Autoantibodies in CNS Trauma and Neuropsychiatric Disorders: A New Generation of Biomarkers

Central nervous system (CNS) trauma is a growing public health concern resulting from various types of cerebral insults, leading to acute neurological and non-neurological manifestations that can leave life-long consequences. To date, there are no standardized therapeutic and management protocols dealing with brain trauma. Current research is uncovering novel biomarkers that can aid in diagnosis, management and therapy. Current status of brain injury biomarkers includes the presence, absence or altered expression levels of certain neural (neuronal astrocytic or glial) related genes/proteins, protein degradation products and microRNAs which are discussed in different chapters of this book. Recently, there has been an increased interest in the new emerging role of autoantibodies—which have been long identified—as new generation biomarkers in the areas of neurotrauma, neuropsychiatric disorders and neurotoxicity. In this chapter, we will discuss the genesis and implications of autoantibodies in neurotrauma; focusing on the area of spinal cord injury (SCI) and shedding light on recent application in traumatic brain injury (TBI). In addition, the potential pathogenic mechanistic role of autoantibodies in the areas of Autism spectrum disorder (ASD) and neurotoxicity will be evaluated as this may reflect on the neural injury observed in brain trauma. The key value of these new generation biomarkers is that—unlike their corresponding autoantigens that may serve as acute markers of injury—these identified autoantibodies represent long-lasting, chronic signature biomarkers that can be associated with advanced chronic stages of injury sequelae. Such work has the potential to be applied in the fields of neurotrauma and neuropsychiatric fields that may reflect underlying mechanisms and can be utilized for diagnosis, staging and treatment guidance as well as be the target for therapy. Autoimmune diseases, characterized by the presence of autoantibodies, affect about 5%–7% of the world’s population; 3% of these are brain reactive autoantibodies with no overt effects (Diamond et al., 2013; Fairweather and Rose, 2004; National Institutes of Health Autoimmune Diseases Coordinating Committee Report, 2002). These brain-specific autoantibodies have a restricted access to our brain tissues unless under pathologic conditions (Diamond et al., 2013). Autoimmune response mechanisms have been observed in a number of CNS disorders involving multiple sclerosis (MS), paraneoplastic syndromes, brain trauma, and dementia-related disorders (Cross et al., 2001; Popovic et al., 1998; Sjogren and Wallin, 2001). A number of neurological disorders are associated with blood–brain barrier (BBB) disruption or increased permeability observed in Alzheimer disease (AD), stroke, TBI, and schizophrenia (Fazio et al., 2004; Marchi et al., 2003, 2004; Neuwelt et al., 2011). Injury to the BBB such as in brain injury may lead to the release of intracellular proteins either intact or proteolytic fragments from protease activation into the cerebrospinal fluid (CSF) or blood stream. The leakage of such entities into the circulation may lead to the formation of autoantibodies that have been defined as brain-reactive antibodies that recognize self- (auto-) antigens i.e., an antigen that is normally found in a subject tissue or cell or organelles. For a schematic representation of the above mechanism, please refer to Figure 29.1. Several hypotheses have been proposed for the development of these brain-specific autoantibodies and it has been argued whether their presence contributes to the pathogenic outcome of the disease in question or maybe they are epiphenomenal in nature. Recent studies by Davies and Skoda have indicated that patients with SCI or TBI would develop autoantibodies that target a number of CNS self-antigens including GM1 gangliosides, myelin-associated glycoprotein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors, and β-III-tubulin and nuclear antigens (Davies et al., 2007; Skoda et al., 2006). Based on the data presented by Ankeny in the area of SCI and by Zhang and Marchi in the areas of TBI (Ankeny and Popovich, 2010; Marchi et al., 2013a; Zhang et al., 2014), it is reasonable to regard the presence of an actual anti-brain reactivity as a potential threat to brain tissue integrity (Rudehill et al., 2006). As such, there is an increased interest in this newly discovered mine of biomarkers for several reasons. Autoantibodies can be correlated to disease activity/severity and are shown to be related to particular clinical manifestation or tissue injury presenting years before disease onset and may constitute potential biomarkers of the disease. Autoantibodies act as a predictive marker of disease occurrence and valuable indicators for therapeutic response to biologics as well as to side effects. These autoantibodies can be a useful tool for diagnosis and management relevant to organ-specific or non–organ-specific disorders (Tron, 2014). Several brain-derived autoantibodies are presented in Table 29.1.