RESUMO
Dopamine has emerged as a fundamental regulator of inflammation. In this regard, it has been shown that dopaminergic signalling pathways are key players promoting homeostasis between the central nervous system and the immune system. Dysregulation in the dopaminergic system affects both innate and adaptive immunity, contributing to the development of numerous autoimmune and inflammatory pathologies. This makes dopamine receptors interesting therapeutic targets for either the development of new treatments or repurposing of already available pharmacological drugs. Dopamine receptors are broadly expressed on different immune cells with multifunctional effects depending on the dopamine concentration available and the pattern of expression of five dopamine receptors displaying different affinities for dopamine. Thus, impaired dopaminergic signalling through different dopamine receptors may result in altered behaviour of immunity, contributing to the development and progression of autoimmune pathologies. In this review we discuss the current evidence involving the dopaminergic system in inflammatory bowel disease, multiple sclerosis and Parkinson's disease. In addition, we summarise and analyse the therapeutic approaches designed to attenuate disease development and progression by targeting the dopaminergic system. Graphical Abstract Targetting the dopaminergic system in autoimmunity. Effector T-cells (Teff) orchestrate inflamamtion involved in autoimmunity, whilst regulatory T-cells (Tregs) suppress Teff activity promoting tolerance to self-constituents. Dopamine has emerged as a key regulator of Teff and Tregs function, thereby dopamine receptors have becoming important therapeutic targets in autoimmune disorders, especially in those affecting the brain and the gut, where dopamine levels strongly change with inflammation.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Autoimunidade/efeitos dos fármacos , Dopaminérgicos/administração & dosagem , Dopaminérgicos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Animais , Doenças Autoimunes/imunologia , Autoimunidade/fisiologia , Dopamina/imunologia , Dopamina/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/imunologia , Doença de Parkinson/metabolismo , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".
ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Proteína C-Reativa/efeitos dos fármacos , Endotelina-1/efeitos dos fármacos , Hipotireoidismo/complicações , Tiroxina/uso terapêutico , Proteína C-Reativa/análise , Autoimunidade/efeitos dos fármacos , Estudos de Casos e Controles , Endotelina-1/análise , Antioxidantes/metabolismoRESUMO
Since the discovery of autoimmunity as the main pathophysiologic process involved in type 1 diabetes, many attempts have tried to delay or stop beta cell destruction. Most research protocols in humans have investigated the effects of therapeutic agents targeting specific steps of the autoimmune response. In spite of safety and some degree of beta cell preservation, the clinical impact of such approaches was similar to placebo. Recently, research groups have analyzed the effects of a more intense and wider immunologic approach in newly diagnosed type 1 diabetic individuals with the "immunologic reset," i.e., high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation. This more aggressive approach has enabled the majority of patients to experience periods of insulin independence in parallel with relevant increments in C-peptide levels during mixed meal tolerance test. However, on long-term follow-up, almost all patients resumed exogenous insulin use, with subsequent decrease in C-peptide levels. This has been at least in part explained by persistence of islet-specific T-cell auto-reactivity. Here, we discuss future steps to induce immune tolerance in individuals with type 1 diabetes, with emphasis on risks and possible benefits of a more intense transplant immunosuppressive regimen, as well as strategies of beta cell replacement not requiring immunomodulation.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Terapia de Imunossupressão , Células Secretoras de Insulina/transplante , Animais , Autoimunidade/efeitos dos fármacos , Biomarcadores , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Tolerância Imunológica , Terapia de Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Transplante das Ilhotas Pancreáticas , Transplante Autólogo , Resultado do TratamentoRESUMO
AIM: Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by the progressive destruction of ß cells, mediated by the interaction between T cells and several cytokines. The pathogenesis of T1D has established its possible relationship with miRNAs. In this study, we analyze the expression profile of miR-15a and miR-16 in peripheral blood mononuclear cells (PBMCs) and their possible association with apoptosis, inflammation, or autoimmunity markers. PATIENTS AND METHODOLOGY: 38 T1D patients and 41 control subjects were recruited. mRNAs were analyzed by means of qPCR and TaqMan probes. PBMCs were treated with different concentrations of glucose (baseline, 11 and 25 mM) with or without an inflammatory stimulus as TNF-α (10 ng/ml). RESULTS: A decrease in the levels of the miR-15a expression in basal conditions is observed in T1D patients compared to healthy control subjects (relative units 0.5 vs. 1.8, p < 0.05). This change in miR-15a and miR-16 is not affected by the addition of TNF-α. No association is observed with inflammatory markers (IL-6, TNF-α, vCAM) or apoptosis (bcl2 expression). The relationship with immunological markers shows an interaction effect between miR16 and IA-2 (p < 0.03). CONCLUSION: TNF-α does not affect the expression profile of miR-15a and miR16 in PBMCs. A weak correlation is observed between miR-16 and with the autoimmunity profile (IA-2 autoantibody).
