RESUMO
BACKGROUND: The aim of this study was to investigate serum S100B and brain-derived neurotrophic factor (BDNF) in systemic lupus erythematous (SLE) patients, with and without neuropsychiatric (NP) manifestation activity. METHODS: We assessed 47 SLE patients and 20 selected healthy individuals. Disease activity was assessed according to the SLE disease activity index (SLEDAI). Serum BDNF and S100B were measured by enzyme-linked immunosorbent assay. RESULTS: Serum S100B protein was significantly higher in SLE patients. BDNF levels were significantly decreased in active SLE, when compared with inactive SLE, but not when compared with controls. S100B was clearly higher in the NPSLE group, when compared with the non-NPSLE or control groups. Receiver operating characteristic analysis of S100B revealed an area under the curve of 0.706 that discriminated NPSLE patients with peripheral polyneuropathy. CONCLUSIONS: Our findings reinforce the use of serum S100B as a biomarker in SLE, particularly for NPSLE. Moreover, we found a strong association between serum S100B and peripheral neuropathy, indicating a specific utility for this biomarker in SLE that warrants clinical investigation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Cuba , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de DoençaRESUMO
The identity of the protein antigens targeted by anti-cytoplasmic antibodies in lupus was discovered 30 years ago. These antigens are three acidic ribosomal phosphoproteins, P0, P1, and P2. Precise identification of the shared epitope on these three proteins enabled sensitive and specific immunoassays to be developed. Anti-P antibodies are highly specific for systemic lupus erythematosus (SLE) and occur in 15%-35% of patients, depending on ethnicity as well as the age of onset. Increased frequencies of detection of anti-P have been reported in childhood SLE as well as in neuropsychiatric, renal, and hepatic disease. While longitudinal studies by the Systemic Lupus International Collaborating Clinics (SLICC) consortium supported the association of anti-P with neuropsychiatric lupus, the predictive value of antibody determination remains controversial. This is likely explained by the heterogeneity of neuropsychiatric lupus as well as by the different methodologies used for assay. A number of experimental studies have suggested a direct pathogenic role for anti-P antibodies in brain disease. Findings include cross reactivity between anti-P and a neuronal surface antigen, which was detected in areas of the brain involved in memory, cognition, and emotion. Direct injection of anti-P antibodies into the brains of rodents was also associated with abnormal electrical activity and behavioral disturbances. Taken together, research over the last 30 years has established anti-P antibodies as a useful diagnostic marker of SLE and at least a subset of patients with neuropsychiatric disease. Further research is required to fine tune the association of anti-P with clinical manifestations and establish beyond high probability a pathophysiologic role for the antibodies.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Fosfoproteínas/imunologia , Proteínas Ribossômicas/imunologia , Fatores Etários , Animais , Autoanticorpos/sangue , Biomarcadores/metabolismo , Epitopos/imunologia , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/etnologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options.
Assuntos
Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Autoanticorpos/metabolismo , Transtornos Cerebrovasculares/diagnóstico por imagem , Cefaleia/diagnóstico , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico por imagem , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/terapia , Imageamento por Ressonância Magnética , Mielite/diagnóstico por imagem , Testes Neuropsicológicos , Convulsões/diagnóstico , SíndromeRESUMO
ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options.
RESUMO Lúpus eritematoso sistêmico (LES) é uma doença autoimune crônica que envolve múltiplos órgãos e sistemas, caracterizada pela produção de auto anticorpos e lesão tecidual. A etiologia do LES é parcialmente conhecida e envolve interação entre fatores genéticos e ambientais. Até 50% dos pacientes com LES apresentam envolvimento neurológico no decorrer da doença. Manifestações neurológicas estão associadas a prejuízo na qualidade de vida e altas taxas de mortalidade e morbidade. Foram identificadas 19 síndromes neuropsiquiátricas em pacientes com LES, divididas entre manifestações do sistema nervoso central e periférico. O objetivo deste artigo é revisar as manifestações neuropsiquiátricas mais importantes. Serão abordadas as características clínicas, os aspectos radiológicos e opções de tratamento dos eventos neuropsiquiátricos.
