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1.
Nat Immunol ; 25(4): 671-681, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38448779

RESUMO

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.


Assuntos
Autoanticorpos , Proteína HMGB1 , Animais , Camundongos , Complemento C1q , Proteína HMGB1/metabolismo , Doenças Neuroinflamatórias , Qualidade de Vida , Receptor para Produtos Finais de Glicação Avançada/metabolismo
2.
J Autoimmun ; 132: 102911, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36127204

RESUMO

Neuropsychiatric lupus (NPSLE) is a debilitating manifestation of SLE which occurs in a majority of SLE patients and has a variety of clinical manifestations. In the central nervous system, NPSLE may result from ischemia or penetration of inflammatory mediators and neurotoxic antibodies through the blood brain barrier (BBB). Here we focus on cognitive dysfunction (CD) as an NPSLE manifestation; it is common, underdiagnosed, and without specific therapy. For a very long time, clinicians ignored cognitive dysfunction and researchers who might be interested in the question struggled to find an approach to understanding mechanisms for this manifestation. Recent years, however, propelled by a more patient-centric approach to disease, have seen remarkable progress in our understanding of CD pathogenesis. This has been enabled through the use of novel imaging modalities and numerous mouse models. Overall, these studies point to a pivotal role of an impaired BBB and microglial activation in leading to neuronal injury. These insights suggest potential therapeutic modalities and make possible clinical trials for cognitive impairment.


Assuntos
Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Animais , Camundongos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Barreira Hematoencefálica , Anticorpos , Lúpus Eritematoso Sistêmico/complicações
3.
Curr Rheumatol Rep ; 23(4): 25, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782842

RESUMO

A wide range of patients with systemic lupus erythematosus (SLE) suffer from cognitive dysfunction (CD) which severely impacts their quality of life. However, CD remains underdiagnosed and poorly understood. Here, we discuss current findings in patients and in animal models. Strong evidence suggests that CD pathogenesis involves known mechanisms of tissue injury in SLE. These mechanisms recruit brain resident cells, in particular microglia, into the pathological process. While systemic immune activation is critical to central nervous system injury, the current focus of therapy is the microglial cell and not the systemic immune perturbation. Further studies are critical to examine additional potential therapeutic targets and more specific treatments based on the cause and progress of the disease.


Assuntos
Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Animais , Encéfalo , Disfunção Cognitiva/etiologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Qualidade de Vida
4.
Mol Med ; 26(1): 103, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33167852

RESUMO

The response to viral infection generally includes an activation of the adaptive immune response to produce cytotoxic T cells and neutralizing antibodies. We propose that SARS-CoV-2 activates the innate immune system through the renin-angiotensin and kallikrein-bradykinin pathways, blocks interferon production and reduces an effective adaptive immune response. This model has therapeutic implications.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Pneumonia Viral/imunologia , Animais , Bradicinina/metabolismo , COVID-19 , Humanos , Calicreínas/metabolismo , Modelos Imunológicos , Pandemias , Sistema Renina-Angiotensina , SARS-CoV-2
6.
Blood ; 128(18): 2218-2228, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27683415

RESUMO

A healthy immune system results from a balance of stimulatory and inhibitory pathways that allow effective responses to acute insults, without descending into chronic inflammation. Failed homeostasis is characteristic of autoimmune diseases such as systemic lupus erythematosus. Although HMGB1 induces proinflammatory M1-like macrophage differentiation, we describe a mechanism by which C1q modulates this activity and collaborates with HMGB1 to induce the differentiation of monocytes to anti-inflammatory M2-like macrophages. These anti-inflammatory macrophages are unresponsive to dendritic cell induction factors, effectively removing them from participation in an adaptive immune response. This pathway is mediated through a complex with RAGE and LAIR-1 and depends on relative levels of C1q and HMGB1. Importantly, these data provide insight into a homeostatic mechanism in which C1q and HMGB1 can cooperate to terminate inflammation, and which may be impaired in C1q-deficient patients with autoimmune disease.


Assuntos
Diferenciação Celular/imunologia , Complemento C1q/metabolismo , Proteína HMGB1/metabolismo , Macrófagos/citologia , Transdução de Sinais/imunologia , Polaridade Celular , Complemento C1q/imunologia , Proteína HMGB1/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo
7.
Trends Immunol ; 36(11): 709-724, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26494046

RESUMO

The brain is normally sequestered from antibody exposure by the blood brain barrier. However, antibodies can access the brain during fetal development before the barrier achieves full integrity, and in disease states when barrier integrity is compromised. Recent studies suggest that antibodies contribute to brain pathology associated with autoimmune diseases such as systemic lupus erythematosus and neuromyelitis optica, and can lead to transient or permanent behavioral or cognitive abnormalities. We review these findings here and examine the circumstances associated with antibody entry into the brain, the routes of access and the mechanisms that then effect pathology. Understanding these processes and the nature and specificity of neuronal autoantibodies may reveal therapeutic strategies toward alleviating or preventing the neurological pathologies and behavioral abnormalities associated with autoimmune disease.


