preparation. In many clinical trials, oral bacterial lysates have been shown to decrease the risk of recurrent respiratory infections in children and adults and reduce the need for antibiotics.
- Klíčová slova
- bakteriální lyzáty,
- MeSH
- adaptivní imunita účinky léků MeSH
- adjuvancia imunologická * aplikace a dávkování farmakologie terapeutické užití MeSH
- infekce dýchací soustavy imunologie patologie prevence a kontrola MeSH
- infekce močového ústrojí imunologie prevence a kontrola MeSH
- infekce reprodukčního traktu imunologie MeSH
- lidé MeSH
- přirozená imunita účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The adenylyl cyclase (AC) signaling pathway is suggested to be a key regulator of immune system functions. However, specific effects of cyclic adenosine monophosphate (cAMP) on T helper (Th) cell differentiation and functions are unclear. The involvement of cAMP in the Th cell differentiation program, in particular the development of Th1, Th2, and Th17 subsets, was evaluated employing forskolin (FSK), a labdane diterpene well known as an AC activator. FSK mediated an elevation in Th1-specific markers reinforcing the Th1 cell phenotype. The Th2 differentiation was supported by FSK, though cell metabolism was negatively affected. In contrast, the Th17 immunophenotype was severely suppressed leading to the highly specific upregulation of CXCL13. The causality between FSK-elicited cAMP production and the observed reinforcement of Th2 differentiation was established by using AC inhibitor 2',5'-dideoxyadenosine, which reverted the FSK effects. Overall, an FSK-mediated cAMP increase affects Th1, Th2 and Th17 differentiation and can contribute to the identification of novel therapeutic targets for the treatment of Th cell-related pathological processes.
- MeSH
- aktivace lymfocytů * MeSH
- AMP cyklický * MeSH
- buněčná diferenciace MeSH
- buňky Th17 MeSH
- kolforsin farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
Úvod: Přestože je infliximab (IFX) dosud „zlatým standardem“ biologické léčby Crohnovy nemoci (CN), jeho účinnost se může lišit v závislosti na mnoha faktorech. Jedním z nich je individuální reakce pacienta na lék. Významným klinickým problémem je imunogenicita IFX, kdy může až u 60 % léčených pacientů dojít k vývoji protilátek proti léčivu, což vede ke ztrátě odpovědi na léčbu a/nebo k nežádoucím reakcím na terapii. Od roku 2020 je k léčbě nemocných s CN k dispozici infliximab k subkutánnímu podání (IFX-SC), jehož farmakokinetika se vyznačuje stabilní a vysokou údolní koncentrací léčiva (TL – trough level) v krevním oběhu. Je možné, že jedním z důsledků této vlastnosti IFX-SC je jeho nižší míra imunogenicity. Předkládáme prospektivní studii sledování pacientů s diagnózou CN s velmi těžkým až refrakterním průběhem, kteří byli léčeni IFX-SC. Cílem studie bylo sledování imunogenicity IFX-SC včetně sledování dynamiky TL a protilátek proti léčivu (anti-IFX). Je popsána dynamika klinických, zobrazovacích a laboratorních markerů CN v průběhu jednoho roku sledování a léčby. Materiál a metodika: Do studie bylo zařazeno 23 pacientů s diagnózou CN s anamnézou selhání 2–6 předchozích linií biologické léčby, přičemž jednou z proběhlých terapií byl nitrožilní infliximab (IFX-IV). Pacienti byli rozděleni do dvou ramen indukční léčby na základě přítomnosti anti-IFX. Udržovací terapie představovala 120 mg s.c. ? 14 dní, v případě potřeby intenzifikace se jednalo o 240 mg s.c. ? 14 dní. Nemocní byli sledováni v týdnech (W – week) W0, W4, W14, W30 a W52, přičemž byly zaznamenány Harvey-Bradshawův index (HBI), sérová hladina C-reaktivního proteinu (CRP), fekální koncentrace kalprotektinu (FC), hladina léku (TL IFX) a anti-IFX. Dále bylo stanoveno endoskopické a ultrasonografické skóre nemoci (SES-CD a IUS) a u všech pacientů byl vyšetřen haplotyp HLA DQA1*05. Data byla analyzována pomocí softwaru MedCalc® s použitím neparametrických statistických metod a binární logistické regrese. Výsledky: U 13 z 23 pacientů (56,5 %) bylo zaznamenáno 52týdenní setrvání na léčbě IFX-SC se signifikantním poklesem všech sledovaných klinických, zobrazovacích i laboratorních markerů aktivity CN. V průběhu terapie došlo u 8 ze 16 vstupně anti-IFX pozitivních osob k sérokonverzi k negativním anti-IFX (50 %). Žádný z pacientů léčených IFX-SC ve W52 již nepotřeboval konkomitantní léčbu imunomodulátory. Během 52 týdnů terapie nebyla ve sledované kohortě zaznamenána ani jedna nová senzibilizace infliximabem. Závěr: Subkutánní cesta podání infliximabu může být vhodným a úspěšným řešením v situaci, kdy je žádoucí reindukce terapie infliximabem, a to včetně pacientů s přítomností neutralizujících protilátek proti léčivu.
