RESUMEN
OBJECTIVE: To investigate the potential role of circulating autoantibodies specific to neuronal cell surface antigens in the pathophysiology of neuropsychiatric disorders. METHODS: Two different kinds of immunoscreening approaches were used to identify autoantigens associated with neuropsychiatric disorders in the serum of patients with schizophrenia. The presence of autoantibodies specific to the identified autoantigens was then tested in patients with various psychiatric disorders and in patients with systemic lupus erythematosus (SLE) and concomitant neuropsychiatric manifestations. Furthermore, the potential pathogenic role of these autoantibodies was assessed both in vitro and in vivo. RESULTS: GAPDH was identified as a novel autoantigen associated with neuropsychiatric disorders. Serum anti-GAPDH IgG was detected in the serum of 51% of patients with schizophrenia and 50% of patients with major depression. Moreover, SLE patients with comorbid psychiatric manifestations presented significantly higher serum levels of anti-GAPDH antibodies than did SLE patients without psychiatric manifestations (P = 0.004 by chi-square test). Of note, a significant positive correlation (R = 0.48, P = 0.0049, by Spearman's rank correlation test) was found between the levels of serum anti-GAPDH antibodies and cognitive dysfunction in patients with SLE. In vitro analysis of the effects of purified human anti-GAPDH autoantibodies on SH-SY5Y cells showed an immediate neurite retraction. Finally, in vivo administration of anti-GAPDH autoantibodies in the right cerebral ventricle of C57BL/6J mice resulted in specific behavioral changes associated with a detrimental cognitive and emotional profile. CONCLUSION: Overall, these data suggest that anti-GAPDH autoantibodies play a role in the pathogenesis of neuropsychiatric disorders, thus representing a potentially promising tool for the screening of individual vulnerability to these disabling conditions.
Asunto(s)
Autoanticuerpos/inmunología , Trastorno Bipolar/inmunología , Disfunción Cognitiva/inmunología , Trastorno Depresivo Mayor/inmunología , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Esquizofrenia/inmunología , Adulto , Animales , Autoanticuerpos/farmacología , Autoantígenos , Conducta Animal/efectos de los fármacos , Biomarcadores , Línea Celular Tumoral , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Femenino , Humanos , Inmunoglobulina G/inmunología , Inyecciones Intraventriculares , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuritas/efectos de los fármacos , Adulto JovenRESUMEN
Although the psychotic phenomena of schizophrenia have been extensively investigated, somatic delusions and hallucinations have seldom been reported and their mechanisms are substantially unexplored. Here, we aimed to identify the brain structural correlates of somatic psychotic phenomena using combined volumetry and diffusivity structural neuroimaging techniques. Seventy-five individuals with a DSM-IV-TR diagnosis of schizophrenia and 75 healthy controls (HC) underwent a comprehensive clinical assessment, a high-resolution T1-weighted magnetic resonance imaging and a diffusion tensor imaging protocol using a 3T MRI scanner. Voxel-based volumetry and mean diffusivity (MD) of gray matter (GM) and fractional anisotropy (FA) of white matter (WM) of the whole brain were calculated for each subject. Reduced left fronto-insular GM volume was found in patients with somatic delusions compared with patients without somatic delusions and HC. Increased GM volume was found in the bilateral thalami, primarily in the right ventral-anterior thalamic nucleus projecting to the prefrontal-temporal cortices and the bilateral pars triangularis of the inferior frontal lobe, of patients with somatic hallucinations and HC compared with patients without somatic hallucinations. No differences emerged in GM MD and in WM FA between patients with and without psychotic somatic phenomena (i.e. delusions or hallucinations). These findings provide the first evidence that a frontal-thalamic structural perturbation mediates somatic psychotic phenomena in schizophrenia.