RESUMO
Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.
Assuntos
Citocinas/genética , Inflamação/diagnóstico , Locos de Características Quantitativas , Biomarcadores/sangue , Estudos de Coortes , Citocinas/sangue , Citocinas/imunologia , Dinamarca , Elementos Facilitadores Genéticos/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Inflamação/sangue , Inflamação/imunologia , Masculino , Polimorfismo de Nucleotídeo Único , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. In an experimental autoimmune glaucoma model with systemic S100B immunization, a loss of RGCs is accompanied by a decreased synaptic signal at 28 days. Here, we aimed to study synaptic alterations in these two models. In one group, rats received a systemic S100B immunization (n = 7/group), while in the other group, S100B was injected intraocularly (n = 6-7/group). Both groups were compared to appropriate controls and investigated after 14 days. While inhibitory post-synapses remained unchanged in both models, excitatory post-synapses degenerated in animals with intraocular S100B injection (p = 0.03). Excitatory pre-synapses tendentially increased in animals with systemic S100B immunization (p = 0.08) and significantly decreased in intraocular ones (p = 0.04). Significantly more n-methyl-d-aspartate (NMDA) receptors (both p ≤ 0.04) as well as gamma-aminobutyric acid (GABA) receptors (both p < 0.03) were observed in S100B animals in both models. We assume that an upregulation of these receptors causes the interacting synapse types to degenerate. Heightened levels of excitatory pre-synapses could be explained by remodeling followed by degeneration.
Assuntos
Doenças Autoimunes/imunologia , Glaucoma/imunologia , Receptores de GABA/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/toxicidade , Sinapses/imunologia , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Glaucoma/induzido quimicamente , Glaucoma/patologia , Pressão Intraocular/efeitos dos fármacos , Masculino , Nervo Óptico/imunologia , Nervo Óptico/patologia , Ratos , Ratos Endogâmicos Lew , Ratos Wistar , Células Ganglionares da Retina/imunologia , Células Ganglionares da Retina/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Sinapses/patologiaRESUMO
BACKGROUND: Cognitive Dysfunction (CD) can occur in Systemic Lupus Erythematosus (SLE) before the occurrence of Neuropsychiatric Lupus Erythematosus (NPSLE). Given the reversibility and fluctuation of SLE-related CD, the research for possible predictors is of great significance for early detection and intervention. OBJECTIVE: We sought to determine the prevalence, involved domains, and possible predictors of CD in SLE patients. METHODS: We conducted a retrospective cross-sectional study at Nanfang Hospital from 2018 to 2019. A total of 78 SLE patients were recruited. The Montreal Cognitive Assessment (MoCA) scale was used to screen cognitive function. Demographic, clinical, and laboratory characteristics were collected. The serum anti-methyl-d-aspartate receptor (anti-NMDAR) antibody and S100ß were measured by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression analysis and ROC curve were used to assess the predictor of SLE-related CD. RESULTS: Of 78 recruited patients,53 (67.9%) had CD. It mainly involved delayed recall, abstract generalization, verbal repetition, and fluency. The disease activity index (SLEDAI) was not associated with SLE-related CD (p > 0.05). Multivariate logistic regression showed that an increase in each year of education there was a decrease in the likelihood of CD (OR 0.261, CI 0.080-0.857, p = 0.027) whereas with each unit increase in serum anti-NMDAR antibody there was an increased likelihood of SLE-related CD (OR 1.568, CI 1.073-2.292, p = 0.020). CONCLUSION: The prevalence of SLE-related CD was 67.9% in our study and SLE-related CD was not associated with disease activity. Serum anti-NMDAR antibody can be used as a predictor for SLE-related CD.
