RESUMO
A 77-year-old man with a history of lung cancer at the age of 71 developed involuntary right leg movement for a month. Neurological examination revealed a right-sided hemi-chorea. Autoimmune disease was suspected owing to the presence of oligoclonal bands and the elevated IgG-index in the cerebrospinal fluid. We detected anti-SRY-Related HMG-Box Gene 1 (SOX1) antibodies, known to be serological markers of Lambert-Eaton syndrome with small cell lung cancer, but not tumors. The results of tests for antiphospholipid, anti-LGI1, and anti-CASPR2 antibodies associated with non-paraneoplastic autoimmune chorea were all negative. This is the first suggestive case of autoimmune chorea in which anti-SOX1 antibodies were detected.
Assuntos
Autoanticorpos/sangue , Autoimunidade , Coreia/etiologia , Coreia/imunologia , Fatores de Transcrição SOXB1/imunologia , Idoso , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Coreia/diagnóstico , Imagem de Difusão por Ressonância Magnética , Humanos , Síndrome Miastênica de Lambert-Eaton/complicações , Neoplasias Pulmonares/complicações , Masculino , Carcinoma de Pequenas Células do Pulmão/complicaçõesAssuntos
Coreia/imunologia , Hidrolases/imunologia , Linfoma Difuso de Grandes Células B/complicações , Proteínas Associadas aos Microtúbulos/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Humanos , MasculinoRESUMO
Among the neurological manifestations of systemic lupus erythematosus (SLE), chorea is rare, presenting in less than 7% of the pediatric SLE patients. It can appear early in the onset of SLE, be the first or even the sole clinical feature of the illness and has strongly been associated with the presence of antiphospholipid antibodies. We report on the case of a 13-year old boy, admitted with acute onset chorea and finally diagnosed with SLE. Subsequently, we present a short review of the literature on the epidemiology, suggested pathogenesis, clinical presentation and treatment of this rare presentation of SLE.
Assuntos
Coreia/imunologia , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/diagnóstico , Síndrome de Sweet/diagnóstico , Adolescente , Antidiscinéticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Biópsia/efeitos adversos , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Coreia/diagnóstico por imagem , Coreia/tratamento farmacológico , Complemento C3/análise , Diagnóstico Diferencial , Erros de Diagnóstico , Humanos , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Imageamento por Ressonância Magnética , Masculino , Pele/imunologia , Pele/patologia , Síndrome de Sweet/patologiaRESUMO
68-year-old female presented with involuntary movements. MRI was normal. Cerebrospinal fluid analysis was normal. whole body CT and biopsy confirmed diagnosis of metastatic adenocarnimoa. The autoimmune panel was positive for anti-Yo antibodies.
Assuntos
Anticorpos/sangue , Coreia/imunologia , Discinesias/imunologia , Proteínas do Tecido Nervoso/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Células de Purkinje/imunologia , Idoso , Coreia/sangue , Discinesias/sangue , Feminino , Humanos , Imageamento por Ressonância Magnética , Síndromes Paraneoplásicas do Sistema Nervoso/sangueRESUMO
Chorea, a movement disorder characterised by a continuous flow of unpredictable muscle contractions, has a myriad of genetic and non-genetic causes. Although autoimmune processes are rare aetiology of chorea, they are relevant both for researchers and clinicians. The aim of this article is to provide a review of the epidemiology, clinical and laboratory features, pathogenesis and management of the most common autoimmune causes of chorea. Emphasis is given particularly to Sydenham's chorea, systemic lupus erythematosus, primary antiphospolipid antibody syndrome, paraneoplastic chorea and anti-N-methyl-d-aspartate receptor encephalitis.
Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Coreia/epidemiologia , Coreia/imunologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Doenças Autoimunes do Sistema Nervoso/etiologia , Humanos , Lúpus Eritematoso Sistêmico/diagnósticoRESUMO
The mechanisms involved in the symptoms of Sydenham’s chorea (SC) remain obscure. Taking into account the autoreactive antibody-mediated hypothesis of SC pathogenesis, the persistence of chorea may be associated with increased levels of B1 lymphocytes and other lymphocyte subsets. We evaluated lymphocyte subsets, including B1 and T cells, in patients with remitted (RSC) and persistent (PSC) SC by flow cytometry. Our results showed neither difference in the frequency of T and B lymphocytes subpopulations nor in their activation and functional states. These findings undermine the view of PSC as a sustained cytotoxic cellular-mediated condition. Alternative mechanisms may explain the pathogenesis of PSC.
