'Moonlighting' surface antigens: a paradigm for autoantibody pathogenicity in neurology?

Abstract

This scientific commentary refers to ‘Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition’ by Werner et al. (doi:10.1093/awv324). The field of CNS autoantibody-mediated diseases has provided a new source of potentially treatable neurological conditions, with pathophysiology that is of increasing interest to neurologists, immunologists and neuroscientists (Irani et al. , 2014). These syndromes can feature seizures, cognitive impairment, movement disorders, dysautonomia, rigidity or startle. Most of the more recently discovered autoantibodies target the extracellular domain of natively-expressed neuronal surface proteins, and have the potential to be pathogenic if they gain access to their antigens in vivo . These syndromes are often treatable and only a minority are associated with malignant tumours (Leypoldt et al. , 2015; Varley et al. , 2015). By contrast, the more established paraneoplastic antigens, such as Hu, Yo and Ma2, are associated with malignant tumours and a poor response to immunotherapies. These antibodies are directed to intracellular proteins and are not thought to be pathogenic. Concordantly, antibody passive transfer experiments have yielded negative results (Tanaka et al. , 1995). This is one reason why the pathogenesis of the autoantibody-associated disease stiff-person syndrome (SPS) remains enigmatic. The most common antibodies in SPS target the intracellular enzyme glutamic acid decarboxylase (GAD). However, the possible role of GAD antibodies in disease causation has been somewhat superseded by the discovery that GAD antibodies coexist with neuronal surface antibodies with causative potential (Lancaster et al. , 2010; Chang et al. , 2013). Antibodies against …