Assuntos
Autoanticorpos/imunologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Lúpus Eritematoso Sistêmico/psicologia , Adolescente , Adulto , Autoanticorpos/sangue , Disfunção Cognitiva/sangue , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Curva ROC , Receptores de N-Metil-D-Aspartato/imunologia , Estudos Retrospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Adulto JovemRESUMO
Surface plasmon resonance (SPR) biosensors are often used in the detection of solid, liquid or gaseous samples in diagnostics, pharmaceutics and military defense. Plasmon waveguide resonance (PWR) mode is obtained when a dielectric waveguide layer is added to the metal film. In this study, a self-referenced PWR (SRPWR) silicon dioxide (SiO2) chip was examined. The self-referenced measurement is important to compensate for temperature fluctuations, other instabilities and allows RI signal measurement without an additional reference sample, thus minimising the sample volume needed. The chip was fabricated with a multi-layer of metals and dielectrics, consisting of a 420 nm SiO2 layer, a 40 nm Ag layer and another 480 nm SiO2 layer. This chip was shown to give one internal plasmon excited on the bottom interface SiO2/Ag, which is used as self-reference in the detection. The top layer acts as a waveguide layer and can be designed to give modes with ultrahigh penetration depth. A direct assay was developed, where the recognition molecule (specific antibody) was immobilized onto the SiO2 plasmonic chip surface, via a covalent coupling protocol based on 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde. The SRPWR biosensor was developed for the sensing of two chosen stroke biomarkers: NT-proBNP and S100ß, which are sensitive and specific for stroke diagnostics. For both biomarkers, a linear decreasing pattern in the RI signal was recognized with the increasing biomarkers concentrations. Biomarkers detection was conducted in deionized water and validation was done in spiked porcine plasma. The SiO2 based plasmonic chip demonstrates a limit-of-detection of less than 1 ng/mL that is clinically relevant for both stroke biomarkers.
Assuntos
Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Dióxido de Silício/química , Acidente Vascular Cerebral/sangue , Ressonância de Plasmônio de Superfície/instrumentação , Animais , Anticorpos Imobilizados/imunologia , Biomarcadores/sangue , Humanos , Peptídeo Natriurético Encefálico/imunologia , Fragmentos de Peptídeos/imunologia , Testes Imediatos , Propilaminas/química , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Silanos/química , Ressonância de Plasmônio de Superfície/métodos , SuínosRESUMO
Due to exceptional electron-accepting ability, light-absorption, and a delocalized conjugated structure, buckminsterfullerene (C60) has attracted fascinating interest in the field of organic solar cells. However, poor delocalization and accumulation of electrons for pristine C60 in physiological aqueous solution and difficulties in conjugation with biomolecules limit its extended photovoltaic applications in bioassay. Herein, we reported the noncovalent coupling of C60 to an electronically complementary porphyrin-derived metal-organic framework (PCN-224) with carboxyl-group terminals. Such assembly not only offered a friendly interface for bioconjugation but also resulted in a long-range ordering C60@PCN-224 donor-acceptor system that demonstrated an unprecedented photocurrent enhancement up to 10 times with respect to each component. As an example, by further cooperating with Nanobodies, the as-prepared C60@PCN-224 was applied to a photoelectrochemical (PEC) immunosensor for S100 calcium-binding protein B with by far the most promising detection activities. This work may open a new venue to unlock the great potential of C60 in PEC biosensing with excellent performances.
Assuntos
Técnicas Eletroquímicas/métodos , Fulerenos/química , Imunoensaio/métodos , Estruturas Metalorgânicas/química , Biomarcadores/sangue , Técnicas Biossensoriais/métodos , Fulerenos/efeitos da radiação , Humanos , Luz , Limite de Detecção , Estruturas Metalorgânicas/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiação , Estudo de Prova de Conceito , Reprodutibilidade dos Testes , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Anticorpos de Domínio Único/imunologiaRESUMO
The brain is one of the earliest organs to be influenced during sepsis. Sepsis-associated encephalopathy (SAE) is frequent, but seldomly recognized and has no testified pharmacological therapy. In this study, we demonstrated that pentamidine, an antiprotozoal drug, is a good candidate since it blocks S100B/RAGE/NF-κB signaling pathway. Pentamidine ameliorated cecal ligation and puncture (CLP)-induced brain damage assessed by crystal violet staining and hematoxylin and eosin (H&E) staining. Moreover, pentamidine reduced neuroinflammation in mouse hippocampi. Immunofluorescence and Western blot analysis also showed that pentamidine inhibited CLP-induced gliosis and S100B/RAGE/NF-κB pathway activation. Interestingly, it could also attenuate oxidative stress indicated by decreased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and attenuation of malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) consumption. Thus the S100B/RAGE/NF-κB pathway may be crucial in the pathogenesis of SAE and may be a promising pharmacological target to prevent SAE.