Os mecanismos subjacentes aos sintomas da coreia de Sydenham (CS) permanecem desconhecidos. Considerando-se a hipótese de que a patogênese da CS é mediada por anticorpos autorreativos, a persistência da coreia está provavelmente associada a níveis aumentados de linfócitos B1 e outros subtipos de linfócitos. No presente trabalho, foram avaliados subtipos de linfócitos B e T em pacientes com CS em remissão (CSR) e persistente (CSP), por citometria de fluxo. Nossos resultados demonstraram que não há diferença na frequência das subpopulações de linfócitos T e B circulantes e no perfil de ativação e estado funcional dessas células. Esses resultados enfraquecem a hipótese de que a CSP seja uma condição imune sustentada mediada por células citotóxicas. São necessários estudos que investiguem mecanismos alternativos que expliquem a patogênese da CSP.
Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Autoimunidade/fisiologia , Subpopulações de Linfócitos B/patologia , Coreia/imunologia , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos B/imunologia , Citometria de Fluxo , Contagem de Linfócitos , Subpopulações de Linfócitos T/imunologiaRESUMO
The mechanisms involved in the symptoms of Sydenham's chorea (SC) remain obscure. Taking into account the autoreactive antibody-mediated hypothesis of SC pathogenesis, the persistence of chorea may be associated with increased levels of B1 lymphocytes and other lymphocyte subsets. We evaluated lymphocyte subsets, including B1 and T cells, in patients with remitted (RSC) and persistent (PSC) SC by flow cytometry. Our results showed neither difference in the frequency of T and B lymphocytes subpopulations nor in their activation and functional states. These findings undermine the view of PSC as a sustained cytotoxic cellular-mediated condition. Alternative mechanisms may explain the pathogenesis of PSC.
Assuntos
Autoimunidade/fisiologia , Subpopulações de Linfócitos B/patologia , Coreia/imunologia , Subpopulações de Linfócitos T/patologia , Adolescente , Adulto , Subpopulações de Linfócitos B/imunologia , Feminino , Citometria de Fluxo , Humanos , Contagem de Linfócitos , Masculino , Subpopulações de Linfócitos T/imunologia , Adulto JovemRESUMO
In recent years, autoantibodies to proteins or receptors expressed on the surface of neurons have been detected in movement and psychiatric disorders. These autoantibodies can assist in better recognition of clinical syndromes and offer novel treatment opportunities via immunotherapies, potentially leading to improved patient outcome. In this review, we describe several autoimmune syndromes associated with movement and psychiatric disorders, including anti-N-methyl-d-aspartate receptor encephalitis, basal ganglia encephalitis, Sydenham chorea, and autoantibody-associated psychosis and schizophrenia. However, rather than focusing on clinical aspects of these diseases, as they have been reviewed in detail elsewhere, we mainly focus on the scientific aspects of the different methodologies for detecting antibodies, with an emphasis on the current gold standard in the field, the cell-based assay, and on issues related to the use of live versus permeabilized cells. We also reflect on the implications associated with the choice of patient serum and cerebrospinal fluid for antibody testing, on the mechanism of antibody entry into the central nervous system through the blood-brain barrier, and the essential issue of antibody pathogenicity.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/patologia , Imunoterapia/métodos , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Doenças Autoimunes/psicologia , Doenças Autoimunes/terapia , Doenças dos Gânglios da Base/patologia , Coreia/diagnóstico , Coreia/imunologia , Coreia/terapia , Humanos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/terapia , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Esquizofrenia/terapiaRESUMO
We reported a 72-year-old man with thymoma who presented with hemichorea. Although his brain CT and MRI revealed no abnormality, regional cerebral blood flow changes, identified by single photon emission computed tomography, suggested that the mechanism underlying the chorea seemed to be a dysfunction of the subthalamic nucleus and pallidum. His hemichorea was completely resolved after thymectomy. Absence of serum anti-neural autoantibodies, including small-cell lung carcinoma-related chorea anti-CRMP-5 antibody, suggests that mechanisms different from cross-talk neural-targeted tumor immune response can be responsible for the thymoma-associated paraneoplastic chorea.
Assuntos
Coreia/diagnóstico , Timoma/diagnóstico , Neoplasias do Timo/diagnóstico , Idoso , Anticorpos , Coreia/complicações , Coreia/imunologia , Humanos , Hidrolases , Masculino , Proteínas Associadas aos Microtúbulos , Proteínas do Tecido Nervoso/imunologia , Timoma/complicações , Neoplasias do Timo/complicaçõesRESUMO
Immune-mediated extrapyramidal movement disorders typically occur in previously healthy children. Immune-mediated movement disorders may occur as a postinfectious, paraneoplastic, or idiopathic process. Sydenham chorea (SC) is the classical poststreptococcal movement and psychiatric disorder, and may be associated with other features of rheumatic fever. The outcome is typically good, although residual chorea, psychiatric disturbance, and relapses are possible. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a syndrome of streptococcal-induced tics and obsessive-compulsive disorder. Although a number of investigators have reported an association between streptococcal infection and neuropsychiatric syndromes, the PANDAS hypothesis is controversial. Encephalitis lethargica is an encephalitic illness with parkinsonism, dyskinesias, and psychiatric disturbance as dominant features. The exact disease mechanism is not understood, although an autoimmune process is suspected. NMDA-R encephalitis is a new entity characterized by encephalitis with dramatic psychiatric disturbance, dyskinesias, cognitive alteration, and seizures. Patients have autoantibodies against the NMDA-R that appear to be pathogenic: immune therapies appear warranted to minimize disability. Movement disorders are also described associated with systemic lupus erythematosus and antiphospholipid syndrome. The differential diagnosis and investigation approach of acute-onset movement disorders are also discussed.
Assuntos
Doenças dos Gânglios da Base/imunologia , Coreia/imunologia , Doença de Parkinson Pós-Encefalítica/imunologia , Infecções Estreptocócicas/imunologia , Doenças dos Gânglios da Base/etiologia , Criança , Coreia/etiologia , Humanos , Doença de Parkinson Pós-Encefalítica/complicações , Infecções Estreptocócicas/complicaçõesRESUMO
PURPOSE OF REVIEW: To give an overview of the current hypotheses of the pathogenesis of rheumatic fever and group A streptococcal autoimmune sequelae of the heart valve and brain. RECENT FINDINGS: Human monoclonal antibodies (mAbs) derived from rheumatic heart disease have provided evidence for crossreactive autoantibodies that target the dominant group A streptococcal epitope of the group A carbohydrate, N-acetyl-beta-D-glucosamine (GlcNAc), and heart valve endothelium, laminin and laminar basement membrane. T cells in peripheral blood and in rheumatic heart valves revealed the presence of T cells crossreactive with streptococcal M protein and cardiac myosin. For initiation of disease, evidence suggests a two-hit hypothesis for antibody attack on the valve endothelium with subsequent extravasation of T cells through activated endothelium into the valve to form granulomatous lesions and Aschoff bodies. Autoantibodies against the group A streptococcal carbohydrate epitope GlcNAc and cardiac myosin and its peptides appear during progression of rheumatic heart disease. However, autoantibodies against collagen that are not crossreactive may form because of the release of collagen from damaged valve or to responses to collagen bound in vitro by certain serotypes of streptococci. In Sydenham chorea, human mAbs derived from disease target the group A carbohydrate epitope GlcNAc and gangliosides and dopamine receptors found on the surface of neuronal cells in the brain. Human mAbs and autoantibodies in Sydenham chorea were found to signal neuronal cells and activate calcium calmodulin-dependent protein kinase II (CaMKII) in neuronal cells and recognize the intracellular protein biomarker tubulin. SUMMARY: To summarize, pathogenic mechanisms of crossreactive autoantibodies which target the valve in rheumatic heart disease and the neuronal cell in Sydenham chorea share a common streptococcal epitope GlcNAc and target intracellular biomarkers of disease including cardiac myosin in the myocardium and tubulin, a protein abundant in the brain. However, intracellular antigens are not believed to be the basis for disease. The theme of molecular mimicry in streptococcal autoimmune sequelae is the recognition of targeted intracellular biomarker antigens such as cardiac myosin and brain tubulin, while targeting extracellular membrane antigens such as laminin on the valve surface endothelium or lysoganglioside and dopamine receptors in the brain. Antibody binding to these cell surface antigens may lead to valve damage in rheumatic heart disease or neuropsychiatric behaviors and involuntary movements in Sydenham chorea.
