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Title: Clinical delineation and immunopathogenesis of autoimmune encephalitis
Author: Varley, James
ISNI:       0000 0004 8507 6644
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Neuroglial surface antibody (NSAb)-mediated diseases are autoimmune brain diseases including autoimmune encephalitis (AE). Early immunotherapy improves outcome making prompt diagnosis crucial. In N-methyl D-aspartate receptor antibody encephalitis (NMDAR-AbE), improved description of the associated movement disorder (MD) should aid early recognition. Similarly, clarifying the purported association between NMDAR-antibodies and systemic lupus erythematosus (SLE) would help clinicians. Finally, the underlying immunology in patients with AE secondary to leucinerich glioma inactivated protein-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies remains unexplored and a likely source of novel, targeted immunotherapies. To improve recognition, MD experts rated 76 videos of 34 patients with NMDAR-AbE. The associated MD was described as a characteristic triad of dystonia, chorea and stereotypy, distributed across the body and variable over time. Patients with NMDARAbE are defined by the presence of conformationally-sensitive autoantibodies, these were not found in patients with neuropsychiatric SLE. In fact, existing linear protein assay techniques demonstrated high artefact rates. This suggested a lack of autoantibodies with pathogenic potential in NPSLE. In a different form of AE, a novel class II HLA association was demonstrated in 48% of CASPR2-antibody patients (HLA-DRB1*11:01, n=31) and a known association was confirmed in 91% of LGI1-antibody patients (HLA-DRB1*07:01, n=68). This suggested an important role for T helper cells and, experimentally, evidence was found of antigenspecific T cells in these patients. Individuals with CASPR2-antibodies and HLADRB1* 11:01 had higher autoantibody titres and less clinical improvement with immunotherapy. Lymphocytes from these patients, when cultured, produced CASPR2- antibody matching serum CASPR2-antibody subclass and epitope-specificity. However, a marker of germinal centre activity, serum CASPR2-IgM, was seen only rarely. CASPR2- antibody patients carrying HLA-DRB1*11:01 produced more autoantibody in culture and to a wider range of CASPR2-epitopes in culture and serum. This may explain the poorer response to immunotherapy seen in these patients, highlighting the B-T cell interface as a key therapeutic target.
Supervisor: Irani, Sarosh ; Waters, Patrick Sponsor: Association of British Neurologists ; Guarantors of Brain ; OBRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available