Assuntos
Antiprotozoários/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pentamidina/uso terapêutico , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Animais , Lesões Encefálicas/imunologia , Lesões Encefálicas/patologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Pancreatic cancer (PC) patients have poor prognosis and survival rate. Gemcitabine, the drug of choice has a dismal 15% response rate. Earlier, we reported that Garcinol alone and in combination with gemcitabine showed a dose-dependent favorable response on PC cell lines. This study probes the in vivo effects of dietary Garcinol on PC progression in transgenic PC mice (KPC; K-ras and p53 conditional mutant). KPC male mice were divided into: KC- Control diet; KGr-0.05% Garcinol diet; KGm-Gemcitabine injected; KGG - Garcinol diet + Gemcitabine injected groups. Changes in tumor progression, toxicity, or cell morphology were monitored by magnetic resonance imaging, Fore-stomach, and blood smear, respectively. Pancreatic Intraepithelial Neoplasia (mPanIN) grading with hematoxylin and eosin (H&E) staining was conducted on pancreas and validated by immunohistochemistry. The KGr group showed improved survival, no observable toxicity with marked reduction in papilloma formation in the fore-stomach, and a higher ratio of NK and NKT cells compared to Non-NK lymphocytes. Additionally, the KGr, KGm, and KGG groups showed reduction in tumor volumes and reduced number of advanced mouse PanIN3. Dietary Garcinol alone and in combination with gemcitabine retarded the progression of PC in transgenic PC mice, arresting the cancer in the earlier stages, improving prognosis and survival.
Assuntos
Neoplasias Pancreáticas/dietoterapia , Terpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Suplementos Nutricionais , Genes p53 , Genes ras , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Proteína Smad4/imunologia , Taxa de Sobrevida , Terpenos/efeitos adversos , GencitabinaRESUMO
In glaucoma, latest studies revealed an involvement of the complement system with and without an elevated intraocular pressure. In the experimental autoimmune glaucoma model, immunization with antigens, such as S100B, lead to retinal ganglion cell (RGC) loss and optic nerve degeneration after 28 days. Here, we investigated the timeline of progression of the complement system, toll-like-receptor 4 (TLR4), and the transcription factor nucleus factor-kappa B (NFκB). Therefore, rats were immunized with S100B protein (S100) and analyzed at 3, 7, and 14 days. RGC numbers were comparable at all points in time, whereas a destruction of S100 optic nerves was noted at 14 days. A significant increase of mannose binding lectin (MBL) was observed in S100 retinas at 3 days. Subsequently, significantly more MBL+ cells were seen in S100 optic nerves at 7 and 14 days. Accordingly, C3 was upregulated in S100 retinas at 14 days. An increase of interleukin-1 beta was noted in S100 aqueous humor samples at 7 days. In this study, activation of complement system via the lectin pathway was obvious. However, no TLR4 alterations were noted in S100 retinas and optic nerves. Interestingly, a significant NFκB increase was observed in S100 retinas at 7 and 14 days. We assume that NFκB activation might be triggered via MBL leading to glaucomatous damage.
