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: 2.47).
04/2010; 221(1-2). DOI: 10.1016/j.jneuroim.2010.02.007
Neuromyelitis optica (NMO) is a devastating neuroinflammatory disorder that specifically targets the spinal cord and optic nerves. Aquaporin-4 (AQP4) is the target of the NMO-IgG biomarker. AQP4 is expressed as two isoforms: M1 and M23, which have different functions in the central nervous system (CNS). We characterized the expression pattern of these AQP4 isoform mRNAs in humans and found a pattern of AQP4 expression that correlates with NMO disease localization. The ratio of M1:M23 mRNA is highest in the optic nerve and spinal cord, followed by brainstem, then the cerebral and cerebellar cortices.
Available from: Veit Rothhammer
- "However, only M23 is arranged in large orthogonal arrays of particles (OAP) in the plasma membrane of AQP4 expressing cells . In an mRNA expression study, it has been suggested that M1 and M23 might be differentially expressed in various parts of the CNS with M1 prevailing in the optic nerve and spinal cord and M23 in the brain and cerebellum . It is not known whether M1 and M23 are also differentially targeted by NMO-IgG in vivo, which could explain in part the lesion distribution in the spinal cord and optic nerves of NMO patients. "
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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 · 3.23 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
Available from: Romain Marignier
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ABSTRACT: Devic's neuromyelitis optica (DNMO) is a demyelinating and inflammatory disease of the central nervous system (CNS) essentially restricted to the spinal cord and the optic nerves. It is a rare disorder with a prevalence estimated at less than 1/100,000 in Western countries. Since the first description by Eugène Devic in 1894, the relationship between DNMO and multiple sclerosis (MS) has been controversial. Recent clinical, epidemiological, pathological and immunological data demonstrate that MS and DNMO are distinct entities. This distinction between DNMO and MS is crucial, as prognosis and treatment are indeed different. DNMO is now considered to be an autoimmune, antibody-mediated disease especially since the identification of a specific serum autoantibody, named NMO-IgG and directed against the main water channel of the CNS, aquaporin-4 (AQP4). The assessment of AQP4 antibodies (Abs) has initially been proposed to differentiate DNMO and MS. It has also enlarged the clinical spectrum of DNMO and proved to be helpful in predicting relapses and conversion to DNMO after a first episode of longitudinally extensive transverse myelitis or isolated optic neuritis. Lastly, the discovery of the pathogenic role of AQP4 Abs in DNMO leads to a better understanding of detailed DNMO immunopathology and the elaboration of relevant novel treatment strategies specific to DNMO. In this review, we summarize the present and future therapeutic implications generated by the discovery of the various pathogenic mechanisms of AQP4 Abs in DNMO pathophysiology.
Therapeutic Advances in Neurological Disorders 09/2010; 3(5):311-21. DOI:10.1177/1756285610382478 · 3.14 Impact Factor
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