RESUMO
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
Assuntos
Autoantígenos/uso terapêutico , Autoimunidade/imunologia , Fatores Imunológicos/uso terapêutico , Regeneração Nervosa/imunologia , Doenças Neurodegenerativas/terapia , Neuroproteção/imunologia , Peptídeos/uso terapêutico , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/terapia , Animais , Acetato de Glatiramer/uso terapêutico , Humanos , Imunização Passiva , Imunomodulação , Proteína Básica da Mielina/uso terapêutico , Doenças Neurodegenerativas/imunologia , Doença de Parkinson/imunologia , Doença de Parkinson/terapia , Fragmentos de Peptídeos/uso terapêutico , Deficiências na Proteostase , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapiaRESUMO
BACKGROUND AND PURPOSE: Dysregulation of the miR-15a/16-1 cluster in plasma has been reported in patients with stroke as a potential biomarker for diagnostic and prognostic use. However, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. This study is aimed at investigating the regulatory role of the miR-15a/16-1 cluster in ischemic brain injury and insight mechanisms. METHODS: Adult male miR-15a/16-1 knockout and wild-type mice, or adult male C57 BL/6J mice injected via tail vein with the miR-15a/16-1-specific inhibitor (antagomir, 30 pmol/g), were subjected to 1 hour of middle cerebral artery occlusion and 72 hours of reperfusion. The neurological scores, brain infarct volume, brain water content, and neurobehavioral tests were then evaluated and analyzed. To explore underlying signaling pathways associated with alteration of miR-15a/16-1 activity, major proinflammatory cytokines were measured by quantitative polymerase chain reaction or ELISA and antiapoptotic proteins were examined by Western blotting. RESULTS: Genetic deletion of the miR-15a/16-1 cluster or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain water content, and improved neurological outcomes in stroke mice. Inhibition of miR-15a/16-1 significantly decreased the expression of the proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule 1, tumor necrosis factor alpha, and increased Bcl-2 and Bcl-w levels in the ischemic brain regions. CONCLUSIONS: Our data indicate that pharmacological inhibition of the miR-15a/16-1 cluster reduces ischemic brain injury via both upregulation of antiapoptotic proteins and suppression of proinflammatory molecules. These results suggest that the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke.
Assuntos
Antagomirs/farmacologia , Isquemia Encefálica/tratamento farmacológico , MicroRNAs/antagonistas & inibidores , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Antagomirs/administração & dosagem , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/metabolismoRESUMO
Brain injuries are often associated with intensive care admissions, and carry high morbidity and mortality rates. Ischemic stroke is one of the most frequent causes of injury to the central nervous system. It is now increasingly clear that human stroke causes multi-organ systemic disease. Brain inflammation may lead to opposing local and systemic effects. Suppression of systemic immunity by the nervous system could protect the brain from additional inflammatory damage; however, it may increase the susceptibility to infection. Pneumonia and urinary tract infection are the most common complications occurring in patients after stroke. The mechanisms involved in lung-brain interactions are still unknown, but some studies have suggested that inhibition of the cholinergic anti-inflammatory pathway and release of glucocorticoids, catecholamines, and damage-associated molecular patterns (DAMPs) are among the pathophysiological mechanisms involved in communication from the ischemic brain to the lungs after stroke. This review describes the modifications in local and systemic immunity that occur after stroke, outlines mechanisms of stroke-induced immunosuppression and their role in pneumonia, and highlights potential therapeutic targets to reduce post-stroke complications. Despite significant advances towards a better understanding of the pathophysiology of ischemic stroke-induced immunosuppression and stroke-associated pneumonia (SAP) in recent years, many unanswered questions remain. The true incidence and outcomes of SAP, especially in intensive care unit settings, have yet to be determined, as has the full extent of stroke-induced immunosuppression and its clinical implications.
