Komplementový systém je velmi důležitou složkou vrozené (tzv. nespecifické) imunity, která je součástí první linie obrany proti infekcím. Vedle toho hraje komplement významnou roli při odklízení apoptotických a poškozených endogenních buněk a podle nedávných objevů významnou měrou přispívá k homeostáze organismu. Komplementový systém zahrnuje několik desítek solubilních a membránově vázaných proteinů, které po aktivaci fungují jako kaskáda, na jejímž konci je likvidace infekčního agens. K aktivaci komplementu dochází jednou ze 3 cest (klasická, lektinová a alternativní) a všechny 3 cesty vedou k centrální složce C3. Štěpením C3 začíná aktivace tzv. efektorové terminální kaskády, která se prozánětlivými mechanismy, opsonizací a na konci vytvořením kanálu v bazální membráně podílí na eliminaci patogenů. Důležitou roli představuje systematická kontrola aktivace komplementu, protože jde o prevenci před poškozením vlastních tkání. Striktní kontrolu vyžaduje především alternativní cesta, která zajišťuje více než 80 % aktivity terminální kaskády komplementu. Dysregulace komplementu a zvl. jeho alternativní cesty stojí na pozadí mnoha závažných akutních i chronických onemocnění. Adresa pro korespondenci: Doc. MUDr. Eva Honsová, PhD. Unilabs Patologie Evropská 2589/33b 160 00 Praha 6 email: eva.honsova@unilabs.com
The complement system is an important component of innate immunity, which is part of the first line of defense against infections. In addition, complement plays an important role in the removal of apoptotic and damaged endogenous cells and, according to recent discoveries, contributes significantly to the homeostasis of the organism. The complement system includes several dozen soluble and membrane-bound proteins, which, after activation, function as a cascade, at the end of which is the elimination of the infectious agent. Complement activation occurs through one of 3 pathways (classical, lectin, and alternative) and all 3 pathways lead to the central C3 component. The cleavage of C3 starts the activation of the so-called effector terminal cascade, which participates in the elimination of pathogens through pro-inflammatory mechanisms, opsonization and, at the end, the creation of a channel in the basement membrane. The systematic control of complement activation plays an important role, because that represents prevention against damage to one’s own tissues. Especially, the alternative pathway, which provides more than 80% of the activity of the terminal complement cascade, requires tight control. Dysregulation of complement and especially its alternative pathways is behind many acute and chronic diseases.
- MeSH
- aktivace komplementu * fyziologie imunologie MeSH
- alternativní dráha komplementu fyziologie imunologie MeSH
- atypický hemolyticko-uremický syndrom genetika patofyziologie patologie MeSH
- komplement * fyziologie imunologie škodlivé účinky MeSH
- lidé MeSH
- nemoci ledvin patofyziologie patologie MeSH
- trombotické mikroangiopatie genetika patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Paroxysmální noční hemoglobinurie je potenciálně závažné onemocnění krvetvorby s jasnou patofyziologií vzniku. Inhibitory C5 složky komplementu se staly globální první volbou léčby onemocnění. Pro pacienty s extravaskulární hemolýzou je v rámci léčby indikováno podání pegcetakoplanu. Další možností je nový blokátor alternativní dráhy komplementu iptakopan. Iptakopan prokázal v klinických studiích fáze III APPLY‐PNH a APPOINT‐PNH splnění primárních cílů studie, a to zvýšení hodnoty hemoglobinu minimálně o 20 g/l oproti výchozímu stavu a zvýšení koncentrace hemoglobinu alespoň na 120 g/l. Bezpečnostní profil iptakopanu je příznivý.
Paroxysmal nocturnal hemoglobinuria is a potentially serious hematopoietic disease with a clear pathophysiology. Inhibitors of the complement component 5 have become the global first choice for the treatment of the disease. For patients with extravascular haemolysis, pegcetacoplan is indicated as part of treatment. Another option is a new alternative complement pathway inhibitor iptacopan. It was shown that iptacopan, in the phase III clinical trials APPLY‐PNH and APPOINT‐PNH, guaranteed the achievement of the primary objectives consisting of increase in haemoglobin levels by 20 g/l and to levels above 120 g/l. The safety profile of iptacopan is favorable.