Assuntos
Doenças Autoimunes/imunologia , Ativação do Complemento/imunologia , Glaucoma/imunologia , Nervo Óptico/imunologia , Retina/imunologia , Células Ganglionares da Retina/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Glaucoma/metabolismo , Glaucoma/patologia , Imunização , Pressão Intraocular , Masculino , NF-kappa B/metabolismo , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Ratos , Ratos Endogâmicos Lew , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , VacinaçãoRESUMO
Rheumatoid arthritis (RA) has been associated with cognitive impairment and peripheral production of autoantibodies. Autoantibodies against central nervous system (CNS) proteins and S100 calcium-binding ß (S100ß) were found increased in diseases characterized by cognitive impairment like Alzheimer disease and Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). The aim of this study was to investigate the plasma levels of autoantibodies against myelin basic protein (anti-MBP), myelin oligodendrocyte glycoprotein (anti-MOG) and S100ß, and their relationships with cognitive performance in RA patients. Twenty patients with active rheumatoid arthritis and 19 age-, sex-, and schooling-matched healthy controls were recruited. Multiple dimensions of cognitive function were evaluated by structured clinical questionnaires. Autoantibodies and S100ß levels were assessed by ELISAs. Patients had significantly higher levels of anti-MBP IgG (17.51 ± 1.36 vs. 5.24 ± 0.53 ng/mL), anti-MOG IgG (5.68 ± 1.34 vs. 0.51 ± 0.49 ng/mL), and S100ß protein (2.24 ± 0.50 vs. 0.47 ± 0.06) than controls (all p < 0.0001). After adjusting for potential confounders, RA group presented worse cognitive performance involving the working memory and executive functions such as inhibition, flexibility, and mental control in parallel to higher autoantibodies and S100ß levels than healthy controls (all p < 0.001). Levels of anti-MBP were negatively associated with delayed verbal recall (DVR; r = -0.42, p = 0.005), Stroop Color-Word (r = -0.48, p = 0.004), and N-Back Total scores (r = -0.59, p < 0.0001) and positively with Trail Making Test B (TMB, r = 0.53, p = 0.001). Negative correlation was found between levels of anti-MOG and DVR (r = -0.64, p < 0.0001), N-Back Total scores (r = -0.35, p = 0.03), Stroop Color-Word (r = -0.51, p = 0.001), and positively with TMB (r = 0.50, p = 0.003). S100ß levels were associated with DVR (r = -0.51, p = 0.002), TMB (r = 0.46, p = 0.008), Stroop Color-Word (r = -0.67, p < 0.0001), and N-Back Total (r = -0.52, p = 0.003). RA is associated with impaired cognitive performance associated with higher levels of CNS-related autoantibodies and S100ß levels. Given the importance of myelin integrity to cognition, our data indicate that these autoantibodies may be harmful to proper cognitive function.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/psicologia , Autoanticorpos/sangue , Disfunção Cognitiva/sangue , Idoso , Brasil , Estudos de Casos e Controles , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteína Básica da Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.
Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Adolescente , Transtorno Bipolar/complicações , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/imunologia , Filho de Pais com Deficiência , Fator de Crescimento Epidérmico/sangue , Fator de Crescimento Epidérmico/imunologia , Feminino , Humanos , Inflamação/complicações , Inflamação/imunologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia , Interleucina-7/sangue , Interleucina-7/imunologia , Masculino , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Fator de Células-Tronco/sangue , Fator de Células-Tronco/imunologiaRESUMO
HIV in the central nervous system (CNS) mainly infects microglial cells which are known to express toll-like receptors (TLRs). This paper aimed to study the role of soluble TLR2 (sTLR2), sTLR4, and other inflammatory markers in cerebrospinal fluid (CSF) in HIV/Simian immunodeficiency virus (SIV)-related neurological sequelae. We determined sTLR2 and sTLR4 levels in CSF and serum/plasma of SIV-infected rhesus macaques with and without neurological sequelae, as well as in HIV-infected patients with and without cognitive impairments and Alzheimer's disease (AD) patients and matched controls. CSF cytokines and chemokines levels were analyzed in macaques as markers of neuroinflammation, while neopterin and S100B CSF concentrations were measured in HIV-infected patients as microglial and astrocyte marker, respectively. We found detectable levels of sTLR2 and sTLR4 in CSF of macaques and humans. Furthermore, CSF sTLR2 and sTLR4 concentrations were higher in SIV-infected macaques with neurological sequelae compared to those without neurological complications (p = 0.0003 and p = 0.0006, respectively). CSF IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels were elevated in macaques with neurological sequelae, and a positive correlation was found between CSF levels of sTLR2/4 and IL-8 and MCP-1. Also in humans, elevated CSF sTLR4 levels were found in HIV-infected patients with cognitive impairments compared to HIV-infected patients with normal cognition (p = 0.019). Unlike CSF S100B levels, neopterin correlated positively with sTLR2 and sTLR4. No difference was found in plasma and CSF sTLR2 and sTLR4 levels between AD patients and control subjects (p = 0.26). In conclusion, CSF sTLR2 and sTLR4 may play a role in HIV/SIV-related neuroinflammation and subsequent neuropathology.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Infecções por HIV/líquido cefalorraquidiano , Síndrome de Imunodeficiência Adquirida dos Símios/líquido cefalorraquidiano , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Adulto , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Doença de Alzheimer/virologia , Animais , Astrócitos/imunologia , Astrócitos/patologia , Astrócitos/virologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL2/líquido cefalorraquidiano , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/virologia , Feminino , Expressão Gênica , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Interleucina-8/líquido cefalorraquidiano , Interleucina-8/genética , Interleucina-8/imunologia , Macaca mulatta , Masculino , Microglia/imunologia , Microglia/patologia , Microglia/virologia , Pessoa de Meia-Idade , Neopterina/líquido cefalorraquidiano , Neopterina/genética , Neopterina/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidade , Solubilidade , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genéticaRESUMO
In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/µL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid ß42. Individuals with CD4 351-500 cells/µL (N = 40) had significantly higher CSF levels of interleukin (IL)-1ß, amyloid ß42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.
Assuntos
Complexo AIDS Demência/líquido cefalorraquidiano , Complexo AIDS Demência/diagnóstico , Linfócitos T CD4-Positivos/imunologia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/fisiopatologia , Adulto , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/imunologia , Biomarcadores/líquido cefalorraquidiano , Fator Neurotrófico Derivado do Encéfalo/líquido cefalorraquidiano , Fator Neurotrófico Derivado do Encéfalo/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/líquido cefalorraquidiano , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interleucina-12/líquido cefalorraquidiano , Interleucina-12/imunologia , Interleucina-2/líquido cefalorraquidiano , Interleucina-2/imunologia , Masculino , Metaloproteinase 1 da Matriz/líquido cefalorraquidiano , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 7 da Matriz/líquido cefalorraquidiano , Metaloproteinase 7 da Matriz/imunologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/imunologia , Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Fator de Crescimento Derivado de Plaquetas/imunologia , Estudos Prospectivos , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/imunologia , UgandaRESUMO
Disturbances of hemorheology, hemostasis and fibrinolysis play an important role in the pathogenesis and pathophysiology of chronic cerebral ischemia. Physiological functioning of the endothelium is disturbed under the action of damaging factors. Divaza is created on the basis of release-active antibodies to S100b protein and antibodies to endothelial NO-synthase. The efficacy of divaza in the treatment of chronic cerebral ischemia and related diseases (cognitive impairment, anxiety) was demonstrated. A normalizing effect of divaza in the dose of 2 tablets 3 times daily between meals during 12 weeks on endothelial function is shown.