Introduction: Despite infliximab (IFX) still being the “gold standard” of biological therapy for Crohn’s disease (CD), its effectiveness may vary depending on many factors. One of these factors is the individual patient’s reaction to the drug. A significant clinical problem is the immunogenicity of IFX, where up to 60% of treated patients may develop antibodies against the drug, leading to a loss of response to treatment and/or adverse reactions to therapy. Since 2020, subcutaneous infliximab (IFX-SC) has been available for treating CD patients, characterized by its stable and high trough level (TL) concentration in blood. It is possible that one consequence of this property of IFX-SC is its lower rate of immunogenicity. We present a prospective study of patients diagnosed with CD with severe to refractory courses, treated with IFX-SC. The aim of the study was to monitor the immunogenicity of IFX-SC, including the dynamics of TL and anti-drug antibodies (anti-IFX). The dynamics of clinical, imaging, and laboratory markers of CD over one year of monitoring and treatment are described. Materials and methods: The study included 23 patients diagnosed with CD who had failed 2 to 6 previous lines of biological therapy, one of which was intravenous infliximab (IFX-IV). Patients were divided into two arms of induction therapy based on the presence of anti-IFX. Maintenance therapy consisted of 120 mg s.c. every 14 days, and intensification was 240 mg s.c. every 14 days if necessary. Patients were monitored at weeks W0, W4, W14, W30, and W52, recording Harvey-Bradshaw Index (HBI), serum C-reactive protein (CRP), fecal calprotectin (FC) concentrations, drug trough levels (TL IFX) and serum anti-drug antibodies (anti-IFX). Endoscopic and ultrasonographic disease scores (SES-CD and IUS) were determined, and HLA DQA1*05 haplotype was examined in all patients. Data were analyzed using MedCalc® Statistical Software with non-parametric statistical methods and binary logistic regression. Results: 52-week persistence on IFX-SC treatment was recorded in 13 out of 23 patients (56.5%), with a significant decrease in all monitored clinical, imaging, and laboratory markers of CD activity. During the therapy, 8 out of 16 initially anti-IFX positive individuals seroconverted to negative anti-IFX (50%). None of the patients treated with IFX-SC in W52 needed concomitant immunomodulator treatment. No new sensitization to infliximab was recorded in the cohort during the 52-week therapy. Conclusion: The subcutaneous route of infliximab administration may be a suitable and successful solution in situations where reinduction of infliximab therapy is desired, including patients with the presence of neutralizing antibodies against the drug.
Vaccine-induced protection against tick-borne encephalitis virus (TBEV) is mediated by antibodies to the viral particle/envelope protein. The detection of non-structural protein 1 (NS1) specific antibodies has been suggested as a marker indicative of natural infections. However, recent work has shown that TBEV vaccines contain traces of NS1, and immunization of mice induced low amounts of NS1-specific antibodies. In this study, we investigated if vaccination induces TBEV NS1-specific antibodies in humans. Healthy army members (n = 898) were asked to fill in a questionnaire relating to flavivirus vaccination or infection, and blood samples were collected. In addition, samples of 71 suspected acute TBE cases were included. All samples were screened for the presence of TBEV NS1-specific IgG antibodies using an in-house developed ELISA. Antibodies were quantified as percent positivity in reference to a positive control. For qualitative evaluation, cut-off for positivity was defined based on the mean OD of the lower 95% of the vaccinated individuals + 3 SD. We found significantly higher NS1-specific IgG antibody titers (i.e., quantitative evaluation) in individuals having received 2, 3, or 4 or more vaccine doses than in non-vaccinated individuals. Similarly, the percentage of individuals with a positive test result (i.e., qualitative evaluation) was higher in individuals vaccinated against tick-borne encephalitis than in unvaccinated study participants. Although NS1-specific IgG titers remained at a relatively low level when compared to TBE patients, a clear distinction was not always possible. Establishing a clear cut-off point in detection systems is critical for NS1-specific antibodies to serve as a marker for distinguishing the immune response after vaccination and infection.