Assuntos
Apoptose/fisiologia , Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Mediadores da Inflamação/metabolismo , MicroRNAs/biossíntese , Adolescente , Adulto , Apoptose/efeitos dos fármacos , Autoimunidade/efeitos dos fármacos , Biomarcadores/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Chile/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Fator de Necrose Tumoral alfa/toxicidade , Adulto JovemAssuntos
Corticosteroides/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Hepatite B/virologia , Hospedeiro Imunocomprometido , Imunoglobulina G/imunologia , Ativação Viral , Idoso , Antivirais/uso terapêutico , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do TratamentoRESUMO
In this work, the immunomodulatory activity of the acetone extract and the fructans obtained from Agave tequilana were evaluated, on the systemic autoimmunity type-SLE model generated by the administration of 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane) on Balb/c female mice. The systemic autoimmunity type-SLE was observed seven months after the application of TMPD, in which the animals from the negative control group (animals with damage and without any other treatment) developed articular inflammation, proteinuria, an increment of the antinuclear antibody titters and tissue pro-inflammatory cytokines levels (IL-1ß, IL-6, TNF-α e IFN-γ) as well as the anti-inflammatory cytokine IL-10. The administration of the different treatments and the extracts of A. tequilana, provoked the decrease of: articular inflammation, the development of proteinuria, ssDNA/dsDNA antinuclear antibody titters and cytokines IL-1ß, IL-6, TNF-α, IFN-γ and IL-10. The phytochemical analysis of the acetone extract identified the presence of the following compounds: ß-sitosterol glycoside; 3,7,11,15-tetramethyl-2-hexadecen-1-ol (phytol); octadecadienoic acid-2,3-dihydroxypropyl ester; stigmasta-3,5-dien-7-one; cycloartenone and cycloartenol. Therefore, A. tequilana contains active compounds with the capacity to modify the evolution of the systemic autoimmunity type-SLE on a murine model.
Assuntos
Agave/química , Autoimunidade/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Extratos Vegetais/farmacologia , Terpenos/efeitos adversos , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/imunologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Chronic inflammation associated with hepatitis C virus (HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α (IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies (ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings (RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings (anti-RR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.
Assuntos
Anticorpos Antinucleares/imunologia , Antivirais/efeitos adversos , Autoimunidade/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , IMP Desidrogenase/imunologia , Interferon-alfa/efeitos adversos , Ribavirina/efeitos adversos , Quimioterapia Combinada , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/imunologia , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/química , Imunidade Humoral/efeitos dos fármacos , Conformação Proteica , Tolerância a Antígenos Próprios/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To analyze the impact of selenium supplementation on serum antiTPO levels and thyroid echogenicity in patients with CAT, evaluating the response in subgroups with different GPx1 genotypes. METHODS: CAT patients (n = 55) with positive antiTPO were randomized to selenomethionine (SeMet) 200 µg daily (n = 28) or placebo (n = 27) for 3 months. Assessments included GPx1 genotyping at baseline and serum levels of plasma selenium, erythrocyte GPx1 activity, antiTPO and thyroid echogenicity at baseline, and 3 and 6 months. RESULTS: In the SeMet group, the increase in plasma levels of selenium and erythrocyte GPx1 activity was similar among patients with different GPx1 genotypes. In the overall cohort, patients randomized to SeMet showed a 5 % decrease in antiTPO levels at 3 months (p = non-significant) and 20 % at 6 months (p < 0.001 versus 3 months). In contrast, patients in the placebo group did not show significant changes in antiTPO levels at any time point. Subgroup analysis showed that patients with different GPx1 genotypes presented comparable responses in antiTPO levels and echogenicity index to SeMet. CONCLUSIONS: Selenium supplementation decreased serum antiTPO levels in CAT patients, with similar response among patients with different GPx1 genotypes.
Assuntos
Autoimunidade/efeitos dos fármacos , Suplementos Nutricionais , Glutationa Peroxidase/genética , Iodeto Peroxidase/imunologia , Selenometionina/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Tireoidite Autoimune/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Genótipo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Selenometionina/administração & dosagem , Glândula Tireoide/imunologia , Tireoidite Autoimune/genética , Tireoidite Autoimune/imunologia , Resultado do Tratamento , Adulto Jovem , Glutationa Peroxidase GPX1RESUMO
Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy.