29.1. INTRODUCTION

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.

FIGURE 29.1

The trajectory and genesis of autoantibodies as potential biomarkers. Upon neurotrauma to the CNS, several pathologic events are activated, including a breach in the BBB coupled with the activation of injurious pathways (e.g., excitotoxicity, necrosis, (more...)

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.

TABLE 29.1

Summary of Autoantibodies and their Targets in Relation to Neurological and Nonneurological Diseases

29.2. BBB, IMMUNE SYSTEM, MOLECULAR MIMICRY, AND CNS INTERACTION

The CNS has a delicate interaction with the immune system. The CNS immune homeostasis is in the quiescence and self-tolerance state. Specific anatomical structures, including the BBB, limit interactions between the CNS and the systemic immune system (Diamond et al., 2013). The BBB is a dynamic system that can be regulated in vivo by stimuli that can modulate—in specific circumstances—the entry of typically nonpermeating molecules (antibodies) into brain tissue (Banks, 2005). The relative quiescence state involves that low neuronal major histocompatibility complex antigens expression exist to limit inflammatory damage in an organ with limited regenerative capacity and extraordinary ongoing metabolic demand (Diamond et al., 2013). The CNS immune environment suggests that the brain immune system components are involved in different processes in the CNS different than in other tissues (Diamond et al., 2013). For example, complement components in the CNS exert important effects on neuronal synapse development (Stephan et al., 2012; Veerhuis et al., 2011), whereas cytokines, which are proinflammatory in peripheral organs, regulate synaptic activity in the CNS (Pavlowsky et al., 2010; Piton et al., 2008; Stellwagen and Malenka, 2006). Similarly, microglia, the CNS-resident myeloid cells, are characterized by their resting state with a limited capacity for antigen presentation and phagocytosis (Prinz et al., 2011).

The concept of BBB and its selective permeability plays a major role in biomarker research under normal circumstances and pathological conditions (CNS trauma). The BBB is composed of endothelial cells and astroglial cellular barriers with tight junctions. These barriers are composed of the vascular endothelial cells and the tight junctions that effectively orchestrate the traffic of brain chemicals. The selective permeability exerts regulated control in excluding most macromolecules from entering the brain and prevents neurotransmitters from leaking to the circulation. Most of the CNS (spinal cord and brain)-derived proteins are relatively sequestered in their localization due to the BBB control (Reiber, 2001, 2003). However, when the BBB is compromised, these macromolecules of proteins and their breakdown products are released in the CSF and may leak into the peripheral circulation comprising attractive candidates as signature biomarkers indicative of injury modalities (see Chapter 20).

The concept of the immune privilege of the CNS refers strictly to the parenchyma, which has limited interaction with blood vessels, meninges, or ventricles and is not localized within a circumventricular organ (Galea et al., 2007). The CNS parenchyma either expresses many antigens that are not found to an appreciable degree in other tissues or expresses a given antigen in a form not present in other tissues. The presence of CNS-reactive antibodies in circulation is, in general, harmless to the host; however, under pathologic conditions, when the BBB integrity is compromised, one would expect antibody-mediated pathology to occur (Diamond et al., 2013). Once they encounter their cognate antigens, B cells differentiate via antigen-specific T-cell interaction into a germinal center response in which immunoglobulin genes undergo class-switch recombination and somatic hypermutation. Under regular conditions, the BBB selectivity is permeable to some systemic circulating antibodies (Bard et al., 2000). However, in some cases of BBB disruption, as in brain trauma, a high influx of circulating antibodies and other serum proteins, leukocytes, macrophages, and red blood cells gain access to the brain vicinity and to injured lesions (Baloyannis and Gonatas, 1979; Soares et al., 1995). Thus, it is expected that neural cells (neurons and glial cells) will be exposed to circulating antibodies and serum proteins after brain trauma (Aihara et al., 1994).

Among the major mechanisms proposed that might explain the self-antigen–autoantibody response is the molecular mimicry mechanism. Molecular mimicry usually involves a foreign antigen mimicking a self-antigen and mounting an aberrant autoimmune response against self-antigens because of cross-reactivity. Under normal conditions, a low level of autoimmunity is necessary for normal function (Davidson and Diamond, 2001). Substantial evidence highlights the role of free radical generation and nonenzymatic lipid peroxidation as a posttranslational protein modification (Keller and Mattson, 1998). This covalent modification can alter the immunogenicity of these proteins (Uchida and Stadtman, 1992; Yahya et al., 1996). It has been shown that autoantibodies recognize proteins cross-linked to lipid peroxidation that have been identified in normal mice and humans (Kergonou et al., 1988; Yahya et al., 1996). As such, lipid peroxidation in injured neural cells may elicit circulating immunoglobulins that can recognize these proteins. In mounting immune response, the primary antibody secretion exhibits a lag phase of 2 to 6 days for the immunoglobulin G (IgG) secretion after antigen occurrence (Dudley, 1992; Poletaev and Boura, 2011), that is the time needed for antigen presentation and clonal expansion and generation of B cells.

29.3. AUTOANTIBODIES GENESIS AND MECHANISMS IN THE CNS: AGING PROCESS

The concept of autoantibodies can be traced back to the early 1970s (Ingram et al., 1974). In a very interesting report, Ingram et al. discussed the role of autoantibodies in aging. They proposed that, with advancing age, there is a natural increase in the prevalence of autoantibodies against neurons of the brain. The earliest site of binding for these autoantibodies is localized in the occipital lobe (visual cortex). However, the binding sites can vary between individuals (Ingram et al., 1974). For the origin of these autoantibodies and their genesis, they debated that our CNS constituents are naturally not antigenic but may be converted to be immunogens by a number of mechanisms including (1) release of brain debris into circulation from normally sequestered immunoprivileged sites, (2) formation of complexes with other substances such as viruses or environmental components, (3) alteration of configuration (Behan et al., 1973), or via (4) exposure of the neural proteins to antibodies as a result of cellular injury or death. Concerning the latter, the “free solution form” theory has been proposed to occur after necrotic cell death where autosensitization is coupled with the release of autoantigens from intact organs into peripheral circulation.

This is observed in several conditions as in stroke or TBI where a massive cell death with necrotic mechanisms followed by apoptotic cell death sequelae is observed. For the first option, it has been proposed that aging induces BBB disruption (Nandy, 1972; Threatt et al., 1971), coupled with the exposure of immunological privileged sites (Levy et al., 1972). Regarding formation of complexes with a foreign microorganism, it involves the presence of common antigens with the neural components leading to the development of autoantibodies capable of interacting with both entities. Of interest, there is another possibility of cross-reactivity arising from the fact that the CNS appears to possess normal self-antigens coexisting and shared with other organs (e.g., the thymus tissue) (Murphy et al., 1970). Such a condition is known as “a progressive qualitative or quantitative change” in the neural tissue. As to the alteration of configuration, cytoplasmic structural changes such as the development of neurofibrillary tangles are suggestive of misfolded proteins in addition to other modifications (Terry and Wisnewski, 1972). Interestingly, these studies go back to the early 1970s and still hold today and offer some explanation to what is observed in SCI and TBI records, as will be discussed later.

In cases of aging and senile dementia conditions, the brain is characterized by cellular loss and neuronal damage sustained over long periods and is associated with astrogliosis and high levels of gliofibrillar acid protein (GFAP) in the CNS (Bjorklund et al., 1985). GFAP is a major intermediate filament protein in the CNS, and its levels are elevated in cases of inflammatory response of reactive astrocytes (Eng et al., 1971). It has been shown to be a biomarker of cerebral infarctions, head injuries, and other conditions associated with reactive gliosis (Hayakawa et al., 1979; Mori et al., 1978).

In their work, Mecocci et al. evaluated serum GFAP autoantibodies in patients (n = 108) divided into vascular dementia, presenile AD, and senile AD and were compared with controls (Mecocci et al., 1992). Autoantibodies against GFAP were found elevated in vascular dementia, which is correlated with an increase in BBB permeability with no prognostic value to AD (Mecocci et al., 1992). Vascular dementia, compared with other types of dementia, allowed immune competent cells to gain access to the CNS antigens. These autoantibodies can be considered a secondary phenomenon to BBB disruption in which the exact role of anti-GFAP antibodies in the pathogenesis of AD is not clear. In addition, the presence of altered immune response in the case of degenerative dementia such as in AD; autoantibodies against cholinergic neurons, astrocytes, neurofilaments, or GFAP proteins have been identified in degenerative dementia with potential diagnostic importance (Bahmanyar et al., 1983; Kingsley et al., 1988; Mcraedegueurce et al., 1987; Tanaka et al., 1988, 1989).

29.4. NEUROPROTECTIVE ROLE OF AUTOANTIBODIES

The neuroprotective role of natural autoreactive monoclonal antibodies has been discussed by Wright et al. (2009). They proposed a new role of natural IgM autoantibodies that can bind to the surface of neurons stimulating neurite outgrowth and inhibiting neuronal apoptosis; this has a therapeutic potential in CNS neurodegenerating diseases such as amyotrophic lateral sclerosis, stroke, and SCI (Wright et al., 2009). The binding of these autoantibodies would activate intracellular signaling promoting glial and neuronal survival, which may involve crossing the BBB and accumulating at injured sights (Howe et al., 2004; Paz Soldan et al., 2003; Pirko et al., 2004). This signaling pathway involves antibody–protein glycolipid interactions leading to a slight calcium influx activating mitogen-activated protein (MAP) kinases inducing a cascade that downregulates caspase-3 activation.

29.5. AUTOANTIBODIES IN TBI

Among the dominant pathologic features of TBI is the occurrence of primary mechanical shear stress and secondary mediated cell death mechanisms involving the hyperactivation of the caspase and the calpain proteases (Arbour, 2013; Wang, 2000; Xing et al., 2009a, 2009b; Zheng et al., 2008). Furthermore, in the pathophysiology of TBI, there is major compromise in the BBB integrity that contributes to the release of neural proteins into the CSF along with the breakdown products (BDPs) representing protease substrates that may leak into the peripheral circulation. The proteins include UCH-L1, MAP-2, NF-H, αII-spectrin BDPs, and synaptotagmin, which have been proposed as putative biomarkers (discussed fully in Chapters 20, 21, and 22). Recently, the concept of autoimmunity has been revisited in the area of neurotrauma, a discipline that is not an autoimmune disease per se, but involves the production of autoantibodies. The role of these antibodies has been debated as neuroprotective or correlated to pathogenic conditions as discussed in the following section. These autoantibodies have been “newly” exploited in the field of neurotrauma biomarker research. Recently, two main TBI studies have been published by Zhang et al. and Marchi et al. that reflect the true utility of autoantibodies as TBI biomarkers (Marchi et al., 2013b; Zhang et al., 2014).

In one recent study on football players, Marchi et al. tested the hypothesis whether BBB disruption is coupled with increased influx of S100β astrocytic protein in blood, which may lead to the production of autoantibodies (Marchi et al., 2013b). Diffusion tensor imaging was performed to see if these events result in white matter disruption. A total of 67 football players were assessed before and after games and compared with the number of repeated head hits. Moreover, levels of S100β were evaluated and correlated to the diffusion tensor imaging scan data (pre- and postseason) that were performed for a 6-month interval coupled with cognitive and functional assessment. Serum levels of S100β correlated with the magnetic resonance imaging/diffusion tensor imaging findings showed abnormal cognitive changes. Elevated levels of autoantibodies against S100β were correlated to repeated subconcussive events characterized by BBB disruption.

Complementary to this work, a recent study by Zhang et al. evaluated the role of systemic autoantibodies in TBI (Zhang et al., 2014). A systematic analysis of human TBI serum was performed to identify serum autoantibody responses to brain-specific proteins. It was found that human autoantibodies showed prominent immune reactivity to a cluster of proteins in the region of 38–50 kDa identified as GFAP and GFAP BDPs, which increased at 7–10 days postinjury of the IgG subtype. Interestingly, these results were translated into an experimental model of rat TBI showing that human TBI autoantibodies colocalized in injured rat brain and in primary rat astrocytes, which is suggestive that these autoantibodies enter living astroglial cells compromising their survival. Among the major findings from this work is that in vitro digestion indicated that calpain was responsible for fragmenting GFAP protein yielding a 38-kDa BDP fragment. On the clinical level, a global neuroproteomics approach was used on 53 patients with severe TBI and age-matched healthy controls. Sera of subjects were collected on days 0–10 postinjury and screened against control brain tissue. TBI patients showed an average of 3.77-fold increase in anti-GFAP autoantibody levels from early (0–1 days) to late (7–10 days) postinjury. The presence of these autoantibodies was inversely correlated to Glasgow Coma Scale after a 6-month follow-up, suggesting that TBI patients with greater anti-GFAP immune responses had worse outcomes. Taken together, these data suggest that anti-GFAP autoantibodies represent excellent putative markers that can be used to monitor and assess brain injury in chronic conditions of human TBI.

In another study by Ngankam et al., CSF of 100 TBI patients were assessed for myelin-basic protein (MBP) and phospholipids (PL) autoantibodies on the first, 10th, and 21st days postinjury. Interestingly, autoantibodies against MBP and PL were elevated in TBI groups, whereas MBP autoantibodies were shown to correlate with Glasgow Coma Scale in the first days and the level of recovery on the 21st day. PL autoantibodies were correlated to the severity of vascular complications of trauma (Ngankam et al., 2011).

In another study by the Sorokina et al., autoantibodies against different fragments of α7-subunit of acetylcholine receptor were evaluated in children with craniocerebral trauma with different severities. Brain injury severity correlated with the titers of α7-subunit and the autoantibody levels mounted against them during the first week of injury (Sorokina et al., 2011). They hypothesized that inflammatory response coupled with disruption of the BBB increase the release of structural neuronal and glial proteins components in the circulation, which led to the mounting of immune response (autoantibodies) against them. These autoantibodies can hold compensatory role by binding to the damaged receptors providing compensatory-adaptive response (Sorokina et al., 2009). Other autoantibodies can contribute to the pathologic profile by increasing edema, inflammation, and calcium influx, increasing the secretion of proinflammatory cytokines (Sorokina et al., 2006; Whitney and McNamara, 2000). On the compensatory role of α7-subunit, signal transduction of the α7-subunit of AChR is known to support neuronal plasticity (Berg and Conroy, 2002; Drisdel and Green, 2000). In addition, it is suggested that these receptors carry protective roles in suppressing the secretion of the proinflammatory tumor necrosis factor α (TNF-α) mediated via cholinergic pathways, the vagus nerve, and the spleen leading to macrophage activation (source of TNF-α) (Borovikova et al., 2000). Thus, the α7-types of ACHR have been proposed to be evaluated for their diagnostic value in assessing severity of brain injury.

In another study, Sorokina et al. assessed levels of S100β and its cognate autoantibodies in the serum of children with different severity and outcomes of TBI (1–75 days) in chronic phases (15–75 days) after TBI was stratified into five groups (complete recovery, moderate disability, high disability, vegetative state, and fatal outcome). Glasgow Coma Scale was used to assess severity. The maximal level of S100β protein and its autoantibody were observed in patients with fatal outcome. In groups 1–3, the changes of S100β in the blood serum did not depend on the severity of brain damage. The S100β protein levels went up the first day and then declined, whereas S100β autoantibodies were elevated at days 3 and 5 (Sorokina et al., 2010).

In another study by Kamchatnov et al., neuron-specific enolase, GFAP, S100β proteins, and their associated autoantibodies were evaluated in 42 patients with acute ischemic stroke. A reverse correlation between concentrations of neuron-specific enolase and its autoantibodies was observed. Similarly, there was a positive correlation between the restoration of lost functions (from the first to 21st days) and GFAP autoantibody levels (Kamchatnov et al., 2009). In another study by Pinelis et al., acute craniocerebral trauma period is characterized by a marked change in the levels of nitric oxide metabolites and antibodies to two subtypes of glutamate receptor, the AMPA and NMDA receptors. Unfavorable outcome of craniocerebral trauma was associated with the lowest level of autoantibodies and high nitric oxide levels. It was suggested that antibodies to glutamate receptors and receptor hyperstimulation play an important role in the pathogenesis of hypoxia (Pinelis and Sorokina, 2008).

In an elegant work by Stein et al., it was clearly demonstrated that circulating IgG autoantibodies bind to dying neurons in the time frame of 4 hours to 7 days after visual cortex lesion (Stein et al., 2002). They proposed that this autoantibody binding may participate in the phagocytosis and clearance of injured neurons; IgG-positive neurons were in advanced stages of degeneration. The major finding their work is that injured neurons are associated only with the IgG class immunoglobulins that have entered the cortical lesion binding specifically to the injured cells. These autoantibodies are naturally occurring autoantibodies because of the time frame of detection (4 hours). They may be involved in microglial-dependent opsonization initiating phagocytosis because of the Fc receptors that enable binding of IgG opsonized targets (Ulvestad et al., 1994). Finally, in one study by Rudehill et al., serum autoantibodies against neurons, basal lamina, and astrocytic cells were assessed after experimental brain contusion (Rudehill et al., 2006). These autoantibodies were elevated in injured rats at different time points (antineuronal IgG and antivascular basal lamina IgG were detected at 2 weeks and 3 months postinjury, respectively). These autoantibodies were detected in the rat serum but not as tissue bound, 2 weeks postinjury. This is suggestive that the BBB reformation prevented the chronic passage of these autoantibodies to the brain, which is supported by Stein et al.’s findings that IgG bound to injured neurons 4–7 days postinjury but not a 14-day period. The presence of these IgG antibodies suggests a potential pathological role to neural integrity (Rudehill et al., 2006).

Finally, among the devastating outcomes observed in TBI is that it may result in pituitary dysfunction; the exact mechanisms for such an outcome have not been elucidated (Kelly et al., 2000; Tanriverdi et al., 2006). Several mechanisms have been proposed, including direct mechanical injury to the hypothalamus, compression from hemorrhage, edema, or increased intracranial pressure along with an autoimmune response (Tanriverdi et al., 2008b; Yuan and Wade, 1991). In one study by Tanriverdi, antipituitary autoantibodies (APA) post-TBI and pituitary functions were assessed in TBI patients 3 years after TBI (29 TBI patients vs. 60 controls) (Tanriverdi et al., 2008a). Of interest, there was a significant association between APA positivity and hypopituitarism from TBI. APAs were detected in 13 of the 29 TBI patients but none in control. Similarly, pituitary dysfunction development ratio was significantly higher in APA-positive patients (46.2%) compared with APA-negative patients (12.5%). A follow-up study by the same group was performed on amateur boxers assessing anti-hypothalamus (AHA) and APA antibodies in chronic repetitive head trauma (Tanriverdi et al., 2010). Sixty-one actively competing (n = 44) and retired (n = 17) male boxers were assessed for AHA and APA and compared with 60 normal controls. AHAs and APAs were detected in 13 and in 14 of 61 boxers, respectively. Pituitary dysfunction was significantly higher in AHA-positive boxers than in AHA-negative boxers. These results demonstrate the presence of AHAs and APAs in boxers with repeated head injuries; however, the functional value of these autoantibodies requires further studying to establish a causal relation with the injury.

29.6. SCI, B LYMPHOCYTES, AND THE PERPLEXING ROLE OF AUTOANTIBODIES

Among the hallmarks of CNS trauma in the context of SCI and TBI is the activation of several interrelated pathologic responses involving the necrotic, excitotoxic, and inflammatory responses in the primary phase followed by apoptotic cell death in the secondary phase; hence contributing to the worsening of the neurological outcomes. The neuroinflammatory response observed, though it is part of the natural wound-healing process, contributes to the increased damage to the neural tissue specifically in the area of SCI (Dekaban and Thawer, 2009).

Neuroinflammation cascade is a key mechanism occurring post-SCI involving the activation of antibody-producing B cells, in addition to the already well-studied activated neutrophils, monocytes/macrophages, and T lymphocytes (Blight, 1993, 1994; Fleming et al., 2006; Kigerl et al., 2006; Popovich et al., 1999; Sroga et al., 2003). Ankeny et al. discuss elegantly the impact of B-cell activation and its associated autoantibodies in the realm of SCI pathology genesis and exacerbation offering new venues for neurotherapeutic targets for patients with SCI (Ankeny et al., 2006, 2009; Ankeny and Popovich, 2009, 2010). B lymphocytes arise from bone marrow hematopoietic stem cells as immature B-cell stage cells (Dalakas, 2008a, 2008b).

Upon the entry of a “non-self” foreign antigen, our system mounts a host immune response in which mature B cells coupled with T-cell are activated. However, when the encountered antigen is host-derived (DNA, peptide, or protein), a state of autoimmune response is elicited (Ankeny et al., 2009). Usually, during development, negative selection would eliminate highly reactive lymphocytes while positive selection would keep “subthreshold” stimulation of lymphocytes that recognize self-host antigens and increase sensitivity to foreign antigens (Stefanova et al., 2002). This mechanism of positive selection plays a major role in regulating the immune response. Nevertheless, when the threshold level is bypassed, we have a pathologic state of autoimmunity (Stefanova et al., 2002). In the case of CNS trauma, T-dependent and T-independent self-antigens induce an adaptive immune response that has several implications (Ankeny et al., 2006, 2009; Schwartz and Kipnis, 2001).

Upon activation in the presence of its cognate antigens, B cells differentiate into antibody-secreting plasma cells and later into long-lived, antibody-secreting plasma cells (Dalakas, 2008a, 2008b). In addition to secreting antibody, B cells can act as antigen-presenting cells (Dalakas, 2008b; Waubant, 2008). These activated B cells migrate to the secondary lymphoid tissue, bone marrow, and to the CNS (Dalakas, 2008b). The CNS recruitment and B-cell traffic is upregulated in CNS autoimmune disorders as in multiple sclerosis (Corcione et al., 2004b; Dalakas, 2008b).

Activated B lymphocytes and autoantibodies have been shown to be the main players in a number of neurological disorders including systemic lupus erythematosus (SLE), MS, and experimental autoimmune encephalomyelitis (EAE) (Genain et al., 1999; Kowal et al., 2004; Raine et al., 1999). In SLE, antinuclear and anti-DNA antibodies cross-react with neural antigens in the brain, causing excitotoxicity coupled with cognitive decline (DeGiorgio et al., 2001). Similarly, in MS, levels of myelin-reactive antibodies are elevated in CSF and are associated with progressive demyelination and neurological dysfunction (Lyons et al., 1999; Willenborg and Prowse, 1983), whereas in EAE, B-cell activation and autoantibody synthesis are the main triggers to cause demyelination and neuropathology. The role of autoantibodies involves cytotoxic effects on neurons and glia via complement activation and phagocytosis stimulation with cytokine release and protease activation from microglia and macrophages (Abdul-Majid et al., 2002; Beuche and Friede, 1986; Griot-Wenk et al., 1991; Mosley and Cuzner, 1996). In their work, Ankeny et al. show that experimental spinal contusion injury elicits chronic systemic and intraspinal B-cell activation. Immunoblots of sera from injured mice showed reactivity against multiple CNS proteins, including autoantibodies that can bind nuclear antigens (DNA and RNA), as observed in EAE. These autoantibodies show similar neurotoxic potentials via cross-reacting with glutamine receptors, causing neuronal excitotoxicity (Ankeny et al., 2006). They propose that the mechanisms leading to B-cell activation involve SCI-dependent stimulation of cognate B and T cells in response to autoantigens liberated by SCI.

A major finding in human SCI is the elevation of myelin-reactive antibodies in serum and CSF that recognize CNS proteins as autoantigens (Hayes et al., 2002; Kil et al., 1999; Mizrachi et al., 1983). By inducing experimental SCI, long-lasting B-cell activation was observed in both spleen and bone marrow with increased levels of IgG and IgM (Ankeny et al., 2006). Activated B lymphocytes are shown to dwell in the injured spinal cord associated with de novo expression of mRNA that encodes a range of autoantibodies (Ankeny and Popovich, 2009).

29.7. PATHOGENIC ROLE OF SCI AUTOANTIBODIES AND SCI LEVEL DEPENDENCE

Ankeny showed that in a mouse model of moderate severity spinal cord contusion at the mid-thoracic level (T9), there is an induction of a pathologic B-cell response coupled with pathogenic antibody secretion (Ankeny et al., 2009). Functional recovery testing via coordinated stepping of the four limbs applied on SCI mice was demonstrated in 88% of B-cell knockout compared with 35% in wild-type (WT) mice after a 9-week period. Similarly, the neuropathology was less pronounced in the B-cell knockout SCI mice. The pathogenic antibodies from the SCI mice injected in WT mice induced a similar type of neurotoxicity as in WT SCI mice. Interestingly, the pathogenic neurotoxic phenotype observed in SCI was achieved if the injury occurred in the lower half of the spinal cord (T9–T10), whereas at higher levels (T4–T5), a profound immune suppression and diminished B-cell activation was observed (Lucin et al., 2007). This is attributed to the cholinergic anti-inflammatory pathway disruption at high SCI due to the removal of the sympathetic contribution as it injures the intermediolateral column sympathetic fibers that regulate systemic inflammation (Rosas-Ballina and Tracey, 2009). In a further study, Ankeny et al. highlighted the integral role of B cell and autoantibody secretion in mediating axonal and myelin pathology and motor function impairment. Antibody-mediated pathology involved complement activation Fc-receptors bearing cells (e.g., microglia/macrophages) in the spinal cord (Ankeny et al., 2009). It was shown that in mice with normal B-cell function, large deposits of antibody and complement component 1q (C1q) accumulated at sites of axon pathology and demyelination. Of high interest, mice that were B cell–deficient were incapable of antibody production, and lesion pathology was reduced coupled with spontaneous recovery of locomotor function. Furthermore, injection of purified antibodies from SCI mice into naive/uninjured spinal cord led to paralysis and spinal cord pathology (Ankeny et al., 2009). The profile observed by injecting these pathogenic autoantibodies mimicked what is observed in models of muscle and gut ischemia/reperfusion injury, which are complement C1q- and FcRs-dependent (Zhang et al., 2006, 2008). Taken together, these results suggest that controlling B-cell activation and/or plasmapheresis would be among the therapeutic options considered in treating SCI.

SCI initiates a cascade of altered immunological responses from the primary injury phase through the secondary injury phase and it even passes through the chronic rehabilitative phase (Cruse et al., 2000; Kliesch et al., 1996; Yang et al., 2004). On the other hand, the immunological response of patients in the postacute (2–52 weeks) or chronic >52 weeks) stages is not well-characterized (Davies et al., 2007). It is proposed that due to the disrupted sympathetic innervations of the lymphoid tissue coupled with altered neuroendocrine responses and the dysregulation of the afferent input to immunoregulatory neurons would create a state of immune suppression observed in SCI (Iversen et al., 2000). It has been reported that within 2 weeks, there was a decrease in natural and adaptive immune responses, in which the function of both natural killer cells and T cells dropped significantly. In addition to that, the hematopoietic cell lineages including dendritic cells of the decentralized bone marrow were also shown to be reduced (Iversen et al., 2000).

Taken together, the level and severity of SCI influence the kinetics and magnitude of B-cell activation and autoantibody synthesis. Finally, it is hypothesized that the accumulated intraspinal autoantibodies contribute to pathology via activating complement binding to antigen–antibody immune complex; this in turn activates other complement proteins. This will result in activation and recruitment of myeloid lineage cells (e.g., microglia/macrophages) bearing complement receptors.

In one study by Davies et al., inflammatory serum cytokines were assessed in SCI subjects (n = 56) with varying clinical presentations compared with control subjects. Several end points were assessed including levels of the proinflammatory cytokines (interleukin [IL]-1, IL-6, TNF-α), the anti-inflammatory cytokines (IL-4 and IL-10), the regulatory cytokines (IL-2), the IL-1 receptor antagonist (IL-1RA), and autoantibodies against myelin-associated glycoprotein, and GM1 ganglioside (anti-GM1) immunoglobulin (IgG and IgM) (Davies et al., 2007). Furthermore, findings from this work showed that there is an elevation in circulating proinflammatory cytokines and autoantibodies. However, these were present in SCI subjects with or without complications (e.g., pain, ulcers, pressure). These findings may be indicative of a protective autoimmunity or may be due to evident infection.

29.8. B-LYMPHOCYTES AS THERAPEUTIC TARGETS POST-SCI

During B-cell activation, maturation, and antibody secretion process, a number of factors and receptors that can be therapeutic targets in the activated immune response in SCI (Dalakas, 2008a, 2008b) have been identified. Among these, B cell–activating factor (BAFF), lymphotoxin-β, and “a proliferation-inducing ligand” (APRIL) contribute to B-cell survival, maturation, and activation (Dalakas, 2008a, 2008b). Moreover, it is observed that B-cell “follicle-like” structures (as detected in MS) (Corcione et al., 2004a) are present in the lesion area. This reflects that these pathogenic antibodies are in part derived from the lesion and in part systemically introduced due to disruption of the blood–spinal cord barrier (Ankeny et al., 2009). The “follicle-like” structures are partly formed by the BAFF and APRIL factors derived from the infiltrating monocyte/macrophages and proliferating astrocytes. Based on these results, the pathogenic parameters discussed, including the activated B cells and the secreted autoantibodies, render them potential targets for therapy in SCI (Dekaban and Thawer, 2009).

Intravenous immunoglobulin administration therapy has shown to block both autoantibody binding and complement activation, which would be an optimal neuroprotective target in SCI (Gold et al., 2007). Another alternative would be using B-cell depletion as a neuroprotective option, which has been tried as a therapy in a number of CNS autoimmune conditions with the ability to remove activated B cells (Matsushita and Tedder, 2009; Waubant, 2008). Alternatively, the use of anti-CD20 antibody–mediated depletion of B cells can be applied; however, preexisting plasma cells with pathogenic antibodies will not be eliminated by anti-CD20 therapy, which raises some concerns (Dalakas, 2008c; Waubant, 2008). Other options involve the use of drugs that can target factors involved in B cell growth/differentiation (e.g., BAFF, APRIL), limiting the accumulation of pathogenic autoantibodies (Dorner et al., 2009; Levesque and St Clair, 2008). This can be delivered within the intraspinal or intracranial space that can target B cell follicles in the chronically injured CNS (Ankeny et al., 2006, 2009; Ankeny and Popovich, 2009; Katz, 1980).

29.9. AUTOANTIBODIES IN AUTISM SPECTRUM DISORDER

ASDs are a group of heterogeneous neurodevelopmental disorders affecting approximately one in 88 children in the United States (Braunschweig and Van de Water, 2012; Lord et al., 1997). Current diagnosis is based entirely on behavioral testing and the analysis of medical and developmental history (LeCouteur et al., 2008; Lord et al., 2000a; Lord et al., 2000b; Lord et al., 1994). ASD is characterized by core deficits in social interaction and stereotypical movements (Lord et al., 1997). The pathology and etiology of these disorders remain unclear with some implications of genetic, neurological, and environmental factors (Pardo et al., 2005). In addition, ASD has been implicated with altered immune response, which is an important factor contributing to the development of some cases of ASD. These immune response alterations include immune dysfunction (van Gent et al., 1997; Warren et al., 1987, 1996), peripheral immune abnormalities (Ashwood and Van de Water, 2004b; Ashwood et al., 2006), and an ongoing inflammatory response (Croonenberghs et al., 2002; Vargas et al., 2005). Furthermore, there is evidence showing that autism may be due to an ongoing autoimmune process (Ashwood and Van de Water, 2004a; Braunschweig et al., 2013). Several studies have already identified a number of autoantibodies in individuals with autism mounted against various CNS proteins, including glial and neuron-axon filament proteins (Kirkman et al., 2008), MBP (Singh et al., 1993), serotonin receptor (Todd et al., 1988), cerebellar peptides (Vojdani et al., 2004), brain-derived neurotrophic factor (Connolly et al., 2006), and brain endothelial cells (Connolly et al., 1999). Several ongoing studies are under way to describe the identification of several of brain-specific autoantibodies and their relation to ASD development and severity. However, the debate of whether or not these autoantibodies represent putative markers of ASD is still under investigation and most of the described studies that follow are correlative in nature, with some hints of biomarker implication as discussed.

Dysregulation in immune response as well as neuroinflammation coupled with the presence of maternal autoantibodies mounted against brain tissue support the role of the immune system in some of the ASD cases observed (Braunschweig et al., 2008, 2012; Goines and Van de Water, 2010; Vargas et al., 2005). It has been shown that in mothers of ASD children, there is immunoreactivity to proteins of 37- and 73-kDa antigens that were correlated to increased severity of language deficits in the offspring (Braunschweig et al., 2008, 2012). A potential role of these maternal autoantibodies is proposed because of the accessibility of maternal IgG during pregnancy. Maternal IgG is detected in circulation as early as 13 weeks’ gestation. In addition, by 30 weeks’ gestation, the levels of circulating autoantibodies reach 50% of that of the mother and at birth, the levels of these autoantibodies exceed the maternal IgG (Simister, 2003). In addition, the BBB is still in the developmental stages and permits IgG during this period (Bake et al., 2009; Malek et al., 1996). It has been shown that rodents and nonhuman primates exhibit ASD-like behaviors in offspring born to dams exposed to passive transfusion of human IgG from mothers with brain-reactive autoantibodies compared with control serum (Dalton et al., 2003; Martin et al., 2008; Singer et al., 2009). These maternal autism-related autoantibodies were investigated by Braunschweig et al. through proteomics approaches (Braunschweig et al., 2013). Reactivity to specific antigen combinations was noted in 23% of mothers with ASD children compared with 1% in controls. These seven autoantibodies included lactate dehydrogenase A and B, cypin, stress-induced phosphoprotein 1, collapsin response mediator proteins 1 and 2, and Y-box-binding protein, which compose what is known as maternal autoantibody-related (MAR) autism. ASD children from mothers with specific reactivity to these MAR autoantibodies had elevated stereotypical behaviors compared with siblings with no MAR occurrence. The identification of these specific significant biomarkers assists in understanding the etiologic mechanisms and therapeutic potentials for MAR autism. Thus, identifying these MAR autoantibodies provides one potential understanding for the development of the traits observed in the ASD cases. Moreover, the high specificity of the MAR autoantibody profiles may constitute the first biomarker panel predicting ASD risk.

A study by Goines et al. explored the relationship between the presence of brain-specific autoantibodies and several behavioral characteristics of autism in 227 ASD children. It was found that autoantibodies that target pairs of fetal brain proteins at 37/73 kDa and 39/73 kDa are directed against cerebellar proteins. The autoantibodies specific for a 45-kDa cerebellar protein in children were associated with a diagnosis of autism, whereas autoantibodies directed toward a 62-kDa protein were associated with diagnosis of broader diagnosis of ASD. Children with elevated levels of autoantibodies showed lower adaptive and cognitive functions relative to children without the autoantibodies in sera (Goines et al., 2011). Another implication of the contribution of autoantibodies to ASD development comes from maternal IgG experiments. During pregnancy, maternal IgG is passed across the placenta to fetal circulation (Simister, 2003). It was shown that animals exposed to these fetal brain-directed autoantibodies exhibited altered ASD behavior, thus indicative that maternal autoantibodies may be of pathologic significance contributing to the occurrence of ASD (Martin et al., 2008; Singer et al., 2006).

Wills et al. showed that plasma from children with ASD demonstrated immunoreactivity directed against a 52-kDa human cerebellar protein in 21% of subjects with autism, whereas it was present in only 2% of the typically developing controls; these autoantibodies stained positive for Golgi cells of the cerebellum (Wills et al., 2009). This was validated using immunohistochemical staining of sections from Macaca fascicularis monkey cerebellum. Autism has been implicated in a number of brain regions in addition to the cerebellum (Amaral et al., 2008) and the question arises whether the autoantibodies present in autistic individuals identify a broader class of neurons that are distributed throughout the brain with distinct morphological features. Thus, in a different study, plasma from the same individuals who demonstrated positive cerebellar Golgi cell immunoreactivity were applied to stain tissue sections from the full rostrocaudal extent of the macaque monkey brain (Wills et al., 2011b). Significantly, it was found that children with ASD demonstrated autoantibodies are reactive to a subset of GABAergic interneurons throughout the brain. Colocalization studies with GABA antibodies revealed that ASD children recognize GABAergic interneurons in V1 layers. This study raises some major questions about the identity of the autoantigen that these autoantibodies recognize and the reason for a potential pathologic role of these autoantibodies or it is merely an epiphenomenon.

In another study by Mostafa et al., neurokinin-A, a pro-inflammatory neuropeptide and a main component in the neurogenic inflammatory pathway, was evaluated in 70 autistic children (Mostafa and Al-Ayadhi, 2011). It was shown that neurokinin-A titer was elevated and was correlated to the severity of the autistic phenotype. Similarly, antiribosomal P protein autoantibodies were also associated with the occurrence of autism in these children. Several possible pathogenic mechanisms have been proposed for these autoantibodies, including inducing cytotoxic effects, cellular invasion into living cells, and initiating apoptosis (Ben-Ami et al., 2010). Previously, antiribosomal P protein antibody occurrence had been associated with the neuropsychiatric manifestations for SLE involving psychosis, mood disorders, anxiety, and cognitive dysfunction (Ben-Ami et al., 2010; Mostafa et al., 2010). However, a clear mechanistic analysis of the formation of these specific autoantibodies was not described and the question of whether these autoantibodies can be considered a marker of ASD was not evaluated (Mostafa and Al-Ayadhi, 2011).

Finally, other studies have associated the presence of ASD with the presence of folate receptor autoantibodies and their relation to maternal folate receptor-α (FRα) autoantibodies (the blocking or the binding type) (Rothenberg et al., 2004). It has been shown that in ASD cases, either the blocking or the binding type of the FRα autoantibody was detected in 75% of the ASD children and high-dose folinic acid supplementation improved the core symptoms of autism in these children (Frye et al., 2013). Of interest, in a study by Ramaekers et al., ASD children were shown to develop these autoantibodies postnatally (Ramaekers et al., 2013). However, in ASD children with negative autoantibodies, either one or both parents had positivity for the autoantibodies, which may suggest that parental FRα autoantibodies may contribute to the development of autism in their offspring (Ramaekers et al., 2013).

29.10. AUTOANTIBODIES IN THE AREA OF NEUROTOXICITY

Another area of autoantibody investigation is the area of neurotoxicity, involving the exposure of neurotoxins that have been shown to exert an autoimmune response detected in circulation and found to be proportional to injury severity (Abou-Donia et al., 2013; El-Fawal and McCain, 2008; El-Fawal et al., 1999; Evans, 1995; Mason et al., 2013; Moneim et al., 1999). In his review, Evans discusses the role of neurotoxicity and autoantibody response and proposes that debris in damaged CNS cells from neurotoxins may present as novel neoantigens, giving rise to autoantibodies detected at chronic phases of injury (Evans, 1995). These autoantibodies can be considered noninvasive organ-localized markers of valuable importance to evaluate the underlying mechanisms involved (Evans, 1995). It has been shown that toxicant-induced neuronal injury might cause autoantibody formation (Lotti, 1995). These environmental agents can act as autoantigens with autoantibodies that can be measured as a biomarker of neurotoxicity and may provide evidence of neurotoxicity that has disappeared from the brain (Lotti, 1995). This is of very high importance. Several obstacles exist in surveying real-time biomarkers of neurotoxicity including the physical protection of the brain by the skull and the CSF cushion. These features prevent direct monitoring of marker changes and indirect measurement of neurotransmission (metabolites) as in cases of neurotoxicity lacking sensitivity, reproducibility, and reliability (Kanada et al., 1994; Lotti, 1995; Mailman and Lewis, 1987; Moretto et al., 1994)

Several schemes are available explaining the appearance of autoantibodies: (1) changes of cell-specific protein levels as in cases of astrogliosis associated with elevated GFAP (Brock and O’Callaghan, 1987); (2) protein fragmentation from injured cells that can leak into the CSF and then to the periphery, which involves disruption of the BBB and impairment of the scavenging properties of microglia (Bressler and Goldstein, 1991; Kida et al., 1993; Skouen et al., 1993; Sundstrom and Kalimo, 1987; Sundstrom et al., 1985); and (3) the early appearance and long survival of autoantibodies to these proteins might permit practical surveillance of exposure and toxicity levels (Vlajkovic and Jankovic, 1991). However, one must be cautious to make sure that there are low levels of autoantibodies in controls, which may reflect a long-past injury that needs to be normalized when assessing these autoantibodies as biomarkers (Evans, 1995).

In one study by Abou-Donia, a panel of CNS autoantibodies was assessed in the sera of 12 healthy controls and a group of 34 flight crew members who experienced adverse effects after exposure to air emissions containing gaseous, vapor, and particulate contaminants (Abou-Donia et al., 2013). These have adverse effects on the CNS dysfunction (Abou-Donia et al., 2013; Winder and Balouet, 2002). The autoantibodies selected represent several types of neural protein affected by neuronal degeneration. These included triplet proteins, tubulin, microtubule-associated tau proteins (tau), MAP-2, myelin basic protein (MBP), GFAP, and glial S100β protein. After exposure, damaged BBB would allow neuronal and glial proteins to leak from the CNS or damaged peripheral nervous system into the circulation and act as autoantigens that will react with B lymphocytes. These B lymphocytes would convert the short-lived nervous system–specific proteins in the serum into long-term biomarkers for neurological damage (Abou-Donia et al., 2013). Data from this study demonstrated that there is a temporal relationship between exposure to air emissions, clinical condition, and level of serum neural autoantibodies (Abou-Donia et al., 2013).

In another study by al El-Fawal et al., neuronal protein autoantibodies were assessed in organophosphorus-induced delayed neuropathy in a hen model treated with phenyl-saligenin phosphate (PSP) (El-Fawal and McCain, 2008). Serum autoantibodies against neuronal cytoskeletal proteins (e.g., neurofilament triplet [NF]) and glial proteins MBP and GFAP proteins as biomarkers of neurotoxicity were assessed as markers of neurotoxicity. A subgroup of hens was treated with calcium channel blocker verapamil 4 days before PSP treatment to monitor its amelioration. IgG against all neural proteins were detected on days 7 and 21, with titer levels being significantly higher in sera of hens receiving PSP only. NF (Neurofilament light [NF-L], Neurofilament medium [NF-M], and Neurofilament heavy [NF-H]), MBP and GFAP, and anti-GFAP and anti-MBP were highest and correlated with clinical scores showing neuro-axonal degradation accompanied by myelin loss at days 7 and 21 as markers of neuropathy (El-Fawal and McCain, 2008). Thus, CNS autoantibodies monitoring may be used to assess neuropathogenesis from occupational exposures and assess treatment intervention options.

29.11. AUTOANTIBODIES IN THE AREA OF PARANEOPLASTIC SYNDROMES

Another area of autoantibody investigation is the paraneoplastic syndromes of the CNS, which involve neurological disorders associated with cancers and are independent of metastasis or tumor compression of the brain tissue (Posner and Dalmau, 1997a, 1997b; Younger et al., 1991). The role of autoantibodies can be traced to the 1970s in the areas of neuromuscular disorders, which later advanced to recognize specific onconeural antibodies in patients with paraneoplastic neurological disorders (Dalmau and Rosenfeld, 2008). These disorders involve autoimmune pathogenesis where they exhibit autoantibodies directed against antigens shared by the neural cells/components and the cancer tissue (Floyd et al., 1998). The hypothesis proposed is that these autoantibodies share protective roles aimed at stopping the spread of tumor to the brain because these cancerous cells share antigens of neural homology. However, these autoantibodies may lead to the impairment of the neurological functions and may injure neuronal cells, leading to their death. Interestingly, the onset of neurological dysfunction in the paraneoplastic syndromes often precedes the clinical manifestation of the tumor. Thus, detecting these autoantibodies may be of clinical use, leading to the early detection of an occult tumor (Folli et al., 1993). In an article by Vincent et al., they discussed the association of several CNS disorders with the occurrence of autoantibodies; these disorders are often associated with tumors and the use of autoantibody assays can help in their diagnosis (Vincent et al., 2011). These autoantibodies span a number of protein families, including voltage-gated potassium channel complexes, NMDA receptor, AMPA receptors, GABA type B receptors, and glycine receptors (Vincent et al., 2011).

In their work, Berghs et al. have identified autoantibodies against two isoforms of β-IV spectrin, which are enriched at axonal areas and nodes of Ranvier in a patient with paraneoplastic lower motor neuron symptoms (LMNS) and breast cancer (Berghs et al., 2000, 2001). An immune response toward these structural components would induce neuronal cell death causing functional impairment, and eventually the death of motoneurons. Other autoantibodies directed against a surface antigen(s) that is enriched at axon initial segments was identified and hypothesized to contribute to the pathogenesis of LMNS. Along the same line, removal of the breast tumor actually stopped the rapid progression of LMNS and was coupled with significant neurological improvement, concomitant with a decrease in the concentration of the autoantibody titers of β-IV spectrin and surface autoantigens. These autoantibodies may provide new diagnostic capabilities in the area of paraneoplastic neurological disorders.

29.12. CONCLUSION

As discussed, the area of autoantibodies has been recently investigated as new-generation biomarkers in neuropsychiatric disorders, CNS trauma, and neurotoxicity. The importance of detecting autoantibodies and their corresponding cognate proteins as potential biomarkers cannot be overstressed. The latter may serve as acute injury markers, whereas their corresponding autoantibodies represent long-lasting, chronic molecular signature biomarkers associated with advanced chronic stages of injury sequelae. Thus, the timely detection of these composite biomarkers may provide a theragnostic window that may help in diagnosing pathological progression of CNS trauma and help in follow-up prognosis (Sorokina et al., 2009).

Finally, at this stage, one should be cautious in drawing conclusions about the exact utility of autoantibodies, since there are a lot of justifiable questions that haven’t been answered yet. Even upon identifying these autoantibodies, the exact roles of the elevated titers are being argued as naturally occurring epiphenomenon markers or actually representing culprit pathogenic contributors. In addition, it is also questionable whether autoantibodies are able or not to translate the pathologic state into the control subjects if transferred or this is more dependent on the neuropathological condition in question. Other valid queries include whether these autoantibodies trigger irreversible damage to the brain and whether their clearance is accompanied with a cessation of symptomatology. Finally, as demonstrated in SCI studies, the mechanism of how these autoantibodies initiate injury and at what titers or cut offs they induce pathology should be critically evaluated. These considerations must be thoroughly investigated in light of the heterogeneous profile of autoantibodies-related neurological disorders (Diamond et al., 2013).

ACKNOWLEDGMENT

We extend our thanks to Abeer Naser Eddine (PhD) for proofreading this chapter.

REFERENCES

1. Abdul-Majid K.B, Stefferl A, Bourquin C, Lassmann H, Linington C, Olsson T. et al. Fc receptors are critical for autoimmune inflammatory damage to the central nervous system in experimental autoimmune encephalomyelitis. Scandinavian Journal of Immunology. 2002;55:70–81. [PubMed: 11841694]
2. Abou-Donia M.B, Abou-Donia M.M, ElMasry E.M, Monro J.A, Mulder M.F. Autoantibodies to nervous system-specific proteins are elevated in sera of flight crew members: Biomarkers for nervous system injury. Journal of Toxicology and Environmental Health. Part A. 2013;76:363–380. [PubMed: 23557235]
3. Aihara N, Tanno H, Hall J.J, Pitts L.H, Noble L.J. Immunocytochemical localization of immunoglobulins in the rat brain: Relationship to the blood-brain barrier. The Journal of Comparative Neurology. 1994;342:481–496. [PubMed: 8040362]
4. Amaral D.G, Schumann C.M, Nordahl C.W. Neuroanatomy of autism. Trends in Neurosciences. 2008;31:137–145. [PubMed: 18258309]
5. Ankeny D.P, Guan Z, Popovich P.G. B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. The Journal of Clinical Investigation. 2009;119:2990–2999. [PMC free article: PMC2752085] [PubMed: 19770513]
6. Ankeny D.P, Lucin K.M, Sanders V.M, McGaughy V.M, Popovich P.G. Spinal cord injury triggers systemic autoimmunity: Evidence for chronic B lymphocyte activation and lupus-like autoantibody synthesis. Journal of Neurochemistry. 2006;99:1073–1087. [PubMed: 17081140]
7. Ankeny D.P, Popovich P.G. Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury. Neuroscience. 2009;158:1112–1121. [PMC free article: PMC2661571] [PubMed: 18674593]
8. Ankeny D.P, Popovich P.G. B cells and autoantibodies: Complex roles in CNS injury. Trends in Immunology. 2010;31:332–338. [PMC free article: PMC2933277] [PubMed: 20691635]
9. Arbour R.B. Traumatic brain injury pathophysiology, monitoring, and mechanism-based care. Crit Care Nurs Clin. 2013;25:297–319. [PubMed: 23692946]
10. Ashwood P, Van de Water J. Is autism an autoimmune disease? Autoimmunity Reviews. 2004a;3:557–562. [PubMed: 15546805]
11. Ashwood P, Van de Water J. A review of autism and the immune response. Clinical and Developmental Immunology. 2004b;11:165–174. [PMC free article: PMC2270714] [PubMed: 15330453]
12. Ashwood P, Wills S, Van de Water J. The immune response in autism: A new frontier for autism research. Journal of Leukocyte Biology. 2006;80:1–15. [PubMed: 16698940]
13. Bahmanyar S, Moreau-Dubois M.C, Brown P, Cathala F, Gajdusek D.C. Serum antibodies to neurofilament antigens in patients with neurological and other diseases and in healthy controls. Journal of Neuroimmunology. 1983;5:191–196. [PubMed: 6352741]
14. Baig S, Olsson T, Yu-Ping J, Hojeberg B, Cruz M, Link H. Multiple sclerosis: Cells secreting antibodies against myelin-associated glycoprotein are present in cerebrospinal fluid. Scandinavian Journal of Immunology. 1991;33:73–79. [PubMed: 1705050]
15. Bake S, Friedman J.A, Sohrabji F. Reproductive age-related changes in the blood brain barrier: Expression of IgG and tight junction proteins. Microvascular Research. 2009;78:413–424. [PMC free article: PMC2784250] [PubMed: 19591848]
16. Baloyannis S.J, Gonatas N.K. Distribution of anti-HRP antibodies in the central nervous system of immunized rats after disruption of the blood brain barrier. J Neuropathology and Experimental Neurology. 1979;38:519–531. [PubMed: 313978]
17. Banks W.A. Blood-brain barrier transport of cytokines: A mechanism for neuropathology. Current Pharmaceutical Design. 2005;11:973–984. [PubMed: 15777248]
18. Bansal D, Herbert F, Lim P, Deshpande P, Becavin C, Guiyedi V. et al. IgG autoantibody to brain beta tubulin III associated with cytokine cluster-II discriminate cerebral malaria in central India. PLoS One. 2009;4:e8245. [PMC free article: PMC2788233] [PubMed: 20011600]
19. Bard F, Cannon C, Barbour R, Burke R.L, Games D, Grajeda H. et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine. 2000;6:916–919. [PubMed: 10932230]
20. Bartos A, Fialova L, Svarcova J, Ripova D. Patients with Alzheimer disease have elevated intrathecal synthesis of antibodies against tau protein and heavy neurofilament. Journal of Neuroimmunology. 2012;252:100–105. [PubMed: 22948089]
21. Behan P.O, Lowenstein L.M, Stilmant M, Sax D.S. Landry-Guillain-Barre-Strohl syndrome and immune-complex nephritis. Lancet. 1973;1:850–854. [PubMed: 4123402]
22. Ben-Ami S.D, Blank M, Altman A. [The clinical importance of anti-ribosomal-P antibodies] Harefuah. 2010;149:794–810. [PubMed: 21916104]
23. Berg D.K, Conroy W.G. Nicotinic alpha 7 receptors: Synaptic options and downstream signaling in neurons. Journal of Neurobiology. 2002;53:512–523. [PubMed: 12436416]
24. Berghs S, Ferracci F, Maksimova E, Gleason S, Leszczynski N, Butler M. et al. Autoimmunity to beta IV spectrin in paraneoplastic lower motor neuron syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:6945–6950. [PMC free article: PMC34458] [PubMed: 11391009]
25. Berghs S.A, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel J.M. et al. beta IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier. The Journal of Cell Biology. 2000;151:985–1002. [PMC free article: PMC2174349] [PubMed: 11086001]
26. Beuche W, Friede R.L. Myelin phagocytosis in Wallerian degeneration of peripheral nerves depends on silica-sensitive, bg/bg-negative and Fc-positive monocytes. Brain Research. 1986;378:97–106. [PubMed: 3017506]
27. Bitsch A, Dressel A, Meier K, Bogumil T, Deisenhammer F, Tumanial et H. Autoantibody synthesis in primary progressive multiple sclerosis patients treated with interferon beta-1b. Journal of Neurology. 2004;251:1498–1501. [PubMed: 15645350]
28. Bjorklund H, Eriksdotter-Nilsson M, Dahl D, Rose G, Hoffer B, Olson L. Image analysis of GFA-positive astrocytes from adolescence to senescence. Experimental Brain Research. 1985;58:163–170. [PubMed: 3987847]
29. Blight A.R. Remyelination, revascularization, and recovery of function in experimental spinal cord injury. Advances in Neurology. 1993;59:91–104. [PubMed: 8420127]
30. Blight A.R. Effects of silica on the outcome from experimental spinal cord injury: Implication of macrophages in secondary tissue damage. Neuroscience. 1994;60:263–273. [PubMed: 8052418]
31. Borovikova L.V, Ivanova S, Zhang M, Yang H, Botchkina G.I, Watkins L.R. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462. [PubMed: 10839541]
32. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen R.L, Ashwood P. et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Translational Psychiatry. 2013;3:e277. [PMC free article: PMC3731784] [PubMed: 23838888]
33. Braunschweig D, Duncanson P, Boyce R, Hansen R, Ashwood P, Pessah I.N, Hertz-Picciotto I, Van de Water J. Behavioral correlates of maternal antibody status among children with autism. Journal of Autism and Developmental Disorders. 2012;42:1435–1445. [PMC free article: PMC4871696] [PubMed: 22012245]
34. Braunschweig D, Van de Water J. Maternal autoantibodies in autism. Archives of Neurology. 2012;69:693–699. [PMC free article: PMC4776649] [PubMed: 22689191]
35. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen L.A, Pessah I.N. et al. Autism: Maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 2008;29:226–231. [PMC free article: PMC2305723] [PubMed: 18078998]
36. Bressler J.P, Goldstein G.W. Mechanisms of lead neurotoxicity. Biochemical Pharmacology. 1991;41:479–484. [PubMed: 1671748]
37. Brock T.O, O’Callaghan J.P. Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system. Journal of Neuroscience. 1987;7:931–942. [PMC free article: PMC6569013] [PubMed: 3106588]
38. Connolly A.M, Chez M, Streif E.M, Keeling R.M, Golumbek P.T, Kwon J.M. et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biological Psychiatry. 2006;59:354–363. [PubMed: 16181614]
39. Connolly A.M, Chez M.G, Pestronk A, Arnold S.T, Mehta S, Deuel R.K. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. The Journal of Pediatrics. 1999;134:607–613. [PubMed: 10228297]
40. Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A. et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2004a;101:11064–11069. [PMC free article: PMC503741] [PubMed: 15263096]
41. Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A. et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2004b;101:11064–11069. [PMC free article: PMC503741] [PubMed: 15263096]
42. Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M. Activation of the inflammatory response system in autism. Neuropsychobiology. 2002;45:1–6. [PubMed: 11803234]
43. Cross A.H, Trotter J.L, Lyons J.A. B cells and antibodies in CNS demyelinating disease. Journal of Neuroimmunology. 2001;112:1–14. [PubMed: 11108928]
44. Cruse J.M, Lewis R.E, Roe D.L, Dilioglou S, Blaine M.C, Wallace W.F. et al. Facilitation of immune function, healing of pressure ulcers, and nutritional status in spinal cord injury patients. Experimental and Molecular Pathology. 2000;68:38–54. [PubMed: 10640453]
45. Dalakas M.C. B cells as therapeutic targets in autoimmune neurological disorders. Nature Clinical Practice. Neurology. 2008a;4:557–567. [PubMed: 18813230]
46. Dalakas M.C. Invited article: Inhibition of B cell functions - Implications for neurology. Neurology. 2008b;70:2252–2260. [PubMed: 18519875]
47. Dalakas M.C. Invited article: Inhibition of B cell functions: Implications for neurology. Neurology. 2008c;70:2252–2260. [PubMed: 18519875]
48. Dalmau J, Rosenfeld M.R. Paraneoplastic syndromes of the CNS. Lancet Neurology. 2008;7:327–340. [PMC free article: PMC2367117] [PubMed: 18339348]
49. Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J. et al. Maternal neuronal antibodies associated with autism and a language disorder. Annals of Neurology. 2003;53:533–537. [PubMed: 12666123]
50. Darnell R.B, Furneaux H.M, Posner J.B. Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors. Journal of Neuroscience. 1991;11:1224–1230. [PMC free article: PMC6575333] [PubMed: 1851215]
51. Davidson A, Diamond B. Advances in immunology - Autoimmune diseases. New England Journal of Medicine. 2001;345:340–350. [PubMed: 11484692]
52. Davies A.L, Hayes K.C, Dekaban G.A. Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Archives of Physical Medicine and Rehabilitation. 2007;88:1384–1393. [PubMed: 17964877]
53. DeGiorgio L.A, Konstantinov K.N, Lee S.C, Hardin J.A, Volpe B.T, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nature Medicine. 2001;7:1189–1193. [PubMed: 11689882]
54. Dekaban G.A, Thawer S. Pathogenic antibodies are active participants in spinal cord injury. The Journal of Clinical Investigation. 2009;119:2881–2884. [PMC free article: PMC2752091] [PubMed: 19770517]
55. Diamond B, Honig G, Mader S, Brimberg L, Volpe B.T. Brain-reactive antibodies and disease. Annual Review of Immunology. 2013;31:345–385. [PMC free article: PMC4401150] [PubMed: 23516983]
56. Dicou E, Hurez D, Nerriere V. Natural autoantibodies against the nerve growth factor in autoimmune diseases. Journal of Neuroimmunology. 1993;47:159–167. [PubMed: 8370767]
57. Dorner T, Radbruch A, Burmester G.R. B-cell-directed therapies for autoimmune disease. Nature Reviews. Rheumatology. 2009;5:433–441. [PubMed: 19581902]
58. Drisdel R.C, Green W.N. Neuronal alpha-bungarotoxin receptors are alpha7 subunit homomers. Journal of Neuroscience. 2000;20:133–139. [PMC free article: PMC6774106] [PubMed: 10627589]
59. Dudley D.J. The immune-system in health and disease. Bailliere’s Clinical Obstetrics and Gynecology. 1992;6:393–416. [PubMed: 1446415]
60. Ekizoglu E, Tuzun E, Woodhall M, Lang B, Jacobson L, Icoz S. et al. Investigation of neuronal autoantibodies in two different focal epilepsy syndromes. Epilepsia. 2014;55:414–422. [PubMed: 24502404]
61. El-Fawal H.A, McCain W.C. Antibodies to neural proteins in organophosphorus-induced delayed neuropathy (OPIDN) and its amelioration. Neurotoxicology and teratology. 2008;30:161–166. [PubMed: 18353611]
62. El-Fawal H.A, Waterman S.J, De Feo A, Shamy M.Y. Neuroimmunotoxicology: Humoral assessment of neurotoxicity and autoimmune mechanisms. Environmental Health Perspectives. 1999;107 Suppl 5:767–775. [PMC free article: PMC1566239] [PubMed: 10502543]
63. Eng L.F, Vanderhaeghen J.J, Bignami A, Gerstl B. An acidic protein isolated from fibrous astrocytes. Brain Research. 1971;28:351–354. [PubMed: 5113526]
64. Evans H.L. Markers of neurotoxicity - from behavior to autoantibodies against brain proteins. Clinical Chemistry. 1995;41:1874–1881. [PubMed: 7497648]
65. Fairweather D, Rose N.R. Women and autoimmune diseases. Emerging Infectious Diseases. 2004;10:2005–2011. [PMC free article: PMC3328995] [PubMed: 15550215]
66. Fazio V, Bhudia S.K, Marchi N, Aumayr B, Janigro D. Peripheral detection of S100beta during cardiothoracic surgery: What are we really measuring? The Annals of Thoracic Surgery. 2004;78:46–52. discussion 52–43. [PubMed: 15223400]
67. Fernandez-Shaw C, Marina A, Cazorla P, Valdivieso F, Vazquez J. Anti-brain spectrin immunoreactivity in Alzheimer’s disease: Degradation of spectrin in an animal model of cholinergic degeneration. Journal of Neuroimmunology. 1997;77:91–98. [PubMed: 9209273]
68. Fialova L, Bartos A, Svarcova J, Zimova D, Kotoucova J. Serum and cerebrospinal fluid heavy neurofilaments and antibodies against them in early multiple sclerosis. Journal of Neuroimmunology. 2013a;259:81–87. [PubMed: 23632043]
69. Fialova L, Bartos A, Svarcova J, Zimova D, Kotoucova J, Malbohan I. Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. Journal of Neuroimmunology. 2013b;262:113–120. [PubMed: 23870535]
70. Fleming J.C, Norenberg M.D, Ramsay D.A, Dekaban G.A, Marcillo A.E, Saenz A.D. et al. The cellular inflammatory response in human spinal cords after injury. Brain. 2006;129:3249–3269. [PubMed: 17071951]
71. Floyd S, Butler M.H, Cremona O, David C, Freyberg Z, Zhang X. et al. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Molecular Medicine. 1998;4:29–39. [PMC free article: PMC2230265] [PubMed: 9513187]
72. Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G. et al. Autoantibodies to a 128-Kd synaptic protein in 3 women with the Stiff-Man Syndrome and breast-cancer. New England Journal of Medicine. 1993;328:546–551. [PubMed: 8381208]
73. Frye R.E, Sequeira J.M, Quadros E.V, James S.J, Rossignol D.A. Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry. 2013;18:369–381. [PMC free article: PMC3578948] [PubMed: 22230883]
74. Galea I, Bechmann I, Perry V.H. What is immune privilege (not)? Trends in Immunology. 2007;28:12–18. [PubMed: 17129764]
75. Genain C.P, Cannella B, Hauser S.L, Raine C.S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Medicine. 1999;5:170–175. [PubMed: 9930864]
76. Gitlits V.M, Sentry J.W, Matthew L.S, Smith A.I, Toh B.H. Synapsin I identified as a novel brain-specific autoantigen. Journal of Investigative Medicine. 2001;49:276–283. [PubMed: 11352186]
77. Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L. et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain, Behavior, and Immunity. 2011;25:514–523. [PMC free article: PMC3039058] [PubMed: 21134442]
78. Goines P, Van de Water J. The immune system’s role in the biology of autism. Current Opinion in Neurology. 2010;23:111–117. [PMC free article: PMC2898160] [PubMed: 20160651]
79. Gold R, Stangel M, Dalakas M.C. Drug Insight: The use of intravenous immunoglobulin in neurology - therapeutic considerations and practical issues. Nature Clinical Practice. Neurology. 2007;3:36–44. [PubMed: 17205073]
80. Gresa-Arribas N, Titulaer M.J, Torrents A, Aguilar E, McCracken L, Leypoldt F. et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: A retrospective study. Lancet Neurology. 2014;13:167–177. [PMC free article: PMC4006368] [PubMed: 24360484]
81. Griot-Wenk M, Griot C, Pfister H, Vandevelde M. Antibody-dependent cellular cytotoxicity in antimyelin antibody-induced oligodendrocyte damage in vitro. Journal of Neuroimmunology. 1991;33:145–155. [PubMed: 2066397]
82. Hayakawa T, Ushio Y, Mori T, Arita N, Yoshimine T, Maeda Y. et al. Levels in stroke patients of CSF astroprotein, an astrocyte-specific cerebroprotein. Stroke. 1979;10:685–689. [PubMed: 524409]
83. Hayes K.C, Hull T.C, Delaney G.A, Potter P.J, Sequeira K.A, Campbell K. et al. Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. Journal of Neurotrauma. 2002;19:753–761. [PubMed: 12165135]
84. Hedegaard C.J, Chen N, Sellebjerg F, Sorensen P.S, Leslie R.G, Bendtzen K. et al. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: A role in regulating cytokine responses to MBP. Immunology. 2009;128:e451–461. [PMC free article: PMC2753924] [PubMed: 19191913]
85. Howe C.L, Bieber A.J, Warrington A.E, Pease L.R, Rodriguez M. Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiology of Disease. 2004;15:120–131. [PubMed: 14751777]
86. Ingram C.R, Phegan K.J, Blumenthal H.T. Significance of an aging-linked neuron binding gamma globulin fraction of human sera. Journal of Gerontology. 1974;29:20–27. [PubMed: 4129288]
87. Iversen P.O, Hjeltnes N, Holm B, Flatebo T, Strom-Gundersen I, Ronning W. et al. Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury. Blood. 2000;96:2081–2083. [PubMed: 10979951]
88. Joachim S.C, Wax M.B, Boehm N, Dirk D.R, Pfeiffer N, Grus F.H. Upregulation of antibody response to heat shock proteins and tissue antigens in an ocular ischemia model. Investigative Ophthalmology andand Visual Science. 2011;52:3468–3474. [PubMed: 21310899]
89. Jones A.L, Mowry B.J, McLean D.E, Mantzioris B.X, Pender M.P, Greer J.M. Elevated levels of autoantibodies targeting the M1 muscarinic acetylcholine receptor and neurofilament medium in sera from subgroups of patients with schizophrenia. Journal of Neuroimmunology. 2014;269:68–75. [PubMed: 24636402]
90. Kamchatnov P.R, Ruleva N.Y, Dugin S.F, Buriachkovskaya L.I, Chugunov A.V, Mikhailova N.A. et al. Neurospecific proteins and autoantibodies in serum of patients with acute ischemic stroke. Zhurnal Neurologii i Psikhiatrii. 2009;109:69–72. [PubMed: 19894304]
91. Kanada M, Miyagawa M, Sato M, Hasegawa H, Honma T. Neurochemical profile of effects of 28 neurotoxic chemicals on the central nervous system in rats (1). Effects of oral administration on brain contents of biogenic amines and metabolites. Industrial Health. 1994;32:145–164. [PubMed: 7698903]
92. Katz D.H. Adaptive differentiation of lymphocytes: Theoretical implications for mechanisms of cell— cell recognition and regulation of immune responses. Advances in Immunology. 1980;29:137–207. [PubMed: 6774599]
93. Keller J.N, Mattson M.P. Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. Reviews in the Neurosciences. 1998;9:105–116. [PubMed: 9711902]
94. Kelly D.F, Gonzalo I.T, Cohan P, Berman N, Swerdloff R, Wang C. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A preliminary report. Journal of Neurosurgery. 2000;93:743–752. [PubMed: 11059653]
95. Kergonou J.F, Pennacino I, Lafite C, Ducousso R. Immunological relevance of malonic dialdehyde (Mda). 2. Precipitation reactions of human-sera with Mda-crosslinked proteins. Biochemistry International. 1988;16:835–843. [PubMed: 3138998]
96. Kida S, Pantazis A, Weller R.O. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathology and Applied Neurobiology. 1993;19:480–488. [PubMed: 7510047]
97. Kigerl K.A, McGaughy V.M, Popovich P.G. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. The Journal of Comparative Neurology. 2006;494:578–594. [PMC free article: PMC2655318] [PubMed: 16374800]
98. Kil K, Zang Y.C, Yang D, Markowski J, Fuoco G.S, Vendetti G.C. et al. T cell responses to myelin basic protein in patients with spinal cord injury and multiple sclerosis. Journal of Neuroimmunology. 1999;98:201–207. [PubMed: 10430053]
99. Kingsley B.S, Gaskin F, Fu S.M. Human antibodies to neurofibrillary tangles and astrocytes in Alzheimer’s disease. Journal of Neuroimmunology. 1988;19:89–99. [PubMed: 3260906]
100. Kirkman N.J, Libbey J.E, Sweeten T.L, Coon H.H, Miller J.N, Stevenson E.K. et al. How relevant are GFAP autoantibodies in autism and Tourette Syndrome? Journal of Autism and Developmental Disorders. 2008;38:333–341. [PubMed: 17578659]
101. Kliesch W.F, Cruse J.M, Lewis R.E, Bishop G.R, Brackin B, Lampton J.A. Restoration of depressed immune function in spinal cord injury patients receiving rehabilitation therapy. Paraplegia. 1996;34:82–90. [PubMed: 8835031]
102. Kowal C, DeGiorgio L.A, Nakaoka T, Hetherington H, Huerta P.T, Diamond B. et al. Cognition and immunity; antibody impairs memory. Immunity. 2004;21:179–188. [PubMed: 15308099]
103. Le Couteur A, Haden G, Hammal D, McConachie H. Diagnosing autism spectrum disorders in pre-school children using two standardised assessment instruments: The ADI-R and the ADOS. Journal of Autism and Developmental Disorders. 2008;38:362–372. [PubMed: 17605097]
104. Levesque M.C, St Clair E.W. B cell-directed therapies for autoimmune disease and correlates of disease response and relapse. The Journal of Allergy and Clinical Immunology. 2008;121:13–21. quiz 22–33. [PubMed: 18206502]
105. Levy N.L, Mahaley M.S Jr, Day E.D. In vitro demonstration of cell-mediated immunity to human brain tumors. Cancer Research. 1972;32:477–482. [PubMed: 4334410]
106. Lord C, Cook E.H, Leventhal B.L, Amaral D.G. Autism spectrum disorders. Neuron. 2000a;28:355–363. [PubMed: 11144346]
107. Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S. et al. Diagnosing autism: Analyses of data from the Autism Diagnostic Interview. Journal of Autism and Developmental Disorders. 1997;27:501–517. [PubMed: 9403369]
108. Lord C, Risi S, Lambrecht L, Cook E.H Jr, Leventhal B.L, DiLavore P.C. et al. The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders. 2000b;30:205–223. [PubMed: 11055457]
109. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders. 1994;24:659–685. [PubMed: 7814313]
110. Lotti M. Cholinesterase inhibition: Complexities in interpretation. Clinical Chemistry. 1995;41:1814–1818. [PubMed: 7497638]
111. Lu X.Y, Chen X.X, Huang L.D, Zhu C.Q, Gu Y.Y, Ye S. Anti-alpha-internexin autoantibody from neuropsychiatric lupus induce cognitive damage via inhibiting axonal elongation and promote neuron apoptosis. PLoS One. 2010;5:e11124. [PMC free article: PMC2886066] [PubMed: 20559547]
112. Lucin K.M, Sanders V.M, Jones T.B, Malarkey W.B, Popovich P.G. Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Experimental Neurology. 2007;207:75–84. [PMC free article: PMC2023967] [PubMed: 17597612]
113. Lyons J.A, San M, Happ M.P, Cross A.H. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. European Journal of Immunology. 1999;29:3432–3439. [PubMed: 10556797]
114. Maetzler W, Berg D, Synofzik M, Brockmann K, Godau J, Melms A. et al. Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. Journal of Alzheimer’s disease. 2011;26:171–179. [PubMed: 21593566]
115. Mailman R.B, Lewis M.H. Neurotoxicants and central catecholamine systems. Neurotoxicology. 1987;8:123–139. [PubMed: 3031560]
116. Malek A, Sager R, Kuhn P, Nicolaides K.H, Schneider H. Evolution of maternofetal transport of immunoglobulins during human pregnancy. American Journal of Reproductive Immunology. 1996;36:248–255. [PubMed: 8955500]
117. Marchi N, Bazarian J.J, Puvenna V, Janigro M, Ghosh C, Zhong J. et al. Consequences of repeated blood-brain barrier disruption in football players. PloS One. 2013a;8:e56805. [PMC free article: PMC3590196] [PubMed: 23483891]
118. Marchi N, Bazarian J.J, Puvenna V, Janigro M, Ghosh C, Zhong J.H. et al. Consequences of repeated blood-brain barrier disruption in football players. PloS One. 2013b;8:e56805. [PMC free article: PMC3590196] [PubMed: 23483891]
119. Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D. Peripheral markers of blood-brain barrier damage. Clinica Chimica Acta. 2004;342:1–12. [PubMed: 15026262]
120. Marchi N, Rasmussen P, Kapural M, Fazio V, Kight K, Mayberg M.R. et al. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restorative Neurology and Neuroscience. 2003;21:109–121. [PMC free article: PMC4066375] [PubMed: 14530574]
121. Martin L.A, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral D.G. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain, Behavior, and Immunity. 2008;22:806–816. [PMC free article: PMC3779644] [PubMed: 18262386]
122. Mason D.L, Assimon M.M, Bishop J.R, El-Fawal H.A. Nervous system autoantibodies and vitamin D receptor gene polymorphisms in hemodialysis patients. Hemodialysis International. 2013;17:3–11. [PMC free article: PMC3919036] [PubMed: 22897631]
123. Matsushita T, Tedder T.F. B-lymphocyte depletion for the treatment of multiple sclerosis: Now things really get interesting. Expert Review of Neurotherapeutics. 2009;9:309–312. [PubMed: 19271937]
124. Mcraedegueurce A, Booj S, Haglid K, Rosengren L, Karlsson J.E, Karlsson I. et al. Antibodies in cerebrospinal-fluid of some Alzheimer-disease patients recognize cholinergic neurons in the rat central nervous-system. Proceedings of the National Academy of Sciences of the United States of America. 1987;84:9214–9218. [PMC free article: PMC299723] [PubMed: 3321070]
125. Mecocci P, Parnetti L, Donato R, Santucci C, Santucci A, Cadini D. et al. Serum autoantibodies against glial fibrillary acidic protein in brain aging and senile dementias. Brain, Behavior, and Immunity. 1992;6:286–292. [PubMed: 1392102]
126. Mizrachi Y, Ohry A, Aviel A, Rozin R, Brooks M.E, Schwartz M. Systemic humoral factors participating in the course of spinal cord injury. Paraplegia. 1983;21:287–293. [PubMed: 6196708]
127. Moneim I.A, Shamy M.Y, el-Gazzar R.M, El-Fawal H.A. Autoantibodies to neurofilaments (NF), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) in workers exposed to lead. The Journal of the Egyptian Public Health Association. 1999;74:121–138. [PubMed: 17216956]
128. Moody M, Zipp M, Al-Hashimi I. Salivary anti-spectrin autoantibodies in Sjogren’s syndrome. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2001;91:322–327. [PubMed: 11250630]
129. Moretto A, Bertolazzi M, Lotti M. The phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl ester exacerbates organophosphate polyneuropathy without inhibition of neuropathy target esterase. Toxicology and Applied Pharmacology. 1994;129:133–137. [PubMed: 7974486]
130. Mori T, Morimoto K, Hayakawa T, Ushio Y, Mogami H, Sekiguchi K. Radioimmunoassay of astroprotein (an astrocyte-specific cerebroprotein) in cerebrospinal fluid and its clinical significance. Neurologia Medico-chirurgica. 1978;18:25–31. [PubMed: 77492]
131. Morris C.M, Pardo-Villamizar C, Gause C.D, Singer H.S. Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. Journal of the Neurological Sciences. 2009;276:45–48. [PubMed: 18823914]
132. Mosley K, Cuzner M.L. Receptor-mediated phagocytosis of myelin by macrophages and microglia: Effect of opsonization and receptor blocking agents. Neurochemical Research. 1996;21:481–487. [PubMed: 8734442]
133. Mostafa G.A, Al-Ayadhi L.Y. The possible link between the elevated serum levels of neurokinin A and anti-ribosomal P protein antibodies in children with autism. Journal of Neuroinflammation. 2011;8:180. [PMC free article: PMC3261830] [PubMed: 22189180]
134. Mostafa G.A, Ibrahim D.H, Shehab A.A, Mohammed A.K. The role of measurement of serum autoantibodies in prediction of pediatric neuropsychiatric systemic lupus erythematosus. Journal of Neuroimmunology. 2010;227:195–201. [PubMed: 20724007]
135. Mundiyanapurath S, Jarius S, Probst C, Stocker W, Wildemann B, Bosel J. GABA-B-receptor antibodies in paraneoplastic brainstem encephalitis. Journal of Neuroimmunology. 2013;259:88–91. [PubMed: 23628208]
136. Murakami H, Iijima S, Kawamura M, Takahashi Y, Ichikawa H. [A case of acute cerebellar ataxia following infectious mononucleosis accompanied by intrathecal anti-glutamate receptor delta2 antibody] Rinsho shinkeigaku. 2013;53:555–558. [PubMed: 23892968]
137. Murphy W.H, Tam M.R, Lanzi R.L, Abell M.R, Kauffman C. Age dependence of immunologically induced central nervous system disease in C58 mice. Cancer Research. 1970;30:1612–1622. [PubMed: 4318695]
138. Nandy K. Brain-reactive antibodies in mouse serum as a function of age. Journal of Gerontology. 1972;27:173–177. [PubMed: 4110581]
139. Neuwelt E.A, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nature Reviews. Neuroscience. 2011;12:169–182. [PMC free article: PMC3335275] [PubMed: 21331083]
140. Ngankam L, Kazantseva N.V, Gerasimova M.M. Immunological markers of severity and outcome of traumatic brain injury. Zhurnal Neurologii i Psikhiatrii. 2011;111:61–65. [PubMed: 21947074]
141. Niebroj-Dobosz I, Dziewulska D, Janik P. Auto-antibodies against proteins of spinal cord cells in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Folia Neuropathologica. 2006;44:191–196. [PubMed: 17039414]
142. National Institutes of Health; Bethesda, MD: Autoimmune Diseases Research Plan. 2002 National Institutes of Health Autoimmune Diseases Coordinating Committee Report.
143. Op De Beeck K, Van den Bergh K, Vermeire S, Decock S, Derua R, Waelkens E. et al. Immune reactivity to beta-tubulin isotype 5 and vesicular integral-membrane protein 36 in patients with autoimmune gastrointestinal disorders. Gut. 2011;60:1601–1602. [PubMed: 21159894]
144. Outteryck O, Baille G, Hodel J, Giroux M, Lacour A, Honnorat J. et al. Extensive myelitis associated with anti-NMDA receptor antibodies. BMC Neurology. 2013;13:211. [PMC free article: PMC3880834] [PubMed: 24373538]
145. Pardo C.A, Vargas D.L, Zimmerman A.W. Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry. 2005;17:485–495. [PubMed: 16401547]
146. Pavlowsky A, Gianfelice A, Pallotto M, Zanchi A, Vara H, Khelfaoui M. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Current Biology. 2010;20:103–115. [PubMed: 20096586]
147. Paz Soldan M.M, Warrington A.E, Bieber A.J, Ciric B, Van Keulen V, Pease L.R. et al. Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: Relationship to the mechanism of myelin repair. Molecular and Cellular Neurosciences. 2003;22:14–24. [PubMed: 12595235]
148. Pinelis V.G, Sorokina E.G. [Autoimmune mechanisms of modulation of the activity of glutamate receptors in children with epilepsy and craniocerebral injury] Vestnik Rossiiskoi akademii meditsinskikh nauk/Rossiiskaia akademiia meditsinskikh nauk. 2008:44–51. [PubMed: 19189459]
149. Pirko I, Ciric B, Gamez J, Bieber A.J, Warrington A.E, Johnson A.J. et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB Journal. 2004;18:1577–1579. [PubMed: 15319372]
