Antibodies against neuronal surface proteins in central nervous system disorders

Giannoccaro, Maria Pia (2019) Antibodies against neuronal surface proteins in central nervous system disorders, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie, 31 Ciclo. DOI 10.6092/unibo/amsdottorato/8842.
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Over the last two decades, the discovery of antibodies directed against neuronal surface antigens in patients with different forms of encephalitis has provided a basis for immunotherapies in previously undefined disorders. These important findings have raised questions regarding the role of neuronal antibodies in patients with other possibly immune-mediated diseases. Nevertheless, the pathogenicity of specific neuronal surface antibodies has not been adequately demonstrated in animal models. The presence of neuronal surface antigens in other disorders was examined by three approaches in patients with narcolepsy type 1, in patients with chronic neurological conditions (temporal lobe epilepsy and patients with neurodegenerative disorders), and in healthy and other disease controls. To establish an animal model, antibodies against contactin-associated protein 2 (CASPR2) were injected intraperitoneally daily into mice that were given a single lipopolysaccharide injection to open the blood brain barrier. Behavioural performance was studied over five days, and the mouse brains carefully investigated for presence of bound antibodies and neuropathological changes. Overall, patients with central nervous system disorders showed a higher frequency of antibodies compared to controls, but no antibodies specific to any one disorder were identified. Mice with high serum CASPR2 antibodies showed altered working memory and anxiety-like behaviours only in a social context. There were human immunoglobulins bound to the brain parenchyma along with a mild Purkinje cell loss and astrocytosis in the cerebellum, increased c-fos expression in the piriform-entorhinal cortex and hypothalamus, and microglial and astrocyte activation. These results not only support a pathogenic role for CASPR2 antibodies but provide the first demonstration in this field that a brief opening of the blood brain barrier is sufficient to allow access of antibodies into the brain with behavioural and neuropathic consequences. These findings are of relevance to other neuronal antibodies and stimulate further work in the field.

Tipologia del documento
Tesi di dottorato
Giannoccaro, Maria Pia
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Neuroimmunology, neuronal surface antigens, CASPR2, animal model, central nervous system, narcolepsy, autoimmune epilepsy, neurodegenerative disorders
Data di discussione
12 Aprile 2019

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