Anti-aquaporin-4 antibodies in neuromyelitis optica: how to prove their pathogenetic relevance?

Abstract

The discovery of a specific autoantibody response in neuromyelitis optica (NMO) patients, which selectively targets astrocytic end feet at the glia limitans1 and which is directed against the water channel aquaporin-4 (AQP-4)2 was a milestone in defining this disease entity and profoundly changed our view regarding its pathogenesis.3 Indirect evidence, coming from clinical observations and pathology strongly suggest that these autoantibodies play a major role in driving the disease process. The pathological hallmark of NMO lesions is a very selective and characteristic deposition of immunoglobulins and complement on astrocytes at the glia limitans, which is associated with destruction and loss of glial fibrillary acidic protein and AQP-4 positive astrocytes in fresh lesions4 to 6 followed by demyelination and global tissue destruction. As in other antibody-mediated diseases, granulocytes, and in particular eosinophils, are a major component of the inflammatory infiltrates.4 Furthermore, the distribution of the lesions in the brain and spinal cord of NMO patients correlates with the extent of regional AQP-4 expression.6,7 Most importantly, therapies, which eliminate antibodies (plasma exchange),8 or which target Blymphocytes (anti-CD20 antibodies),9 are at least in part effective in NMO patients. Based on this evidence NMO is now considered an antibody-mediated autoimmune disease, however, direct proof of the pathogenic potential of AQP-4 antibodies is so far lacking.