OBJECTIVE: Dendritic cells (DCs) play an important role in pathogenesis of autoimmunity, including type 1 diabetes (T1D). In this study, we investigated DC subpopulations and their responses to TLR stimulation in T1D patients and their relatives. METHODS: We analyzed the frequency of myeloid (mDCs) and plasmacytoid DCs (pDCs) in 97 T1D patients (69 onset, 28 long-term), 67 first-degree relatives, and 64 controls. We additionally tested the IFN-alpha production by pDCs upon stimulation with TLR 7, 8 and 9 agonists. RESULTS: A lower number of mDCs and pDCs were found in T1D patients and their relatives. Of all the tested TLR ligands, only stimulation with CpG 2216 induced IFN-alpha production that was the highest in T1D relatives, except of autoantibody-negative relatives bearing the protective haplotypes. CONCLUSION: Our data demonstrate disturbances in DC number and function expressed most significantly in T1D relatives and point to a potential role of TLR9-induced IFN-alpha production in T1D development.

• Klíčová slova
• Dendritic cell;, Interferon-alpha;, Type 1 diabetes,
• MeSH
• dendritické buňky imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• interferon alfa biosyntéza   krev   MeSH
• leukocyty mononukleární účinky léků   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• mladiství MeSH
• mladý dospělý MeSH
• oligodeoxyribonukleotidy farmakologie   MeSH
• počet buněk MeSH
• předškolní dítě MeSH
• rodina MeSH
• toll-like receptor 9 metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CpG ODN 2216 MeSH Prohlížeč
• interferon alfa MeSH
• ligandy MeSH
• oligodeoxyribonukleotidy MeSH
• toll-like receptor 9 MeSH

Hepatitis C is a major health problem. In recent years, the treatment of choice is alpha-interferon in combination with ribavirin. For patients with failure of this treatment the therapy with consensus or pegylated interferons, in monotherapy or in combination with ribavirin, present other possibilities. We can expect the development more potent antiviral drugs or immune modulators for patients, which are primary resistant to alpha-interferon. (Tab. 3, Ref. 31)

• MeSH
• antivirové látky aplikace a dávkování   MeSH
• chronická hepatitida C farmakoterapie   MeSH
• interferon alfa-2 MeSH
• interferon alfa * aplikace a dávkování   MeSH
• interferon typ I aplikace a dávkování   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• polyethylenglykoly * MeSH
• rekombinantní proteiny MeSH
• ribavirin aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antivirové látky MeSH
• interferon alfa-2 MeSH
• interferon alfa * MeSH
• interferon alfacon-1 MeSH Prohlížeč
• interferon typ I MeSH
• peginterferon alfa-2a MeSH Prohlížeč
• peginterferon alfa-2b MeSH Prohlížeč
• polyethylenglykoly * MeSH
• rekombinantní proteiny MeSH
• ribavirin MeSH

Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs.

• Klíčová slova
• NET, autoimmunity, innate immunity, monocyte-derived dendritic cells, netosis, neutrophils, type 1 diabetes,
• MeSH
• buněčná diferenciace MeSH
• dendritické buňky imunologie   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• extracelulární pasti imunologie   MeSH
• interferon gama metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neutrofily imunologie   MeSH
• přirozená imunita MeSH
• regulace genové exprese MeSH
• rovnováha Th1-Th2 MeSH
• Th1 buňky imunologie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon gama MeSH
• transformující růstový faktor beta MeSH

Type 1 diabetes (T1D) is an autoimmune disorder characterised by the immune-mediated destruction of insulin-producing pancreatic beta cells. The inflammatory process appears to be primarily mediated by pro-inflammatory Th1 lymphocytes, while the role Th17 cells in T1D is currently being investigated. T1D is characterised by the presence of autoantigen-specific autoantibodies. This study was conducted using patients with confirmed T1D and healthy control subjects. We examined the effect of the patient's autoantibody profile on peripheral blood mononuclear cell (PBMC) cytokine production following stimulation with the major diabetogenic autoantigens GAD65 and IA2. IFN-gamma and IL17 production was detected by ELISPOT and the ratio of basic cellular populations in PBMCs was measured by flow cytometry. We demonstrated a significant interaction between the patient's autoantibody profile and mode of stimulation. This suggests that autoantigen stimulation has a different effect on different groups of patients depending on their autoantibody profile. An increased production of IL17 was found in patients with high IA2 autoantibodies compared to patients with low levels of autoantibodies and healthy controls regardless of the mode of stimulation. The titre of IA2 autoantibodies positively correlates with the proportion of Tc lymphocytes and negatively correlates with the proportion of Th lymphocytes. Our results show that a patient's autoantibody profile reflects the type of cellular immune responses. It seems that the high titre of IA2 autoantibodies is related to increased production of IL17 and an increased proportion of Tc lymphocytes. This finding may be useful in designing immunointervention studies to prevent T1D.

