**Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases**

Simone Mader1, Benjamin Obholzer2 and Markus Reindl1 *1Clinical Department of Neurology, Innsbruck Medical University 2University of Innsbruck Austria* 

#### **1. Introduction**

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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 anti-AQP4 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

Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 165

Fig. 1. Discovery of autoantibodies and their target antigens in different CNS diseases.

MS is the most frequent inflammatory demyelinating disease in young adults with a high risk of future disability and a heterogeneous clinical presentation (Noseworthy et al., 2000). Approximately 2.5 million people are affected, experiencing different disease courses. In the majority of patients (85-90%), the disease follows a relapsing–remitting course (RR-MS), characterized by acute relapses and subsequent complete or incomplete remission (Sospedra & Martin, 2005). RR-MS patients often convert into a secondary progressive disease course (SP-MS) (Sospedra & Martin, 2005). In contrast, a minority of patients suffer from the primary-progressive disease course (PP-MS, 10-15%) with a steady disease progression (Sospedra & Martin, 2005). Although the etiology of MS remains unresolved, currently it is believed that components of the myelin sheath are attacked by autoreactive T cells involving the cellular and humoral immune system (Sospedra & Martin, 2005). This infiltration of inflammatory cells within the CNS results in inflammation, thus leading to demyelination of the myelin sheaths, which cover the nerve fibers. Brain MRI shows typically multiple white matter lesions, with frequent development of new lesions. In the last decade, increasing research is focusing on the relevance of B cells and antibodies in MS, investigating their role and contribution in the initiation and propagation of inflammatory demyelinating processes

In at least a subset of MS patients, pathogenic antibodies are believed to cause demyelination and axonal loss. This resulted in an extensive research in order to identify the still unknown target antigen. The detection of intrathecal IgG synthesis and the occurrence of oligoclonal bands (OCB) in the CSF of more than 90% of MS patients supports the impact

**2. B cells and antibodies in MS** 

at different disease stages (Figure 2).


the relevance of autoantibodies for the classification of neurological diseases and discuss novel findings of a potential involvement of T cells in NMO.

Table 1. Important human inflammatory demyelinating diseases. IFN-ß = interferon-beta, GA = glatiramer acetate, AZT = azathioprine, MRI = Magnetic resonance imaging, OCB = oligoclonal bands.

Controversial results regarding the detection of autoantibodies to myelin oligodendrocyte glycoprotein (MOG) in patients with MS have confused researchers for several years. Latest findings showed increased anti-MOG antibody titers in a subgroup of patients with acute disseminated encephalomyelitis (ADEM) and childhood MS, but not in adult MS (O'Connor et al., 2007; Brilot et al., 2009; Di Pauli et al., 2011; Lalive et al., 2011). The target antigen MOG is expressed on the outer surface of the myelin sheath (Figure 1) and can only be detected using cell based assays expressing MOG on their surface. Early stratification from MS is of great relevance as ADEM is usually a self-limiting disease. However, due to the high number of anti-MOG antibody negative ADEM patients, early diagnosis remains challenging in some cases.

An early detection of autoantibodies to the NMDA (*N*-methyl *D*-aspartate) receptor is crucial in anti**-**NMDA**-**receptor encephalitis, an acute form of encephalitis, which can have a neuropsychiatric presentation, seizures, dyskinesias or autonomic instability (Dalmau et al., 2007). This disease is potentially reversible if it is recognized and treated as early as possible. In paraneoplastic courses a removal of the tumour is mandatory, but NMDA-receptor encephalitis can also be non-paraneoplastic and affect both genders. Detection of antibodies to the neuronal cell surface antigen NMDA-receptor (NMDA-R, Figure 1) in serum of patients supported a better understanding of the disease pathomechanism. In this chapter we will report on the latest findings of autoantibodies in CNS diseases, primarily focusing on anti-AQP4 antibodies in NMO, the relevance of anti-MOG antibodies in ADEM and MS and antibodies to NMDA-R in anti-NMDA-receptor encephalitis.

Fig. 1. Discovery of autoantibodies and their target antigens in different CNS diseases.