Assuntos
Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Convulsões/diagnóstico , Autoanticorpos/metabolismo , Síndrome , Imageamento por Ressonância Magnética , Transtornos Cerebrovasculares/diagnóstico por imagem , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/terapia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico por imagem , Cefaleia/diagnóstico , Mielite/diagnóstico por imagem , Testes NeuropsicológicosRESUMO
OBJECTIVE: To define whether anti-ribosomal P (anti-P) autoantibodies from patients with neuropsychiatric systemic lupus erythematosus (NPSLE) impair the function of hippocampal neurons that express the neuronal surface P antigen (NSPA) when accessing the brain via circulating blood. METHODS: We used anti-P antibodies from patients with NPSLE and rabbit-generated anti-P and anti-NSPA antibodies. Primary hippocampal neurons from mice were analyzed to determine antibody cell surface binding (double immunofluorescence), intracellular calcium variations (Fura 2 AM), and apoptosis (caspase 3 activation). Hippocampal-dependent spatial flexible memory was assessed in mice subjected to a water maze test 24 hours after an intravenous injection of anti-P or anti-NSPA, using lipopolysaccharide (LPS) to permeate the blood-brain barrier. Presence of antibodies and apoptosis in the hippocampus was studied using immunohistochemistry and TUNEL assays. RESULTS: Hippocampal neurons expressed NSPA on the cell surface, as revealed by anti-P and anti-NSPA staining colocalization, and responded to both anti-P and anti-NSPA by exhibiting increased intracellular calcium levels. Neuronal apoptosis was induced when anti-P was directly injected by stereotaxis into the hippocampus or added to primary cultures. Upon LPS treatment, intravenously injected anti-P impaired memory but did not elicit neuronal apoptosis in the hippocampus, where it was detectable in low amounts. Anti-NSPA antibodies also impaired memory. CONCLUSION: Anti-P antibodies interact with NSPA on the surface of hippocampal neurons leading to apoptotic death or to functional perturbations, results that are likely dependent on the concentration of these antibodies. Circulating anti-P can access the hippocampus and impair memory without requiring neuronal death when the blood-brain barrier is disrupted. NSPA can mediate antibody-driven diffuse brain dysfunction, and anti-P might contribute to the cognitive impairment that is frequently observed in SLE.
Assuntos
Autoanticorpos/efeitos adversos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Transtornos da Memória/etiologia , Transtornos da Memória/imunologia , Proteínas Ribossômicas/imunologia , Adolescente , Animais , Antígenos de Superfície/metabolismo , Apoptose/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Ribossômicas/metabolismo , Adulto JovemRESUMO
OBJECTIVES: To evaluate the association of the presence of lymphocytotoxic, anti-beta2-glycoprotein I (anti-beta2-GPI) and anti-ribosomal P (anti-P) antibodies in patients with systemic lupus erythematosus (SLE), presenting or not neuropsychiatric (NP) manifestations, stratified according to the activity of the disease. METHODS: A total of 138 patients with SLE (59 with active NPSLE, 49 with active non-NPSLE, and 30 with inactive disease) and 57 healthy controls were studied. Disease activity was assessed by the SLE Disease Activity Index (SLEDAI). The presence of lymphocytotoxic antibodies was assessed using a complement-dependent lymphocytotoxicity assay. The presence of anti-beta2-GPI and anti-P antibodies was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Lymphocytotoxic antibodies were detected primarily in patients with active disease, that is in 35 out of 59 (59.3%) NPSLE and 23 out of 49 (46.9%) non-NPSLE patients, whereas only four out of 30 (13.3%) inactive SLE patients and none of the healthy controls exhibited the autoantibody. The frequency of lymphocytotoxic antibodies in active SLE patients, considered as a whole or stratified into NPSLE or non-NPSLE, was significantly increased in relation to inactive SLE patients (p<0.001 for each comparison). No significant difference was observed when comparing active NPSLE with non-NPSLE patients. No associations were observed between the presence of anti-beta2-GPI or anti-P antibodies and the activity of SLE or the presence of lymphocytotoxic antibodies. CONCLUSIONS: Lymphocytotoxic antibodies occurred more frequently in patients with active SLE than in patients with inactive disease, irrespective of the presence of NP manifestations, a finding that is similar to classical biomarkers of lupus activity (anti-dsDNA and complement). These results indicate that the assessment of the presence of lymphocytotoxic antibodies may be an additional useful tool for the evaluation of SLE activity.
Assuntos
Soro Antilinfocitário/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Proteínas do Sistema Complemento/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Ribossômicas/imunologia , Índice de Gravidade de Doença , beta 2-Glicoproteína I/imunologiaRESUMO
The interesting observation was made 20 years ago that psychotic manifestations in patients with systemic lupus erythematosus are associated with the production of antiribosomal-P protein (anti-P) autoantibodies. Since then, the pathogenic role of anti-P antibodies has attracted considerable attention, giving rise to long-term controversies as evidence has either contradicted or confirmed their clinical association with lupus psychosis. Furthermore, a plausible mechanism supporting an anti-P-mediated neuronal dysfunction is still lacking. We show that anti-P antibodies recognize a new integral membrane protein of the neuronal cell surface. In the brain, this neuronal surface P antigen (NSPA) is preferentially distributed in areas involved in memory, cognition, and emotion. When added to brain cellular cultures, anti-P antibodies caused a rapid and sustained increase in calcium influx in neurons, resulting in apoptotic cell death. In contrast, astrocytes, which do not express NSPA, were not affected. Injection of anti-P antibodies into the brain of living rats also triggered neuronal death by apoptosis. These results demonstrate a neuropathogenic potential of anti-P antibodies and contribute a mechanistic basis for psychiatric lupus. They also provide a molecular target for future exploration of this and other psychiatric diseases.
