Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases

Abstract

In the last decade research on autoantibodies in neurological diseases of the central nervous system (CNS) has been very successful. An increasing number of autoantibodies and their target antigens have been detected, supporting stratification of patients and enabling specific treatment. The detection of autoantibodies depends on the assay used, as antibody binding requires the native conformation of the antigen. Although cumulative data is suggesting an important role of B cells and antibodies in Multiple Sclerosis (MS), numerous studies failed to identify specific biomarkers for MS (Figure 1). Even though several clinical, immunological and radiological studies tried to discover risk factors for disease progression, it remains an open issue to predict the individual disease course. However, recently autoantibodies have been discovered in some rare CNS demyelinating disease closely resembling MS (Table 1). Particularly Neuromyelitis Optica (NMO) gained enormous interest due to the discovery of autoantibodies targeting the water channel protein aquaporin-4 (AQP4) (Lennon et al., 2004; Lennon et al., 2005), which is expressed on astrocytic endfeet at the blood brain barrier (Nicchia et al., 2004) (Figure 1). This inflammatory demyelinating disease represents itself with optic neuritis and longitudinally extensive transverse myelitis (Wingerchuk et al., 1999) and was long considered as a severe variant of MS. Due to the detection and validation of this highly sensitive and specific biomarker, NMO is now regarded as a separate disease entity to MS. Consequently, the anti-AQP4 antibody serostatus was included into the diagnostic criteria of NMO (Jarius et al., 2007; Wingerchuk et al., 2007). Compared to MS, patients with NMO have a worse prognosis and require different treatment strategies according to the dominant humoral immunopathogenesis. With the advent of anti-AQP4 antibodies as biomarkers in NMO spectrum disorders (NMOSD), different NMO antibody assays have been developed, whereby cell based assays using the M23 isoform of AQP4 yield highest sensitivity (Takahashi et al., 2007; Waters & Vincent, 2008; Mader et al., 2010). Despite the high percentage of antiAQP4 IgG positive NMO patients, various studies described a lack of these autoantibodies in a cohort of NMO patients, which we will critically discuss in this chapter. It remains an open question whether these patients form their own subgroup of NMO patients or if the antibodies are not detected due to a sensitivity problem of the applied assays. Moreover, we will address