Assuntos
Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Imunomodulação/fisiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Lesões Encefálicas/imunologia , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/terapia , Isquemia Encefálica/fisiopatologia , Humanos , Imunossupressores/uso terapêutico , Pneumonia/imunologia , Pneumonia/fisiopatologia , Pneumonia/terapia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND: Persistent pathogens have been proposed as risk factors for stroke; however, the evidence remains inconclusive. Mexican Americans have an increased risk of stroke especially at younger ages, as well as a higher prevalence of infections caused by several persistent pathogens. METHODOLOGY/PRINCIPAL: Findings Using data from the Sacramento Area Latino Study on Aging (nâ=â1621), the authors used discrete-time regression to examine associations between stroke risk and (1) immunoglobulin G antibody levels to Helicobacter pylori (H. pylori), Cytomegalovirus, Varicella Zoster Virus, Toxoplasma gondii and Herpes simplex virus 1, and (2) concurrent exposure to several pathogens (pathogen burden), defined as: (a) summed sero-positivity, (b) number of pathogens eliciting high antibody levels, and (c) average antibody level. Models were adjusted for socio-demographics and stroke risk factors. Antibody levels to H. pylori predicted incident stroke in fully adjusted models (Odds Ratio: 1.58; 95% Confidence Interval: 1.09, 2.28). No significant associations were found between stroke risk and antibody levels to the other four pathogens. No associations were found for pathogen burden and incident stroke in fully adjusted models. CONCLUSIONS/SIGNIFICANCE: Our results suggest that exposure to H. pylori may be a stroke risk factor in Mexican Americans and may contribute to ethnic differences in stroke risk given the increased prevalence of exposure to H. pylori in this population. Future studies are needed to confirm this association.
Assuntos
Anticorpos Antibacterianos/sangue , Infecções por Helicobacter/imunologia , Acidente Vascular Cerebral/imunologia , Idoso , Anticorpos Antiprotozoários/imunologia , Anticorpos Antivirais/sangue , Chlamydophila pneumoniae/imunologia , Citomegalovirus/imunologia , Feminino , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 3/imunologia , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/microbiologiaRESUMO
OBJECTIVE: Recent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immunomodulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg-afforded neuroprotection. METHODS: We examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg-neutrophil cocultures using a combined approach including cell-specific depletion, gene knockout mice, and bone marrow chimeras. RESULTS: Systemic administration of purified Tregs at 2, 6, or even 24 hours after middle cerebral artery occlusion resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg-afforded neuroprotection was accompanied by attenuated blood-brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation, and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil-derived matrix metallopeptidase-9 production, thus preventing proteolytic damage of the BBB. In addition to its potent central neuroprotection, Treg treatment was shown to ameliorate poststroke lymphopenia, suggesting a beneficial effect on immune status. INTERPRETATION: Our study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption.
Assuntos
Barreira Hematoencefálica/imunologia , Isquemia Encefálica/terapia , Encéfalo/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T Reguladores/transplante , Animais , Barreira Hematoencefálica/fisiopatologia , Encéfalo/fisiopatologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) have been described in primary Sjögren's syndrome (pSS) with controversial findings regarding aPL prevalence and their association with thrombotic events. We evaluated 100 consecutive pSS patients (American-European criteria) and 89 age-gender-ethnicity-matched healthy controls for IgG/IgM anticardiolipin (aCL), IgG/IgM anti-beta2-glycoprotein-I (aß2GPI), and lupus anticoagulant (LA) (positivity according to APS Sydney's criteria). Clinical analysis followed standardized interview and physical examination assessing thrombotic and nonthrombotic APS manifestations and thrombosis risk factors. aPLs were detected in 16 % patients and 5.6 % controls (p = 0.035). LA was the most common aPL in patients (9 %), followed by aß2GPI (5 %) and aCL (4 %). Thrombotic events occurred in five patients [stroke in two, myocardial infarction in one and deep-vein thrombosis (DVT) in four], but in none of controls (p = 0.061). Mean age at time of stroke was 35 years. Three patients with thrombotic events (including the two with stroke) had APS (Sydney's criteria) and were positive exclusively for LA. Comparison of patients with (n = 16) and without (n = 84) aPL revealed similar mean age, female predominance, and ethnicity (p > =0.387). Frequencies of livedo reticularis (25 vs. 4.8 %, p = 0.021), stroke (12.5 vs. 0 %, p = 0.024), and DVT (18.8 vs. 1.2 %, p = 0.013) were significantly higher in APL + patients. Conversely, frequencies of hypertension, dyslipidemia, diabetes, obesity, smoking, sedentarism, and hormonal contraception were similar in patients with or without aPL (p ≥ 0.253). Our study identified LA as an important marker for APS in pSS, particularly for stroke in young patients, warranting routine evaluation of these antibodies and rigorous intervention in modifiable risk factors.