Assuntos
Anticorpos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Animais , Humanos
9.
Mol Med ; 22: 789-799, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27878209

RESUMO

Long-term sepsis survivors sustain cryptic brain injury that leads to cognitive impairment, emotional imbalance, and increased disability burden. Suitable animal models of sepsis, such as cecal ligation and puncture (CLP), have permitted the analysis of abnormal brain circuits that underlie post-septic behavioral phenotypes. For instance, we have previously shown that CLP-exposed mice exhibit impaired spatial memory together with depleted dendritic arbors and decreased spines in the apical dendrites of pyramidal neurons in the CA1 region of the hippocampus. Here we show that contextual fear conditioning, a form of associative memory for fear, is chronically disrupted in CLP mice when compared to SHAM-operated animals. We also find that the excitatory neurons in the basolateral nucleus of the amygdala (BLA) and the granule cells in the dentate gyrus (DG) display significantly fewer dendritic spines in the CLP group relative to the SHAM mice, although the dendritic arbors and gross morphology of the BLA and DG are comparable between the two groups. Moreover, the basal dendrites of CA1 pyramidal neurons are unaffected in the CLP mice. Taken together, our data indicate that the structural damage in the amygdalar-hippocampal network represents the neural substrate for impaired contextual fear memory in long-term sepsis survivors. Further, our data suggest that the brain injury caused by overwhelming sepsis alters the stability of the synaptic connections involved in associative fear. These results likely have implications for the emotional imbalance observed in human sepsis survivors.

10.
Mol Med ; 21(1): 951-958, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26736178

RESUMO

Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis.

12.
Immunol Rev ; 248(1): 56-67, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22725954

RESUMO

Systemic lupus erythematosus is an autoimmune disease characterized by antibodies that bind target autoantigens in multiple organs in the body. In peripheral organs, immune complexes engage the complement cascade, recruiting blood-borne inflammatory cells and initiating tissue inflammation. Immune complex-mediated activation of Fc receptors on infiltrating blood-borne cells and tissue resident cells amplifies an inflammatory cascade with resulting damage to tissue function, ultimately leading to tissue destruction. This pathophysiology appears to explain tissue injury throughout the body, except in the central nervous system. This review addresses a paradigm we have developed for autoantibody-mediated brain damage. This paradigm suggests that antibody-mediated brain disease does not depend on immune complex formation but rather on antibody-mediated alterations in neuronal activation and survival. Moreover, antibodies only access brain tissue when blood-brain barrier integrity is impaired, leading to a lack of concurrence of brain disease and tissue injury in other organs. We discuss the implications of this model for lupus and for identifying other antibodies that may contribute to brain disease.


Assuntos
Encefalopatias/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Tonsila do Cerebelo/imunologia , Tonsila do Cerebelo/metabolismo , Animais , Anticorpos Antinucleares/química , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Especificidade de Anticorpos/genética , Especificidade de Anticorpos/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encefalopatias/tratamento farmacológico , Encefalopatias/etiologia , Encefalopatias/metabolismo , Hipocampo/imunologia , Hipocampo/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Modelos Imunológicos , Neurônios/imunologia , Neurônios/metabolismo , Peptídeos/imunologia , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo
13.
Curr Opin Neurol ; 33(3): 338-340, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374572
14.
Stroke ; 45(1): 200-4, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24335224

RESUMO

BACKGROUND AND PURPOSE: Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. METHODS: In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. RESULTS: Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R(2) of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). CONCLUSIONS: These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.


Assuntos
Braço/fisiologia , Biomarcadores , Movimento/fisiologia , Robótica , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/fisiopatologia , Idoso , Fenômenos Biomecânicos , Interpretação Estatística de Dados , Determinação de Ponto Final , Etnicidade , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Modelos Anatômicos , Dinâmica não Linear , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes
15.
Proc Natl Acad Sci U S A ; 108(25): 10255-9, 2011 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-21646518

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies, many of which are directed against nuclear antigens, in particular double-stranded (ds) DNA. Both clinical studies and animal models have shown that anti-dsDNA antibodies contribute to kidney disease, which is present in 50% of lupus patients and is a major cause of mortality. We previously demonstrated that a subset of nephrotoxic anti-dsDNA antibodies also recognizes the pentapeptide consensus sequence D/E W D/E Y S/G (DWEYS) present in the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR). Autoantibodies with this specificity are present in ≈40% of lupus patient sera and are both nephrotoxic and neurotoxic. Elevated titers are present in cerebrospinal fluid of patients with central nervous system manifestations of SLE. Administration of the nonnaturally occurring D form of the DWEYS pentapeptide prevents these antibodies from depositing in glomeruli and from mediating neuronal excitotoxicity. To craft a more useful therapeutic, we used the structural features of the DWEYS peptide to design a unique, selective, and potent small molecule peptidomimetic, FISLE-412, which neutralizes anti-dsDNA/NMDAR lupus autoantibodies and prevents their pathogenic interaction with tissue antigens. This compound, or others derived from it, may provide a unique strategy for the development of lupus therapeutics.


Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Peptidomiméticos/imunologia , Peptidomiméticos/uso terapêutico , Animais , Autoanticorpos/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Peptídeos/genética , Peptídeos/imunologia , Peptidomiméticos/síntese química , Peptidomiméticos/química
16.
Biomedicines ; 12(8)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39200170

RESUMO

The close interaction between neurons and astrocytes has been extensively studied. However, the specific behavior of these cells after ischemia-reperfusion injury and hypothermia remains poorly characterized. A growing body of evidence suggests that mitochondria function and putative transference between neurons and astrocytes may play a fundamental role in adaptive and homeostatic responses after systemic insults such as cardiac arrest, which highlights the importance of a better understanding of how neurons and astrocytes behave individually in these settings. Brain injury is one of the most important challenges in post-cardiac arrest syndrome, and therapeutic hypothermia remains the single, gold standard treatment for neuroprotection after cardiac arrest. In our study, we modeled ischemia-reperfusion injury by using in vitro enhanced oxygen-glucose deprivation and reperfusion (eOGD-R) and subsequent hypothermia (HPT) (31.5 °C) to cell lines of neurons (HT-22) and astrocytes (C8-D1A) with/without hypothermia. Using cell lysis (LDH; lactate dehydrogenase) as a measure of membrane integrity and cell viability, we found that neurons were more susceptible to eOGD-R when compared with astrocytes. However, they benefited significantly from HPT, while the HPT effect after eOGD-R on astrocytes was negligible. Similarly, eOGD-R caused a more significant reduction in adenosine triphosphate (ATP) in neurons than astrocytes, and the ATP-enhancing effects from HPT were more prominent in neurons than astrocytes. In both neurons and astrocytes, measurement of reactive oxygen species (ROS) revealed higher ROS output following eOGD-R, with a non-significant trend of differential reduction observed in neurons. HPT after eOGD-R effectively downregulated ROS in both cells; however, the effect was significantly more effective in neurons. Lipid peroxidation was higher after eOGD-R in neurons, while in astrocytes, the increase was not statistically significant. Interestingly, HPT had similar effects on the reduction in lipoperoxidation after eOGD-R with both types of cells. While glutathione (GSH) levels were downregulated after eOGD-R in both cells, HPT enhanced GSH in astrocytes, but worsened GSH in neurons. In conclusion, neuron and astrocyte cultures respond differently to eOGD-R and eOGD-R + HTP treatments. Neurons showed higher sensitivity to ischemia-reperfusion insults than astrocytes; however, they benefited more from HPT therapy. These data suggest that given the differential effects from HPT in neurons and astrocytes, future therapeutic developments could potentially enhance HPT outcomes by means of neuronal and astrocytic targeted therapies.

17.
Curr Opin Neurol ; 31(3): 291-293, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29547403
18.
N Engl J Med ; 362(19): 1772-83, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20400552

RESUMO

BACKGROUND: Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. METHODS: In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. RESULTS: At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. CONCLUSIONS: In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)


Assuntos
Atividade Motora , Modalidades de Fisioterapia , Robótica , Reabilitação do Acidente Vascular Cerebral , Extremidade Superior/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Custos de Cuidados de Saúde , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Modalidades de Fisioterapia/instrumentação , Recuperação de Função Fisiológica , Robótica/economia , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
19.
Ann Neurol ; 82(1): 1-3, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28544007
20.
Bioessays ; 33(8): 588-91, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21681774

RESUMO

A new study entitled "Normal gut microbiota modulates brain development and behavior", published in the Proceedings of the National Academy of Sciences, requires that we reconsider the notion that the brain is an immune-privileged site. The authors demonstrate that intestinal microbiota must be present within a set time-frame for normal synaptogenesis to occur in the brain. In the absence of intestinal microbiota, histopathological and behavioral abnormalities arise. These observations necessitate a new look at the many interconnections of the immune system and the brain, suggesting new frontiers for research and new therapeutic strategies for neurodevelopmental diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Fatores Imunológicos/metabolismo , Intestinos/microbiologia , Neuroimunomodulação , Animais , Comportamento/fisiologia , Encéfalo/imunologia , Encéfalo/fisiologia , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Intestinos/imunologia , Potenciação de Longa Duração , Metagenoma , Receptores Imunológicos/metabolismo , Sinapses/imunologia , Sinapses/fisiologia , Transmissão Sináptica
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