- Klíčová slova
- iptakopan,
- MeSH
- alternativní dráha komplementu účinky léků MeSH
- hemoglobiny analýza MeSH
- humanizované monoklonální protilátky farmakologie klasifikace terapeutické užití MeSH
- inhibitory komplementu * farmakologie klasifikace terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- paroxysmální hemoglobinurie * diagnóza farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Liposomes are one of the most important drug delivery vectors, nowadays used in clinics. In general, polyethylene glycol (PEG) is used to ensure the stealth properties of the liposomes. Here, we have employed hydrophilic, biocompatible and highly non-fouling N-(2-hydroxypropyl) methacrylamide (HPMA)-based copolymers containing hydrophobic cholesterol anchors for the surface modification of liposomes, which were prepared by the method of lipid film hydration and extrusion through 100 nm polycarbonate filters. Efficient surface modification of liposomes was confirmed by transmission electron microscopy, atomic force microscopy, and gradient ultracentrifugation. The ability of long-term circulation in the vascular bed was demonstrated in rabbits after i.v. application of fluorescently labelled liposomes. Compared to PEGylated liposomes, HPMA-based copolymer-modified liposomes did not induce specific antibody formation and did not activate murine and human complement. Compared with PEGylated liposomes, HPMA-based copolymer-modified liposomes showed a better long-circulating effect after repeated administration. HPMA-based copolymer-modified liposomes thus represent suitable new candidates for a generation of safer and improved liposomal drug delivery platforms.
- MeSH
- akrylamidy chemie MeSH
- aktivace komplementu účinky léků MeSH
- cholesterol chemie krev MeSH
- hydrofobní a hydrofilní interakce * MeSH
- králíci MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- liposomy * MeSH
- myši MeSH
- polyethylenglykoly * chemie MeSH
- polymery chemie MeSH
- povrchové vlastnosti * MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. METHODS: For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation. FINDINGS: This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. INTERPRETATION: Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. FUNDING: CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).
- MeSH
- aktivace komplementu MeSH
- autoprotilátky * krev imunologie MeSH
- B-lymfocyty metabolismus imunologie MeSH
- dospělí MeSH
- fenotyp * MeSH
- lidé středního věku MeSH
- lidé MeSH
- myasthenia gravis * krev diagnóza imunologie metabolismus MeSH
- proteom MeSH
- proteomika * metody MeSH
- receptory cholinergní * imunologie metabolismus MeSH
- senioři MeSH
- shluková analýza MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.
- MeSH
- aktivace komplementu MeSH
- autoimunitní nemoci * MeSH
- glomerulus patologie MeSH
- komplement metabolismus MeSH
- ledviny metabolismus MeSH
- lidé MeSH
- nemoci ledvin * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- aktivace komplementu fyziologie imunologie MeSH
- dědičný syndrom nádoru prsu a vaječníků * chirurgie genetika MeSH
- estrogeny * nedostatek MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- předčasná menopauza MeSH
- salpingo-ooforektomie škodlivé účinky MeSH
- syndromy suchého oka * diagnóza etiologie patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Efficacy of immunosuppressive treatment of Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by its toxicity. With the replacement of cyclophosphamide with rituximab, serious adverse events seem to be associated especially with high-dose corticosteroids. Activation of alternative complement pathway plays an important role in the pathogenesis of AAV. Avacopan (C5a receptor inhibitor) was demonstrated to have at least similar efficacy and better safety (in terms of corticosteroid-related adverse events) compared with high-dose corticosteroids in the induction treatment of AAV. Other modes of the inhibition of alternative complement pathway are currently tested in AAV or could be considered on the basis of the experience in other glomerular diseases.