Assuntos
Cardiopatia Reumática/imunologia , Streptococcus pyogenes/imunologia , Antígenos de Bactérias/imunologia , Autoanticorpos/imunologia , Autoimunidade , Coreia/imunologia , Coreia/microbiologia , Reações Cruzadas/imunologia , Humanos , Mimetismo Molecular/imunologia , Neurônios/imunologiaRESUMO
Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.
Assuntos
Coreia/psicologia , Modelos Animais de Doenças , Transtornos Mentais/psicologia , Atividade Motora/imunologia , Infecções Estreptocócicas/psicologia , Streptococcus pyogenes , Adolescente , Animais , Autoanticorpos/biossíntese , Criança , Pré-Escolar , Coreia/imunologia , Coreia/microbiologia , Feminino , Asseio Animal/efeitos dos fármacos , Asseio Animal/fisiologia , Humanos , Masculino , Transtornos Mentais/imunologia , Transtornos Mentais/microbiologia , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/imunologiaRESUMO
OBJECTIVE: To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins. METHODS: We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293. RESULTS: The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups. CONCLUSIONS: Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.
Assuntos
Coreia/imunologia , Imunoglobulina G/metabolismo , Neurônios/metabolismo , Síndrome de Tourette/imunologia , Adolescente , Antineoplásicos/farmacologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Criança , Pré-Escolar , Coreia/sangue , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo , Estatísticas não Paramétricas , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/imunologia , Síndrome de Tourette/sangue , Tretinoína/farmacologiaRESUMO
Until now, there are no conclusive data about the mechanisms involved in motor symptoms of Sydenham's chorea (SC). Taking into account the autoreactive antibody-mediated hypothesis of SC pathogenesis, the SC may be associated with uncontrolled immune mechanisms. Besides the antibody hypothesis, the innate immune system has been underappreciated. Hence, we evaluated the activation state of monocytes, cells that are precursors of macrophages, to characterize the inflammation profile of patients. We assessed the surface molecules CD80, CD86, and human leukocyte antigen DR expression in patients with SC by flow cytometry analysis. Our results showed a decreased CD14(+) (monocyte) frequency, with concomitant increased CD14(-) frequency inside monocyte population. Although monocyte population showed a decreased human leukocyte antigen DR and CD86 frequencies, the CD14(-) population showed an increased frequency of CD80(+) monocyte from SC compared with controls. These data suggest that monocytes showed a reduced costimulatory potential in SC.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação/metabolismo , Coreia/imunologia , Coreia/patologia , Monócitos/metabolismo , Adolescente , Adulto , Apresentação de Antígeno , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Separação Celular , Células Cultivadas , Coreia/sangue , Feminino , Citometria de Fluxo , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Imunidade Inata , Masculino , Monócitos/imunologia , Monócitos/patologiaRESUMO
Antiphospholipid antibodies may cause various neurologic diseases by vascular and immune mechanisms. Ischemic stroke and transient ischemic attacks are the most common neurologic complications in patients with antiphospholipid antibodies but migraine, epilepsy, chorea, or multiple sclerosis also may occur. Although the neurologic presentation of patients with the antiphospholipid syndrome may vary, many patients have striking similarities, such as initial memory loss, aphasia, cognitive dysfunction with progressive cerebral deterioration, and even dementia. In conclusion, antiphospholipid syndrome may constitute a treatable cause of neurologic diseases, and the measurement of antiphospholipid antibodies should be routinely performed in patients with neurologic disorders.
