Update on anti-NMO IgG antibodies

Abstract

Neuromyelitis optica (NMO) or Devic’s syndrome is a severe idiopathic and relapsing, demyelinating disease characterised by optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM). 1 Neuropathologically, NMO is characterised by extensive demyelination with partial necrosis of the spinal cord white and grey matter, acute axonal injury, neutrophil and eosinophil infiltrates, IgG and IgM deposition and perivascular complement activation. NMO is distinguished from classical multiple sclerosis (MS) by clinical, neuroimaging, CSF and serological criteria. 1 The identification of NMO-IgG by indirect immunofluorescence (IIF) was initially described as a highly specific marker with the titre paralleling the disease activity. However, the sensitivity of IIF is variable (58–75%) for clinical NMO. Consequently, numerous methods using aquaporin 4 (AQP4) as the target antigen have been developed in an attempt to improve sensitivity. Apart from cell-based assays, these have failed to improve on the sensitivity of IIF. Recently, it has been demonstrated that NMO-IgG targets mainly the M-23 isoform of AQP4 that structurally organises itself into orthogonol arrays of particles in cell membranes. As AQP4-Ab recognises conformational epitopes, the lower sensitivity of all but the cell-based assays may be due to changes resulting during purification, fixation or other causes of NMO, i.e., parainfectious NMO. As indirect immunofluorescence is the most widely available method for detecting NMO-IgG, the Pathology Queensland experience has raised issues of the ‘true’ sensitivity of NMO-IgG testing for NMO as well as identifying other autoantibodies (including anti-reticulin and anti-nuclear antibodies) that cause interference and make IIF interpretation difficult. These issues may contribute to both false positive and false negative IIF results. Some authors have suggested 2 that the published sensitivities of NMO-IgG may be artificially high and this has prompted the proposed Australian and New Zealand NMO study designed to evaluate the sensitivity and specificity of all currently available methods for NMO-IgG.