Assuntos
Inibidor de Coagulação do Lúpus/sangue , Inibidor de Coagulação do Lúpus/imunologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/imunologia , Acidente Vascular Cerebral/imunologia , Trombose Venosa/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antifosfolipídeos/química , Síndrome Antifosfolipídica/metabolismo , Cardiolipinas/química , Estudos de Casos e Controles , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/complicações , Fatores de Tempo , Trombose Venosa/complicaçõesRESUMO
INTRODUCTION AND METHOD: The study of antiphospholipid antibodies has aroused a great deal of interest among researchers, as some of them are related to neurological diseases and in particular with cerebral ischemia. Cases of strokes in which the aetiology is unknown have been reported in young patients. Until now anticardiolipin antibodies and lupus anticoagulant have received the most attention in studies, but recently descriptions have been published of anticardiolipin antibodies with other particularities that can act as more specific immunity markers for strokes of undetermined origin in young adults. Recent research has been directed towards gaining an understanding of the mechanisms that allow these antibodies to play a direct role in the physiopathology of thrombosis and how certain risk factors smoking, high blood pressure, lipid disorders can exert an influence on the expression of phospholipids in the cerebral endothelium. Several authors have described different pathological mechanisms that help to understand the heterogeneous clinical manifestations of antiphospholipid syndrome. CONCLUSION: There is a need to study the different possible antigens of the antiphospholipid antibodies, as well as their specificities and pathological mechanisms, in greater depth in order to obtain a phospholipid immunity marker that is useful in the diagnosis of young stroke patients who are positive for these antibodies.
Assuntos
Anticorpos Antifosfolipídeos/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Anticorpos Anticardiolipina/imunologia , Anticorpos Anticardiolipina/metabolismo , Anticorpos Antifosfolipídeos/imunologia , Antígenos/imunologia , Antígenos/metabolismo , Biomarcadores , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Humanos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologiaRESUMO
BACKGROUND: Anticardiolipin antibodies (aCL) are a heterogeneous group of antiphospholipid antibodies that are associated with arterial and venous thrombosis. We measured aCL in women, aged 15-49 years, to determine if they are an independent risk factor for thromboembolic disease. STUDY DESIGN: Case--control study METHODS: Fifty cases were studied including venous thromboembolism (n=29), stroke and myocardial infarction (n=21), along with 148 age-matched controls. Serum samples were assayed for aCL and anti-beta2 glycoprotein 1 antibodies using the enzyme-linked immunosorbent assay (ELISA). Information on other risk factors was obtained by a standardized questionnaire. RESULTS: aCL were present in 16/50 (32%) of cases compared with 25/148 (17%) of controls (P[?]=[?]0.02). Unadjusted odds ratio (OR) and 95% confidence interval (95% CI) for thromboembolic disease associated with aCL was 2.32 (1.10--4.87). Other risk factors were hypertension, 2.93 (1.20--7.17) and a history of other heart diseases, 12.78 (1.32--123.60). Adjustment for hypertension, diabetes, oral contraceptive use, smoking, alcohol use, varicose veins, a family history of cardiovascular disease and a history of other heart diseases yielded OR (95%CI) 2.99 (1.32--6.80). beta2 glycoprotein 1-dependent aCL were also an independent risk factor, OR 4.56 (1.76--17.83). Subgroup analysis was carried out separately for cases of MI and stroke and for venous thrombosis. Adjusted OR (95% CI) associated with aCL in cases of MI and stroke was 1.76 (0.46--6.73) and 3.32 (1.15--9.54) for venous thromboembolism. CONCLUSION: aCL are a risk factor for thromboembolic disease in young Jamaican women. They confer a strong independent risk for venous thromboembolism.