• Klíčová slova
• Autoantibodies, GAD65, IA2, IL17, Type 1 diabetes,
• MeSH
• autoprotilátky krev   imunologie   MeSH
• diabetes mellitus 1. typu krev   imunologie   MeSH
• dítě MeSH
• glutamát dekarboxyláza imunologie   MeSH
• interferon gama biosyntéza   krev   MeSH
• interleukin-17 biosyntéza   krev   MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• předškolní dítě MeSH
• průtoková cytometrie MeSH
• regulační T-lymfocyty imunologie   MeSH
• T-lymfocyty pomocné-indukující imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• glutamát dekarboxyláza MeSH
• glutamate decarboxylase 2 MeSH Prohlížeč
• interferon gama MeSH
• interleukin-17 MeSH

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

• MeSH
• buňky Th17 imunologie   MeSH
• diabetes mellitus 1. typu krev   imunologie   MeSH
• dítě MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• myeloidní supresorové buňky imunologie   MeSH
• počet CD4 lymfocytů MeSH
• regulační T-lymfocyty imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon gama MeSH

Interferon gamma (IFN-γ) is one of the key players in the immune system of vertebrates. The evolution and properties of IFN-γ and its receptors in fish species are of special interest as they point to the origin of innate immunity in vertebrates. We studied the phylogeny, biophysical and structural properties of IFN-γ and its receptors. Our phylogeny analysis suggests the existence of two groups of IFN-γ related proteins, one specific for Acanthomorpha, the other for Cypriniformes, Characiformes and Siluriformes. The analysis further shows an ancient duplication of the gene for IFN-γ receptor 1 (IFN- γR1) and the parallel existence of the duplicated genes in all current teleost fish species. In contrast, only one gene can be found for receptor 2, IFN- γR2. The specificity of the interaction between IFN- γ and both types of IFN- γR1 was determined by microscale thermophoresis measurements of the equilibrium dissociation constants for the proteins from three fish species. The measured preference of IFN- γ for one of the two forms of receptor 1agrees with the bioinformatic analysis of the coevolution between IFN- γ and receptor 1. To elucidate structural relationships between IFN-γ of fish and other vertebrate species, we determined the crystal structure of IFN-γ from olive flounder (Paralichthys olivaceus, PoliIFN-γ) at crystallographic resolution of 2.3 Å and the low-resolution structures of Takifugu rubripes, Oreochromis niloticus, and Larimichthys crocea IFN-γ by small angle X-ray diffraction. The overall PoliIFN-γ fold is the same as the fold of the other known IFN- γ structures but there are some significant structural differences, namely the additional C-terminal helix G and a different angle between helices C and D in PoliIFN-γ.

• Klíčová slova
• Bioinformatics, Class 2 cytokine receptors, Crystal structure, Fibronectin type III domain, Fish immunity, Interferon gamma, Jak-Stat pathway, SAXS, Type II interferons,
• MeSH
• fylogeneze MeSH
• interferon gama genetika   metabolismus   MeSH
• molekulární evoluce * MeSH
• receptory interferonů genetika   metabolismus   MeSH
• ryby genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interferon gama MeSH
• interferon receptor, type II MeSH Prohlížeč
• receptory interferonů MeSH

OBJECTIVE: Polymorphisms in the IFIH1 (common rs1990760 and four rare rs35667974, rs35337543, rs35744605, rs35732034) have been convincingly associated with type 1 diabetes. The encoded protein (interferon-induced helicase C domain-containing protein 1) senses double-stranded RNA during replication of Picornavirales, including Enterovirus, a genus suspected in the etiology of type 1 diabetes. We therefore investigated whether the polymorphisms are associated with differences in the frequency of enterovirus RNA in blood. RESEARCH DESIGN AND METHODS: The study included 1001 blood samples, each from a child participating in the Norwegian 'Environmental Triggers of Type 1 Diabetes: the MIDIA study'. The enterovirus RNA was tested using qualitative semi-nested real-time reverse transcriptase PCR on RNA extracted from frozen cell packs after removal of plasma. Stool samples previously analyzed for enterovirus RNA were available in 417 children. RESULTS: The genotypes of IFIH1 rs1990760 were associated with different frequencies of enterovirus RNA in blood (7.0%, 14.4% and 9.5% bloods were enterovirus positive among children carrying the Ala/Ala, Ala/Thr and Thr/Thr genotypes, respectively, p = 0.012). This association remained essentially unchanged after adjustment for age and calendar year. The presence of enterovirus in the concomitantly sampled stool further increased the likelihood of enterovirus RNA in blood (odds ratio 2.40, CI 95% 1.13-4.70), but did not affect the association with IFIH1 rs1990760. The rare polymorphisms (individually, or pooled) were not significantly associated with enterovirus RNA in blood. CONCLUSIONS: The common IFIH1 SNP may modify the frequency of enterovirus RNA in blood of healthy children. This effect can help explain the association of IFIH1 with type 1 diabetes.