Assuntos
Apoptose , Autoanticorpos/química , Cálcio/química , Membrana Celular/metabolismo , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Neurônios/metabolismo , Proteínas/química , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Sistema Nervoso Central/metabolismo , Epitopos/química , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Modelos Biológicos , Peptídeos/química , Ratos , Ribossomos/metabolismo , Sinaptossomos/metabolismoRESUMO
OBJECTIVE: To evaluate the kinin system components and selected cytokines in plasma and cerebrospinal fluid (CSF) of patients with neuropsychiatric lupus (NPL). METHODS: We studied 29 women with active NPL and 29 healthy women matched to patients for age. Low (LKg) and high molecular weight kininogen (HKg) and cytokine concentrations [interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor-a (TNF-a)] were determined by ELISA. The activities of tissue kallikrein, plasma prekallikrein, and kininase II were assayed by their action on selective substrates. RESULTS: Compared to controls, patients with NPL presented increased plasma and CSF levels of LKg, HKg, and prekallikrein, increased activity of tissue kallikrein and kininase II, and increased levels of IL-6, IL-10, and TNF-a (p < 0.001 each comparison). IL-1beta levels were increased in patient plasma (p < 0.001), whereas plasma IL-8 levels did not differ from controls. IL-1beta and IL-8 were not detected in CSF of patients or controls. CONCLUSION: The increased levels of kininogen fractions, kallikreins, and kininase II in patient plasma and CSF indicate overactivity of the kinin system, suggesting intense kinin production. Since kinins may induce the production of proinflammatory cytokines including IL-1beta, IL-6, and TNF-a, these findings support the participation of kinins and cytokines in the acute manifestations of NPL. Most of the variables evaluated in patients' CSF increased proportionally in relation to plasma levels. In contrast, the activity of tissue kallikrein in patient CSF increased out of proportion to plasma levels, appearing to be locally synthesized in response to brain involvement.
Assuntos
Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Cininogênio de Baixo Peso Molecular/sangue , Cininogênio de Baixo Peso Molecular/líquido cefalorraquidiano , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Doença Aguda , Adulto , Feminino , Humanos , Interleucina-1/sangue , Interleucina-1/líquido cefalorraquidiano , Interleucina-10/sangue , Interleucina-10/líquido cefalorraquidiano , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Interleucina-8/sangue , Interleucina-8/líquido cefalorraquidiano , Cininogênio de Alto Peso Molecular/sangue , Cininogênio de Alto Peso Molecular/líquido cefalorraquidiano , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/líquido cefalorraquidiano , Pessoa de Meia-Idade , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/líquido cefalorraquidiano , Pré-Calicreína/líquido cefalorraquidiano , Calicreínas Teciduais/sangue , Calicreínas Teciduais/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/líquido cefalorraquidianoRESUMO
To evaluate lymphocyte death by neglect-apoptosis features in systemic lupus erythematosus (SLE) patients presenting with neuropsychiatric (NPSLE) involvement we studied 40 SLE patients with active disease, 20 with and 20 without neuropsychiatric manifestations, and 20 control individuals. Lymphocyte apoptosis was evaluated by means of DNA staining using flow cytometry, immediately after cell isolation and after incubation with culture medium or autologous serum. Compared with controls, NPSLE and non-NPSLE patients exhibited increased rates of neglect-apoptosis immediately after cell isolation. Only NPSLE patients exhibited an increased neglect-apoptosis rate after incubation with culture medium; however, the neglect-apoptosis rate was associated with lymphopenia in both series of patients. After lymphocyte incubation with autologous serum, only NPSLE patients exhibited a significant negative correlation between the neglect-apoptosis rate and the number of peripheral lymphocytes. The incubation of lymphocytes with autologous serum containing antiphospholipid or anti-SSA/Ro antibodies significantly increased the neglect-apoptosis in NPSLE when compared with non-NPSLE patients with a similar autoantibody profile. In conclusion, NPSLE and non-NPSLE patients shared several abnormalities in terms of lymphocyte neglect-apoptosis. Peculiar findings were observed in NPSLE patients particularly after incubation with autologous serum, such as the fact that the increased lymphocyte death by neglect-apoptosis was associated with lymphopenia and with the presence of antiphospholipid and anti-SSA/Ro antibodies.