Neurological syndromes associated with antibodies against the glutamic acid decarboxylase (GAD)
This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/666797 |
| Acceso en línea: | http://hdl.handle.net/10803/666797 |
| Access Level: | acceso abierto |
| Palabra clave: | Neuroimmunologia Neuroinmunología Neuroimmunology Immunoglobulines Inmunoglobulinas Immunoglobulins Autoimmunitat Autoinmunidad Autoimmunity Ciències de la Salut 616.8 |
| Sumario: | This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers in several autoimmune conditions affecting the endocrine system, the CNS or both simultaneously. High serum GAD-ab levels have expanded the neurological spectrum and have been described in patients with cerebellar ataxia (CA), epilepsy and limbic encephalitis (LE) of autoimmune origin. Even though all the syndromes share the same autoimmune biomarker, it may well be that GAD-ab have a different role in each syndrome. Whether all GAD-associated syndromes share the same pathogenic mechanisms, or what renders certain brain regions vulnerable to autoantibody attack is not clear. In recent years, other antibodies have been found in patients with neurological syndromes attributed to GAD-ab, such as antibodies directed against the alpha subunit of the glycine receptor (GlyRα1) in patients with syndromes of the stiff-person spectrum, or antibodies against GABA receptors (GABAA in patients with severe epilepsy, and GABAB in patients with limbic encephalitis, GAD-ab and an unknown lung cancer), yielding the possibility of an alternative immunological response coexisting with GAD autoimmunity that might be more relevant in certain neurological conditions. In this thesis we explored the immunological determinants linked to the different neurological phenotypes with state-of-the-art techniques, and investigated the prognostic value of GAD-ab in neurological disorders. After studying the largest cohort of patients (121) with neurological syndromes and GAD-ab, we found that: 1) the presence of additional antibodies against antigens of the inhibitory synapse or a different reactivity against particular GAD isoforms or sites of GAD65 do not explain the diversity of the clinical phenotype in non-paraneoplastic neurological syndromes associated with GAD-ab; 2) the immunological response against GAD is different in serum and CSF, indicating a process of antigen-driven intrathecal maturation in patients with non-paraneoplastic syndromes; 3) patients with cerebellar ataxia and GAD-ab may respond to immunotherapy, and maintain good functional status at long-term. Early initiation of treatment likely offers a greater chance of improvement; 4) neurological syndromes with paraneoplastic criteria in the context of GAD autoimmunity have a different clinical presentation and humoral immunity profile. Patients presenting neurological syndromes not typically associated with GAD-ab should be screened for an underlying cancer; 5) among patients with stiff-person spectrum disorders, the immunological classification is an independent predictor of outcome. Those patients with GAD-ab have worse prognosis than antibody-negative patients and patients with GlyR-ab. Our results confirmed that autoimmunity regarding the humoral response is similar among different neurological syndromes, and that GAD-ab is still the most important biomarker in these diseases. From a clinical perspective we contributed to fill some clinical gaps, like the value of GAD-ab in SPS, the management of patients with GAD-associated CA, and he clues to suspect paraneoplastic neurological syndromes. |
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