4 results on '"M Woodhall"'
Search Results
2. Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica.
- Author
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Wilson R, Makuch M, Kienzler AK, Varley J, Taylor J, Woodhall M, Palace J, Leite MI, Waters P, and Irani SR
- Subjects
- Adult, Aged, Cells, Cultured, Correlation of Data, Cytokines metabolism, Female, Flow Cytometry, Humans, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Male, Middle Aged, PAX5 Transcription Factor genetics, PAX5 Transcription Factor metabolism, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-6 metabolism, RNA, Messenger metabolism, X-Box Binding Protein 1 genetics, X-Box Binding Protein 1 metabolism, Aquaporin 4 immunology, Autoantibodies blood, B-Lymphocytes metabolism, Neuromyelitis Optica blood, Neuromyelitis Optica pathology
- Abstract
Autoantibodies to aquaporin-4 (AQP4) are pathogenic in neuromyelitis optica spectrum disorder (NMOSD). However, it is not known which B cells are the major contributors to circulating AQP4 antibodies nor which conditions promote their generation. Our experiments showed CD19+CD27++CD38++ circulating ex vivo antibody-secreting cells did not produce AQP4 antibodies under several culture conditions. To question whether other cells in circulation were capable of AQP4 antibody production, B cells were differentiated into antibody-secreting cells in vitro. Unfractionated peripheral blood mononuclear cells, isolated from 12 patients with NMOSD and a wide range of serum AQP4 antibody levels (91-26 610 units), were cultured with factors that mimicked established associations of NMOSD including T cell help, concurrent infections and cytokines reported to be elevated in NMOSD. Overall, the in vitro generation of CD19+CD27++CD38++ cells across several culture conditions correlated closely with the total IgG secreted (P < 0.0001, r = 0.71), but not the amount of AQP4 antibody. AQP4 antibody production was enhanced by CD40-ligand (P = 0.005), and by interleukin-2 plus toll-like receptor stimulation versus interleukin-21-predominant conditions (P < 0.0001), and did not require antigen. Across NMOSD patients, this in vitro generation of AQP4 antibodies correlated well with serum AQP4 antibody levels (P = 0.0023, r = 0.81). To understand how early within B cell lineages this AQP4 specificity was generated, purified B cell subsets were activated under these optimized conditions. Naïve pre-germinal centre B cells (CD19+CD27-IgD+) differentiated to secrete AQP4 antibodies as frequently as post-germinal centre cells (CD19+CD27+). Taken together, these human cell-culture experiments demonstrate that preformed B cells, rather than ex vivo circulating antibody-secreting cells, possess AQP4 reactivity. Their differentiation and AQP4 antibody secretion is preferentially driven by select cytokines and these cells may make the dominant contribution to serum AQP4 antibodies. Furthermore, as AQP4-specific B cells can derive from likely autoreactive naïve populations an early, pre-germinal centre loss of immunological tolerance appears present in some patients with NMOSD. This study has implications for understanding mechanisms of disease perpetuation and for rational choice of immunotherapies in NMOSD. Furthermore, the in vitro model presents an opportunity to apply condition-specific approaches to patients with NMOSD and may be a paradigm to study other antibody-mediated diseases.awy010media15732448284001.
- Published
- 2018
- Full Text
- View/download PDF
3. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
- Author
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Carvajal-González A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, Lang B, Pettingill P, Carr A, Sheerin UM, Press R, Press R, Lunn MP, Lim M, Maddison P, Meinck HM, Vandenberghe W, and Vincent A
- Subjects
- Adolescent, Adult, Aged, Animals, Antibodies cerebrospinal fluid, Child, Child, Preschool, Comorbidity, Encephalomyelitis drug therapy, Encephalomyelitis epidemiology, Encephalomyelitis physiopathology, Epilepsies, Myoclonic epidemiology, Female, Glutamate Decarboxylase immunology, HEK293 Cells, Humans, Infant, Male, Middle Aged, Muscle Rigidity drug therapy, Muscle Rigidity epidemiology, Muscle Rigidity physiopathology, Myoclonus drug therapy, Myoclonus epidemiology, Myoclonus physiopathology, Neoplasms epidemiology, Outcome Assessment, Health Care, Potassium Channels, Voltage-Gated immunology, Prospective Studies, Rats, Stiff-Person Syndrome drug therapy, Stiff-Person Syndrome epidemiology, Stiff-Person Syndrome physiopathology, Syndrome, Young Adult, Antibodies blood, Encephalomyelitis immunology, Muscle Rigidity immunology, Myoclonus immunology, Receptors, Glycine immunology, Stiff-Person Syndrome immunology
- Abstract
The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2014
- Full Text
- View/download PDF
4. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan.
- Author
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Kitley J, Leite MI, Nakashima I, Waters P, McNeillis B, Brown R, Takai Y, Takahashi T, Misu T, Elsone L, Woodhall M, George J, Boggild M, Vincent A, Jacob A, Fujihara K, and Palace J
- Subjects
- Adult, Age of Onset, Aged, Blindness, Cross-Cultural Comparison, Disability Evaluation, Disease Progression, Ethnicity, Female, Humans, In Vitro Techniques, Japan epidemiology, Kaplan-Meier Estimate, Longitudinal Studies, Male, Middle Aged, Motor Activity, Nervous System Diseases blood, Nervous System Diseases immunology, Nervous System Diseases pathology, Neuromyelitis Optica blood, Neuromyelitis Optica epidemiology, Retrospective Studies, Statistics, Nonparametric, United Kingdom epidemiology, Visual Acuity physiology, Antibodies blood, Aquaporin 4 immunology, Neuromyelitis Optica diagnosis, Neuromyelitis Optica immunology
- Abstract
Neuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of <6/36 in the best eye), motor disability (permanent inability to walk further than 100 m unaided), wheelchair dependence and mortality. Data were collected largely retrospectively through review of case records. After median disease duration of 75 months, 18% had developed permanent bilateral visual disability, 34% permanent motor disability, 23% had become wheelchair dependent and 9% had died. Age at disease onset appeared to be an important predictor of disability type. Young-onset patients in the UK, but not the Japanese cohort, commonly presenting with optic neuritis, had a high risk of visual disability while older patients in both cohorts had a high risk of motor disability, regardless of their onset symptom. Genetic factors also appeared important. The UK cohort seemed to have more severe disease than the Japanese cohort, with more severe onset attacks, a higher relapse frequency and greater disability at follow-up, despite earlier immunosuppression. Moreover, within the UK cohort, there were important differences between ethnic groups, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and higher likelihood of visual disability than Caucasian patients. Thus, age at disease onset and genetic factors are both likely to be important in determining clinical outcomes in aquaporin-4 disease. This has important implications for interpreting clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies, since clinical features and outcomes appear not to be generic across populations and may need to be tailored to individual groups. These factors need to be explored further in future prospective neuromyelitis optica and neuromyelitis optica spectrum disorder studies.
- Published
- 2012
- Full Text
- View/download PDF
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