Pittock, Sean J.

Abstract Aquaporin‐4 ( AQP 4) is a water channel protein that is most highly, but not exclusively, expressed in the central nervous system. In 2005 AQP 4 was shown to be the antigenic target of neuromyelitis optica‐immunoglobulin G ( NMO ‐IgG, or AQP 4‐IgG), an antibody found specifically in patients with NMO and in formes frustes of NMO , such as longitudinally extensive transverse myelitis (LETM) or optic neuritis (ON). This discovery facilitated the clinical, pathological, and radiological distinction of NMO and the spectrum of NMO ‐related disorders from classical multiple sclerosis. In addition to its use as a diagnostic tool, AQP 4‐IgG predicts a high risk of relapse in patients with a clinically isolated syndrome of either LETM or ON. As disability in NMO is attack‐related, early diagnosis and treatment are predicted to have a major effect on long‐term disability. Thus, the importance of sensitive and specific assays to detect AQP 4‐IgG cannot be overstated. Both academic institutions and commercial companies have developed assays to identify AQP 4‐IgG in patients' sera or cerebrospinal fluid. Both AQP 4 isoforms from different species have been used as the antigenic target in the form of frozen tissue sections in indirect immunofluorescence assays, partially purified protein for fluorescence immunoprecipitation assay, radioimmunoprecipitation assay or enzyme‐linked immunosorbent assay, or transfected into cells for cell based assays or flow cytometry. We carried out a systematic review of the literature reporting different methodologies used to identify AQP 4‐IgG, examine whether longitudinal AQP 4‐IgG titers predict relapses in seropositive patients, and attempt to establish a reasonable timeframe for retesting negative serum samples.

AbstractWater channels are a recognized “novel” target for central nervous system, inflammatory, autoimmune, demyelinating diseases, and represent an evolving spectrum of disorders termed neuromyelitis optica (NMO) spectrum disorders (SD). These disorders should now be considered under the umbrella term “autoimmune aquaporin‐4 channelopathy”. NMOSD represent the first multiple sclerosis (MS)‐like disease for which a specific antigen has been identified – the astrocytic water channel aquaporin‐4 (AQP4). MS lacks a distinguishing biomarker. This discovery represents a seismic shift from historic emphasis on the oligodendrocyte and myelin to the astrocyte. The NMO of today represents a relapsing spectrum of disease, not necessarily restricted to the optic nerves and spinal cord, that is different from the monophasic disorder in which near simultaneous bilateral optic neuritis and transverse myelitis occur, as was originally described by Devic. Recent clinical, radiological and pathological findings have documented brain involvement in NMO spectrum disorders, particularly in children. Most patients with NMOSD have brain abnormalities on magnetic resonance imaging, and these are consistent with MS in up to 10% of patients. Others have lesions in areas that highly express AQP4 including the circumventricular organs accounting for intractable nausea and vomiting, and the syndrome of inappropriate antidiuresis as presenting symptoms or heralds of relapse. Diencephalic involvement might explain recently recognized sleep disorders and endocrinopathies. Continued progress in our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of the clinical diagnostic criteria for NMO spectrum disorders. As the clinical spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4‐immunoglobulin G targeting extracellular epitopes of AQP4 cannot be overemphasized.