- MeSH
- alternativní dráha komplementu MeSH
- ANCA-asociované vaskulitidy * MeSH
- cyklofosfamid škodlivé účinky MeSH
- lidé MeSH
- protilátky proti cytoplazmě neutrofilů MeSH
- rituximab terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Infekce SARS-CoV-2 může vyvolat nadměrnou produkci prozánětlivých cytokinů způsobujících rozvoj cytokinové bouře. SARS-CoV-2 indukuje nekontrolovanou odpověď nespecifické imunity a oslabuje specifické imunitní reakce, čímž způsobuje poškození tkání. Pochopení mechanismů nespecifické a specifické imunity indukované SARS-CoV-2 je zásadní pro predikci vývoje onemocnění azavedení účinných opatření pro efektivní kontrolu šíření viru. Podrobně jsou diskutovány reakce imunitního systému a klíčové imunopatogenetické mechanismy onemocnění covid-19.
he SARS-CoV-2 infection can induce an excessive production of pro-inflammatory cytokines causing the cytokine storm syndrome. The uncontrolled nonspecific immune response and the specific immune responses impairment induced by SARS-CoV-2 eventually result in the tissue damage. Understanding the mechanisms of non-specific and specific immunity induced by SARS-CoV-2 is essential to be able to predict the disease outcome and to develop effective strategies to control the virus spread. Reactions of the immune system and the key immunopathogenetic mechanisms involved in covid-19 disease are discussed.
- MeSH
- aktivace komplementu imunologie MeSH
- B-lymfocyty imunologie metabolismus MeSH
- buňky NK imunologie metabolismus MeSH
- COVID-19 * imunologie patofyziologie MeSH
- dendritické buňky imunologie metabolismus MeSH
- eozinofily imunologie metabolismus MeSH
- hemostáza imunologie MeSH
- lidé MeSH
- lymfocyty imunologie metabolismus MeSH
- mastocyty imunologie metabolismus MeSH
- neutrofily imunologie klasifikace metabolismus MeSH
- poměr CD4 a CD8 lymfocytů MeSH
- proteiny eozinofilních granul imunologie metabolismus MeSH
- slizniční imunita imunologie MeSH
- syndrom uvolnění cytokinů patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Non-specific protein adsorption (fouling) triggers a number of deleterious events in the application of biomaterials. Antifouling polymer brushes successfully suppress fouling, however for some coatings an extremely high variability of fouling for different donors remains unexplained. The authors report that in the case of poly(2-hydroxyethyl methacrylate) (poly(HEMA)) this variability is due to the complement system activation that causes massive acceleration in the fouling kinetics of blood plasma. Using plasma from various donors, the fouling kinetics on poly(HEMA) is analyzed and correlated with proteins identified in the deposits on the surface and with the biochemical compositions of the plasma. The presence of complement components in fouling deposits and concentrations of C3a in different plasmas indicate that the alternative complement pathway plays a significant role in the fouling on poly(HEMA) through the "tick-over" mechanism of spontaneous C3 activation. The generated C3b binds to the poly(HEMA) surface and amplifies complement activation locally. Heat-inactivated plasma prevents accelerated fouling kinetics, confirming the central role of complement activation. The results highlight the need to take into account the variability between individuals when assessing interactions between biomaterials and blood plasma, as well as the importance of the mechanistic insight that can be gained from protein identification.
Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
- MeSH
- aktivace komplementu MeSH
- alely MeSH
- biologické markery * MeSH
- dospělí MeSH
- ELISA MeSH
- genetická predispozice k nemoci MeSH
- genetická variace * MeSH
- imunokomplex imunologie MeSH
- jednonukleotidový polymorfismus MeSH
- komplement C3 imunologie MeSH
- komplement genetika metabolismus MeSH
- lidé MeSH
- management nemoci MeSH
- membranoproliferativní glomerulonefritida krev diagnóza etiologie mortalita MeSH
- mladiství MeSH
- mladý dospělý MeSH
- náchylnost k nemoci MeSH
- prognóza MeSH
- ROC křivka MeSH
- studie případů a kontrol MeSH
- určení symptomu MeSH
- vyšetření funkce ledvin MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
