Differential expression of aquaporin-4 isoforms localizes with neuromyelitis optica disease activity

Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
Journal of neuroimmunology (Impact Factor: 2.79). 04/2010; 221(1-2). DOI: 10.1016/j.jneuroim.2010.02.007
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    ABSTRACT: Antibodies to the water channel protein aquaporin-4 (AQP4), which is expressed in astrocytic endfeet at the blood brain barrier, have been identified in the serum of Neuromyelitis optica (NMO) patients and are believed to induce damage to astrocytes. However, AQP4 specific T helper cell responses that are required for the generation of anti-AQP4 antibodies and most likely also for the formation of intraparenchymal CNS lesions have not been characterized. Using overlapping 15-meric peptides of AQP4, we identified the immunogenic T cell epitopes of AQP4 that are restricted to murine major histocompatibility complex (MHC) I-A(b). The N-terminal region of AQP4 was highly immunogenic. More precisely, the intracellular epitope AQP4(22-36) was detected as major immunogenic determinant. AQP4(82-108) (located in the second transmembrane domain), AQP4(139-153) (located in the second extracellular loop), AQP4(211-225) (located in the fifth transmembrane domain), AQP4(235-249) (located in the sixth transmembrane domain), as well as AQP4(289-306) in the intracellular C-terminal region were also immunogenic epitopes. AQP4(22-36) and AQP4(289-303) specific T cells were present in the natural T cell repertoire of wild type C57BL/6 mice and T cell lines were raised. However, active immunization with these AQP4 peptides did not induce signs of spinal cord disease. Rather, sensitization with AQP4 peptides resulted in production of IFN-γ, but also IL-5 and IL-10 by antigen-specific T cells. Consistent with this cytokine profile, the AQP4 specific antibody response upon immunization with full length AQP4 included IgG1 and IgG2, which are associated with a mixed Th2/Th1 T cell response. AQP4 is able to induce an autoreactive T cell response. The identification of I-A(b) restricted AQP4 specific T cell epitopes will allow us to investigate how AQP4 specific autoimmune reactions are regulated and to establish faithful mouse models of NMO that include both cellular and humoral responses against AQP4.
    PLoS ONE 01/2011; 6(1):e16083. DOI:10.1371/journal.pone.0016083 · 3.53 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO), or Devic's disease, is a rare demyelinating disorder of the central nervous system that has a predilection for the optic nerve and spinal cord. Magnetic resonance imaging (MRI) is required to diagnose NMO. Longitudinally extensive transverse myelitis is NMO's imaging hallmark and the presence of a brain MRI that is not diagnostic of multiple sclerosis (MS) also remains part of the diagnostic criteria. It is increasingly recognised that MS and NMO brain imaging can, however, have similar appearances but differences do exist: hypothalamic, periaqueductal grey and area postrema lesions implicate NMO whilst cortical, U-fibre or Dawson's finger lesions are suggestive of MS. The timing of image acquisition, age, ethnicity and aquaporin-4 antibody status are all likely to alter the findings at MRI. This review therefore aims to overview and update the reader on NMO imaging, to provide clinically relevant guidance for diagnosing NMO and differentiating it from MS in order to guide management, and to highlight recent research insights.
    Multiple Sclerosis 05/2014; 20(9). DOI:10.1177/1352458514531087 · 4.86 Impact Factor
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    ABSTRACT: An approach to augmenting the energy multiplication of fusion reactor blankets is proposed. It consists of including, in the blanket, a high- Q element in a fluid state, thereby allowing removal of its contribution to afterheat in case of a loss-of-coolant accident (LOCA). The two general design approaches proposed are including Mn or Cr-containing particles within a gas coolant, and using MnF<sub>2</sub> or CrF<sub>2</sub> in a molten salt system. A preliminary feasibility study indicates that both approaches could be practical, so that a more thorough assessment is recommended
    Fusion Engineering, 1989. Proceedings., IEEE Thirteenth Symposium on; 11/1989

Harleen Saini