Assuntos
Anticorpos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Transtornos de Ansiedade/sangue , Transtornos de Ansiedade/tratamento farmacológico , Isquemia Encefálica/sangue , Isquemia Encefálica/prevenção & controle , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/tratamento farmacológico , Fibrinólise , Hemostasia , Humanos , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/antagonistas & inibidores , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
OBJECTIVE: To compare clinical and immunological parameters in children with schizophrenia and to analyze the possibility of using them in the assessment of the pathological process activity. MATERIAL AND METHODS: We examined 62 patients, 39 boys and 23 girls, aged from 4 to 17 years, with childhood-onset schizophrenia. Mental state of the patients was assessed using a psychopathological method and with PANSS and CGI scales. The activity of leukocyte elastase (LE) and alpha(1)-proteinase inhibitor (α1-PI) was measured by spectrophotometric method. ELISA was used to determine the level of autoantibodies to neuroantigenes to S-100B and basic myelin protein. RESULTS AND CONCLUSION: The activation of innate immunity assessed by the activity of LE and α1-PI and adaptive immunity (levels of autoantibodies to neuroantigenes to S-100B and basic myelin protein) was identified. Significant correlations of the level of immune system activation with the severity of patient's state on СGI-S (r=0.64, p=0.000001) as well as scores on the PANSS negative symptom subscale (r=0.34, p=0.0077) were found. The results suggest the possibility of using these immunological parameters for the objectification of clinical state of children with schizophrenia.
Assuntos
Autoanticorpos/sangue , Proteína Básica da Mielina/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Esquizofrenia Infantil/diagnóstico , Esquizofrenia Infantil/imunologia , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Esquizofrenia Infantil/sangue , Índice de Gravidade de DoençaRESUMO
S100B is a calcium-sensor protein that impacts multiple signal transduction pathways. It is widely considered to be an important biomarker for several neuronal diseases as well as blood-brain barrier (BBB) breakdown. In this report, we demonstrate a BBB deficiency in mice that lack S100B through detection of leaked Immunoglobulin G (IgG) in the brain parenchyma. IgG leaks and IgG-binding to selected neurons were observed in S100B knockout (S100BKO) mice at 6 months of age but not at 3 months. By 9 months, IgG leaks persisted and the density of IgG-bound neurons increased significantly. These results reveal a chronic increase in BBB permeability upon aging in S100BKO mice for the first time. Moreover, coincident with the increase in IgG-bound neurons, autoantibodies targeting brain proteins were detected in the serum via western blots. These events were concurrent with compromise of neurons, increase of activated microglia and lack of astrocytic activation as evidenced by decreased expression of microtubule-associated protein type 2 (MAP2), elevated number of CD68 positive cells and unaltered expression of glial fibrillary acidic protein (GFAP) respectively. Results suggest a key role for S100B in maintaining BBB functional integrity and, further, propose the S100BKO mouse as a valuable model system to explore the link between chronic functional compromise of the BBB, generation of brain-reactive autoantibodies and neuronal dysfunctions.
Assuntos
Autoanticorpos/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Fatores Etários , Animais , Imunoglobulina G/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/imunologia , Permeabilidade , Subunidade beta da Proteína Ligante de Cálcio S100/deficiência , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
Current diagnostic methods for traumatic brain injury (TBI), which accounts for 15% of all emergency room visits, are limited to neuroimaging modalities. The challenges of accurate diagnosis and monitoring of TBI have created the need for a simple and sensitive blood test to detect brain-specific biomarkers. Here we report on an assay for detection of S100B, a putative biomarker for TBI, using antibody-conjugated magnetic beads for capture of the protein, and antibody-conjugated quantum dots for optical detection. From Western Blot, we show efficient antigen capture and concentration by the magnetic beads. Using magnetic bead capture and quantum dot detection in serum samples, we show a wide detection range and detection limit below the clinical cut-off level.