Assuntos
Síndrome Antifosfolipídica/complicações , Doenças do Sistema Nervoso/etiologia , Animais , Anticorpos Antifosfolipídeos/imunologia , Coreia/etiologia , Coreia/imunologia , Transtornos Cognitivos/etiologia , Humanos , Camundongos , Transtornos de Enxaqueca/etiologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Mielite Transversa/etiologia , Mielite Transversa/imunologia , Doenças do Sistema Nervoso/imunologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Trombofilia/sangue , Trombofilia/etiologiaRESUMO
Sydenham's chorea is a CNS disorder and sequela of group A streptococcal infection where deposition of Abs in brain may result in movement and neuropsychiatric abnormalities. We studied human mAbs 24.3.1, 31.1.1, and 37.2.1 derived from chorea and selected for cross-reactivity with group A streptococci and brain Ags. Our novel findings reveal that Sydenham's chorea mAbs target a 55-kDa brain protein with an N-terminal amino acid sequence of MREIVHLQ corresponding to beta-tubulin. Chorea mAb specificity for purified brain tubulin was confirmed in ELISA and Western immunoblot, and significant levels of anti-tubulin IgG were found in acute chorea sera and cerebrospinal fluid. Lysoganglioside G(M1) inhibited binding of chorea mAbs to tubulin and mAb reactivity with human caudate and putamen brain sections was blocked by anti-tubulin mAb. The chorea mAbs labeled both intra- and extracellular Ags of a neuronal cell line providing evidence suggesting mimicry between intracellular brain protein tubulin and extracellular lysoganglioside. In addition, chorea mAb 24.3.1 and acute chorea sera induced calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. Nucleotide sequence analysis of the chorea mAb V(H) genes revealed that mAb 24.3.1 V(H) gene was encoded by the V(H)1 germline gene family which encodes other anti-ganglioside V(H) genes associated with motor neuropathies. mAb recognition of tubulin and the neuronal cell surface with initiation of cell signaling and dopamine release supports an emerging theme in autoimmunity whereby cross-reactive or polyreactive autoantibodies against intracellular Ags recognize cell surface epitopes potentially leading to disease.
Assuntos
Especificidade de Anticorpos , Autoanticorpos/metabolismo , Coreia/imunologia , Coreia/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Tubulina (Proteína)/imunologia , Tubulina (Proteína)/metabolismo , Adolescente , Animais , Anticorpos Monoclonais/análise , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Autoanticorpos/análise , Autoanticorpos/fisiologia , Sequência de Bases , Sítios de Ligação de Anticorpos , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/biossíntese , Linhagem Celular Tumoral , Feminino , Humanos , Hibridomas , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência MolecularRESUMO
Rheumatic fever (RF)/rheumatic heart disease (RHD) is an inflammatory disease with a complex etiology in which Group A streptococci within a genetically susceptible host untreated for strep-throat may deviate the innate and adaptive arms of the immune system towards recognition of autoantigens. The TNFA gene has been associated with a number of autoimmune diseases, including RF. We investigated whether the G-308A and G-238A polymorphisms of the TNFA gene are associated with clinical outcomes of RF in a cohort of 318 patients and 281 healthy controls (HC). Both polymorphisms showed borderline associations with RF (TNFA -308G/A, OR=1.4 [1-2.2], P=0.026; TNFA -238G/A, OR=1.9 [1-3.3], P=0.015). The presence of either one of the minor alleles (-308A and -238A) was more common among patients with RF/RHD than controls (P=0.0006). Stratification of patients according to clinical phenotype also showed significant associations between presence of either one of the minor alleles and RHD (Pc=0.0006) when compared with controls. This association was stronger with the development of aortic valve lesions. In contrast, there was no association between genotype and Sydenham's chorea or RF patients with mild carditis. In conclusion, we show that the TNFA is a susceptibility locus for RF. The ability to predict which RF patients will develop valve lesion may have therapeutic, economic and social implications.