Wednesday, April 17, 2013

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Vanda A. Lennon, M.D., Ph.D., with the Departments of Laboratory Medicine and Pathology and Neurology, discusses research that identifies critical properties of neuromyelitis optica, a potentially debilitating neurological disease that is often misdiagnosed as multiple sclerosis (MS).

Dr. Lennon’s team isolated and identified an antibody unique to NMO that may interfere with the transport of the water. In some areas of autopsied brain tissue studied, there was an accumulation of water in the myelin itself that the team believes may lead to the secondary destruction of the myelin in NMO and potential misdiagnosis of NMO as MS.

The study was published online in the Proceedings of the National Academy of Sciences on Nov. 29, 2011.

ABSTRACT
The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues.

This report identifies two novel properties of NMO-IgG as determinants of pathogenicity: 

  • The binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG.
  • NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation.

We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings:

  • Reactive astrocytes with persistent foci of surface AQP4
  • Vacuolation in adjacent myelin consistent with edema

The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, iflammation, demyelination and necrosis.

Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes. 

Authors
Shannon Hinson, Ph.D., Michael F. Romero, Ph.D., Bogdan F. Popescu, M.D., Ph.D., Claudia F. Lucchinetti, M.D., James (Jim) P. Fryer, Hartwig Wolburg, Petra Fallier-Becker, Susan Noell, Vanda A. Lennon, M.D., Ph.D.

Source: http://physicianupdate.mayoclinic.org/2012/03/22/molecular-outcomes-of-neuromyelitis-optica-nmo-igg-binding-to-aquaporin-4-in-astrocytes/

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