Interaction between an antigen-presenting cell and a T cell, and their subsequent conjugation are a prerequisite for the formation of the immunological synapse and productive, antigen-dependent activation of T cells. This initial interaction is accompanied by recognition of the presented antigen by the T cell receptor, and by changes in the morphology of the interacting cells and in actin cytoskeleton structure in the site of interaction. The experimental protocol below describes a simple assay for quantitative assessment of antigen-presenting cells-T cell conjugation using confocal microscopy or flow cytometry.
ISG20L2, a 3' to 5' exoribonuclease previously associated with ribosome biogenesis, is identified here in activated T cells as an enzyme with a preferential affinity for uridylated miRNA substrates. This enzyme is upregulated in T lymphocytes upon TCR and IFN type I stimulation and appears to be involved in regulating T cell function. ISG20L2 silencing leads to an increased basal expression of CD69 and induces greater IL2 secretion. However, ISG20L2 absence impairs CD25 upregulation, CD3 synaptic accumulation and MTOC translocation towards the antigen-presenting cell during immune synapsis. Remarkably, ISG20L2 controls the expression of immunoregulatory molecules, such as AHR, NKG2D, CTLA-4, CD137, TIM-3, PD-L1 or PD-1, which show increased levels in ISG20L2 knockout T cells. The dysregulation observed in these key molecules for T cell responses support a role for this exonuclease as a novel RNA-based regulator of T cell function.
- MeSH
- aktivace lymfocytů * MeSH
- antigen prezentující buňky MeSH
- endonukleasy MeSH
- lidé MeSH
- mikro RNA * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- adaptivní imunita MeSH
- dítě MeSH
- funkční potraviny MeSH
- imunomodulační látky * terapeutické užití MeSH
- infekce dýchací soustavy terapie MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- Pleurotus * MeSH
- reinfekce terapie MeSH
- selen terapeutické užití MeSH
- vyvíjení léků MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
Diabetes mellitus 1. typu je důsledek autoimunitní inzulitidy, která je podstatně více heterogenní než se dříve předpokládalo. histopatologické nálezy se u autoimunitní inzulitidy liší podle věku jedince, což odráží i patogenetickou heterogenitu onemocnění. tato heterogenita může ovlivnit i imunointervenční strategie a s tímto ohledem začaly být popisovány specifické endotypy choroby. Průlomovým krokem v sekundární prevenci propuknutí diabetu 1. typu bylo v roce 2022 schválení teplizumabu (monoklonální protilátka proti znaku cD3) ve Spojených státech jako prvního tzv. chorobu modifikujícího léku pro osoby ve ii. stadiu rozvoje diabetu (toto stadium je charakterizované přítomností dvou a více autoprotilátek a prediabetickou dysglykemií). teplizumab účinně oddaluje progresi onemocnění do stadia klinického diabetu v průměru asi o dva roky. tento fakt podporuje rozvoj celopopulačních screeningových programů, které mají za cíl pomocí vyšetřování autoprotilátek (podle stanoveného genetického rizika nebo i bez něj) vytipovat jedince vhodné pro aplikaci různých preventivních opatření.
Type 1 diabetes mellitus is consequence of autoimmune insulitis which is significantly more heterogeneous than previously thought. histopathological findings in autoimmune insulitis differ according to the age of the individual, which also reflects the pathogenetic heterogeneity of the disease. immune intervention strategies should be adapted to this heterogeneity. With this in mind, specific endotypes of the disease have begun to be described. a breakthrough step was the approval of teplizumab (a monoclonal anti-cD3 antibody) in the United States in 2022 as the first so-called disease-modifying drug for people in ii. stage of diabetes development (this stage is characterized by the presence of two or more autoantibodies and prediabetic dysglycemia). teplizumab effectively delays progression to clinical diabetes by about two years on average. this fact stimulates the development of population-wide screening programs that, with the help of autoantibody testing (according to the determination of genetic risk or separately), aim to select individuals suitable for the application of various preventive measures.
- Klíčová slova
- autoimunitní inzulitida,
- MeSH
- diabetes mellitus 1. typu * imunologie patofyziologie MeSH
- humorální imunita MeSH
- lidé MeSH
- střevní mikroflóra MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