• MeSH
• DEAD-box RNA-helikasy genetika   MeSH
• diabetes mellitus 1. typu krev   genetika   virologie   MeSH
• Enterovirus genetika   MeSH
• feces virologie   MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie * MeSH
• IFIH1 MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kojenec MeSH
• lidé MeSH
• multivariační analýza MeSH
• RNA virová krev   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Norsko MeSH
• Názvy látek
• DEAD-box RNA-helikasy MeSH
• IFIH1 protein, human MeSH Prohlížeč
• IFIH1 MeSH
• RNA virová MeSH

Growth of tumors induced by Rous sarcoma virus (RSV) is controlled by alleles at the major histocompatibility complex locus in chickens, indicating that immunological host defense mechanisms play a major role. We show here that the resistance phenotype of CB regressor chickens can be partially reverted by treating the animals with a monoclonal antibody that neutralizes the major serotype of chicken type I interferon, ChIFN-alpha. Injection of recombinant ChIFN-alpha into susceptible CC progressor chickens resulted in a dose-dependent inhibition of RSV-induced tumor development. This treatment was not effective, however, in CC chickens challenged with a DNA construct expressing the v-src oncogene, suggesting that the beneficial effect of type I interferon in this system resulted from its intrinsic antiviral activity and probably not from indirect immunmodulatory effects. By contrast, recombinant chicken interferon-gamma strongly inhibited tumor growth when given to CC chickens that were challenged with the v-src oncogene, indicating that the two cytokines target different steps of tumor development.

• MeSH
• buněčné linie MeSH
• časové faktory MeSH
• Coturnix MeSH
• DNA virů genetika   MeSH
• geny src * MeSH
• interferon gama terapeutické užití   MeSH
• interferon typ I terapeutické užití   MeSH
• kur domácí MeSH
• ptačí sarkom imunologie   patologie   prevence a kontrola   MeSH
• rekombinantní proteiny MeSH
• transfekce MeSH
• viry ptačího sarkomu genetika   patogenita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA virů MeSH
• interferon gama MeSH
• interferon typ I MeSH
• rekombinantní proteiny MeSH

The majority of malignant haematological diseases is incurable by contemporary procedures and therefore new approaches are sought, based on recent findings on haematopoiesis and its regulation. One of the new approaches is the use of so-called biological response modifiers between the later interferons. Recently relatively abundant experience was assembled with therapy using alpha interferon. The author presents an account of hitherto achieved therapeutic results obtained with alpha interferon in neoplasias of myelopoiesis and lymphopoiesis.

• MeSH
• interferon typ I terapeutické užití   MeSH
• lidé MeSH
• lymfoproliferativní nemoci terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• interferon typ I MeSH

Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with "sarcoidosis-associated" genes. Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry. Patient's BAL cells expressed higher mRNA T-bet levels than those of controls (mean ± sd fold change 3.64 ± 1.72; p = 0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p > 0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p < 0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes. In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.

• MeSH
• bronchoalveolární lavážní tekutina chemie   cytologie   MeSH
• chemokin CCL5 genetika   metabolismus   MeSH
• dospělí MeSH
• exprese genu MeSH
• interferon gama genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické uzliny metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• plíce metabolismus   MeSH
• plicní sarkoidóza genetika   imunologie   metabolismus   MeSH
• proteiny T-boxu metabolismus   MeSH
• receptory chemokinů genetika   metabolismus   MeSH
• receptory CXCR3 genetika   metabolismus   MeSH
• receptory CXCR6 MeSH
• receptory interleukinu-2 genetika   metabolismus   MeSH
• Th1 buňky imunologie   metabolismus   MeSH
• upregulace * MeSH
• virové receptory genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CCL5 protein, human MeSH Prohlížeč
• chemokin CCL5 MeSH
• CXCR6 protein, human MeSH Prohlížeč
• interferon gama MeSH
• messenger RNA MeSH
• proteiny T-boxu MeSH
• receptory chemokinů MeSH
• receptory CXCR3 MeSH
• receptory CXCR6 MeSH
• receptory interleukinu-2 MeSH
• T-box transcription factor TBX21 MeSH Prohlížeč
• virové receptory MeSH