Assuntos
Biomarcadores/sangue , Lesões Encefálicas/diagnóstico , Pontos Quânticos/química , Anticorpos Imobilizados/química , Anticorpos Imobilizados/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Humanos , Magnetismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
OBJECTIVE: To study the possibility of using immunological parameters for the evaluation of the activity of endogenous process in depression and quality of response to psychopharmacotherapy. MATERIAL AND METHODS: Authors examined 42 patients, aged 20-55 years, with the prevalence of anxiety (n = 22) or apathy (n = 20) in the clinical picture of depression. The following immunological parameters were measured in the blood of the patients: degranulation activity of leukocyte elastase (LE), functional activity of alpha-1-proteinase inhibitor (alpha-1-PI); the level of autoantibodies to neuroantigen S-100B and myelin basic protein. RESULTS AND CONCLUSION: The involvement of inflammatory and autoimmune responses in the pathophysiology of endogenous depression was confirmed. Depression associated with increased levels of autoantibodies to brain neuroantigens (an autoimmune component) had a more complicated structure and showed the tendency to prolonged course and resistance to the therapy. The results suggest that some immunological parameters may be used as markers of patient's clinical status and quality and completeness of psychopathological symptom reduction.
Assuntos
Autoanticorpos/sangue , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/imunologia , Adulto , Biomarcadores/sangue , Transtorno Depressivo/sangue , Feminino , Humanos , Elastase de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Proteína Básica da Mielina/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Adulto Jovem , alfa 1-Antitripsina/sangueRESUMO
Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαß features remains unclear. Here, we analyzed the TCRαß repertoire of CD4(+) T cells specific for the S100ß protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100ß1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαß repertoire of S100ß-specific CD4(+) T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate- to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4(+) T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4(+) T-cell repertoire; the latter is deleted by re-enforced negative selection.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Central/imunologia , Ilhotas Pancreáticas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Animais , Diabetes Mellitus Tipo 1/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Serina Endopeptidases/deficiência , Serina Endopeptidases/imunologiaRESUMO
The importance of certain neurotrophic proteins found in maternal blood and milk for breastfed infants has remained ambiguous. This study was conducted to present evidence of the impact of an induced deficit of active S100B protein on neonate development. Newborn mice from two groups of mothers, immunized or sham-immunized against S100B, were subjected to various behavioral tests, and the development of their morphological characteristics was recorded from birth until weaning. Morphological problems, including weight gain and fur coating, a delay in the maturation of neurobehavioral systems and a deficit in neuromotor functions, including visual abilities, somato-sensory and posture reactions, muscular strength, locomotion, and fear/orienting processes, were observed in pups of immunized mothers. The S100B protein of external or internal origin in infants may be considered to be a specific factor that determines neuro- and morphological development and a risk-avoidance ('homeward-bent' or fearful) phenotype. The suppression of activity of the S100B protein results in a slower neonatal development and the formation of a risk-tolerant (fearless) phenotype of the offspring. This study thus considers the mechanism of neuroplastic regulation on the extent of sensation-seeking or risk-taking (homeless-like or fearless) and sensation- or risk-avoidance (home-bound or fearful) features in individual phenotypes.
Assuntos
Transtornos do Neurodesenvolvimento/sangue , Transtornos do Neurodesenvolvimento/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Afeto , Fatores Etários , Animais , Animais Recém-Nascidos , Anticorpos/sangue , Anticorpos/toxicidade , Peso Corporal , Ensaio de Imunoadsorção Enzimática , Feminino , Masculino , Camundongos , Atividade Motora , Força Muscular , Transtornos do Neurodesenvolvimento/imunologia , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reflexo/fisiologia , Subunidade beta da Proteína Ligante de Cálcio S100/imunologiaRESUMO
Type 1 diabetes results from destruction of insulin-producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non-beta cell-specific antigens has also been reported, including targeting of the calcium-binding protein S100ß. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100ß, determined their affinity for the human leucocyte antigen (HLA)-DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100ß reactivity, characterized by interferon (IFN)-γ secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100ß as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non-beta cell-specific autoantigens may have a role in type 1 diabetes pathogenesis.