150. Piton A, Michaud J.L, Peng H, Aradhya S, Gauthier J, Mottron L. et al. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Human Molecular Genetics. 2008;17:3965–3974. [PubMed: 18801879]
151. Poletaev A, Boura P. The immune system, natural autoantibodies and general homeostasis in health and disease. Hippokratia. 2011;15:295–298. [PMC free article: PMC3876841] [PubMed: 24391407]
152. Popovic M, Caballero-Bleda M, Puelles L, Popovic N, Popovic N. Importance of immunological and inflammatory processes in the pathogenesis and therapy of Alzheimer’s disease. International Journal of Neuroscience. 1998;95:203–236. [PubMed: 9777440]
153. Popovich P.G, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes B.T. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Experimental Neurology. 1999;158:351–365. [PubMed: 10415142]
154. Porcelli B, Ferretti F, Vindigni C, Scapellato C, Terzuoli L. Detection of autoantibodies against actin filaments in celiac disease. Journal of Clinical Laboratory Analysis. 2013;27:21–26. [PMC free article: PMC6807443] [PubMed: 23292801]
155. Posner J.B, Dalmau J. Paraneoplastic syndromes. Current Opinion in Immunology. 1997a;9:723–729. [PubMed: 9368783]
156. Posner J.B, Dalmau J.O. Paraneoplastic syndromes affecting the central nervous system. Annual Review of Medicine. 1997b;48:157–166. [PubMed: 9046952]
157. Prinz M, Priller J, Sisodia S.S, Ransohoff R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neuroscience. 2011;14:1227–1235. [PubMed: 21952260]
158. Raine C.S, Cannella B, Hauser S.L, Genain C.P. Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: A case for antigen-specific antibody mediation. Annals of Neurology. 1999;46:144–160. [PubMed: 10443879]
159. Ramaekers V.T, Quadros E.V, Sequeira J.M. Role of folate receptor autoantibodies in infantile autism. Molecular Psychiatry. 2013;18:270–271. [PubMed: 22488256]
160. Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clinica Chimica Acta. 2001;310:173–186. [PubMed: 11498083]
161. Reiber H. Proteins in cerebrospinal fluid and blood: Barriers, CSF flow rate and source-related dynamics. Restorative Neurology and Neuroscience. 2003;21:79–96. [PubMed: 14530572]
162. Rosas-Ballina M, Tracey K.J. Cholinergic control of inflammation. Journal of Internal Medicine. 2009;265:663–679. [PMC free article: PMC4540232] [PubMed: 19493060]
163. Rothenberg S.P, da Costa M.P, Sequeira J.M, Cracco J, Roberts J.L, Weedon J. et al. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. The New England Journal of Medicine. 2004;350:134–142. [PubMed: 14711912]
164. Rudehill S, Muhallab S, Wennersten A, von Gertten C, Al Nimer F, Sandberg-Nordqvist A.C. et al. Autoreactive antibodies against neurons and basal lamina found in serum following experimental brain contusion in rats. Acta Neurochirurgia. 2006;148:199–205. [PubMed: 16362182]
165. Schwartz M, Kipnis J. Protective autoimmunity: Regulation and prospects for vaccination after brain and spinal cord injuries. Trends in Molecular Medicine. 2001;7:252–258. [PubMed: 11378514]
166. Simister N.E. Placental transport of immunoglobulin G. Vaccine. 2003;21:3365–3369. [PubMed: 12850341]
167. Singer H.S, Morris C, Gause C, Pollard M, Zimmerman A.W, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model. Journal of Neuroimmunology. 2009;211:39–48. [PubMed: 19362378]
168. Singer H.S, Morris C.M, Williams P.N, Yoon D.Y, Hong J.J, Zimmerman A.W. Antibrain antibodies in children with autism and their unaffected siblings. Journal of Neuroimmunology. 2006;178:149–155. [PubMed: 16842863]
169. Singh V.K, Warren R.P, Odell J.D, Warren W.L, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain, Behavior, and Immunity. 1993;7:97–103. [PubMed: 7682457]
170. Sjogren M, Wallin A. Pathophysiological aspects of frontotemporal dementia - emphasis on cytoskeleton proteins and autoimmunity. Mechanisms of Ageing and Development. 2001;122:1923–1935. [PubMed: 11589911]
171. Skoda D, Kranda K, Bojar M, Glosova L, Baurle J, Kenney J. et al. Antibody formation against beta-tubulin class III in response to brain trauma. Brain Research Bulletin. 2006;68:213–216. [PubMed: 16377426]
172. Skouen J.S, Larsen J.L, Vollset S.E. Cerebrospinal fluid proteins as indicators of nerve root compression in patients with sciatica caused by disc herniation. Spine. 1993;18:72–79. [PubMed: 8434328]
173. Soares H.D, Hicks R.R, Smith D, McIntosh T.K. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. Journal of Neuroscience. 1995;15:8223–8233. [PMC free article: PMC6577921] [PubMed: 8613756]
174. Sorokina E.G, Semenova J.B, Granstrem O.K, Karaseva O.V, Meshcheryakov S.V, Reutov V.P. et al. S100B protein and autoantibodies to S100B protein in diagnostics of brain damage in craniocerebral trauma in children. Zhurnal Neurologii i Psikhiatrii. 2010;110:30–35. [PubMed: 20823827]
175. Sorokina E.G, Semenova Zh.B, Bazarnaya N.A, Meshcheryakov S.V, Reutov V.P, Goryunova A.V. et al. Autoantibodies to glutamate receptors and products of nitric oxide metabolism in serum in children in the acute phase of craniocerebral trauma. Neuroscience and Behavioral Physiology. 2009;39:329–334. [PubMed: 19340572]
176. Sorokina E.G, Storozhevykh T.P, Senilova Y.E, Granstrem O.K, Reutov V.P, Pinelis V.G. Effect of antibodies against AMPA glutamate receptors on brain neurons in primary cultures of the cerebellum and hippocampus. Bulletin of Experimental Biology and Medicine. 2006;142:51–54. [PubMed: 17369901]
177. Sorokina E.G, Vol’pina O.M, Semenova Zh B, Karaseva O.V, Koroev D.O, Kamynina A.V. et al. [Autoantibodies to alpha7-subunit of neuronal acetylcholine receptor in children with traumatic brain injury] Zhurnal Nevrologii i Psikhiatrii. 2011;111:56–60. [PubMed: 21512503]
178. Sotgiu S, Giua A, Murrighile M.R, Ortu R. A case of anti-myelin-associated glycoprotein polyneuropathy and multiple sclerosis: One disease instead of two? BMJ Case Reports. 2009:2009. [PMC free article: PMC3029969] [PubMed: 21686895]
179. Sroga J.M, Jones T.B, Kigerl K.A, McGaughy V.M, Popovich P.G. Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. The Journal of Comparative Neurology. 2003;462:223–240. [PubMed: 12794745]
180. Stefanova I, Dorfman J.R, Germain R.N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature. 2002;420:429–434. [PubMed: 12459785]
181. Stein T.D, Fedynyshyn J.P, Kalil R.E. Circulating autoantibodies recognize and bind dying neurons following injury to the brain. Journal of Neuropathology and Experimental Neurology. 2002;61:1100–1108. [PubMed: 12484573]
182. Stellwagen D, Malenka R.C. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440:1054–1059. [PubMed: 16547515]
183. Stephan A.H, Barres B.A, Stevens B. The complement system: An unexpected role in synaptic pruning during development and disease. Annual Review of Neuroscience. 2012;35:369–389. [PubMed: 22715882]
184. Storoni M, Petzold A, Plant G.T. The use of serum glial fibrillary acidic protein measurements in the diagnosis of neuromyelitis optica spectrum optic neuritis. PloS One. 2011;6:e23489. [PMC free article: PMC3158082] [PubMed: 21876753]
185. Sundstrom R, Kalimo H. Extracellular edema and glial response to it in the cerebellum of suckling rats with low-dose lead encephalopathy. An electron microscopic and immunohistochemical study. Acta Neuropathologica. 1987;75:116–122. [PubMed: 3434220]
186. Sundstrom R, Muntzing K, Kalimo H, Sourander P. Changes in the integrity of the blood-brain barrier in suckling rats with low dose lead encephalopathy. Acta Neuropathologica. 1985;68:1–9. [PubMed: 4050351]
187. Tanaka J, Murakoshi K, Takeda M, Kato Y, Tada K, Hariguchi S. et al. A high-level of anti-GFAP autoantibody in the serum of patients with Alzheimer’s disease. Biomedical Research-Tokyo. 1988;9:209–216.
188. Tanaka J, Nakamura K, Takeda M, Tada K, Suzuki H, Morita H. et al. Enzyme-linked immunosorbent-assay for human autoantibody to glial fibrillary acidic protein - higher titer of the antibody is detected in serum of patients with Alzheimer’s disease. Acta Neurologica Scandinavia. 1989;80:554–560. [PubMed: 2618583]
189. Tanriverdi F, De Bellis A, Battaglia M, Bellastella G, Bizzarro A, Sinisi A.A. et al. Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: Is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity? European Journal of Endocrinology. 2010;162:861–867. [PubMed: 20176736]
190. Tanriverdi F, De Bellis A, Bizzarro A, Sinisi A.A, Bellastella G, Pane E. et al. Antipituitary antibodies after traumatic brain injury: Is head trauma-induced pituitary dysfunction associated with autoimmunity? European Journal of Endocrinology/European Federation of Endocrine Societies. 2008a;159:7–13. [PubMed: 18463108]
191. Tanriverdi F, Senyurek H, Unluhizarci K, Selcuklu A, Casanueva F.F, Kelestimur F. High risk of hypopituitarism after traumatic brain injury: A prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma. The Journal of Clinical Endocrinology and Metabolism. 2006;91:2105–2111. [PubMed: 16522687]
192. Tanriverdi F, Ulutabanca H, Unluhizarci K, Selcuklu A, Casanueva F.F, Kelestimur F. Three years prospective investigation of anterior pituitary function after traumatic brain injury: A pilot study. Clinical Endocrinology. 2008b;68:573–579. [PubMed: 17970777]
193. Terry R.D, Wisnewski H. Aging and the Brain. Plenum Press; New York: 1972. Ultrastructure of senile dementia and of experimental analogs. In.
194. Thomas L, Mailles A, Desestret V, Ducray F, Mathias E, Rogemond V. et al. Autoimmune N-methyl-D-aspartate receptor encephalitis is a differential diagnosis of infectious encephalitis. The Journal of Infection. 2014;68:419–425. [PubMed: 24355654]
195. Threatt J, Nandy K, Fritz R. Brain-reactive antibodies in serum of old mice demonstrated by immunofluorescence. Journal of Gerontology. 1971;26:316–323. [PubMed: 4937292]
196. Todd R.D, Hickok J.M, Anderson G.M, Cohen D.J. Antibrain antibodies in infantile autism. Biological Psychiatry. 1988;23:644–647. [PubMed: 3355880]
197. Trippe J, Steinke K, Orth A, Faustmann P.M, Hollmann M, Haase C.G. Autoantibodies to glutamate receptor antigens in multiple sclerosis and Rasmussen’s encephalitis. Neuroimmunomodulation. 2014;21:189–194. [PubMed: 24504116]
198. Tron F. [Autoantibodies as biomarkers] Presse Medicále. 2014;43:57–65. [PubMed: 24387998]
199. Tsuburaya R.S, Miki N, Tanaka K, Kageyama T, Irahara K, Mukaida S. et al. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a Japanese boy with recurrent optic neuritis. Brain and Development. 2014 Feb 28; [PubMed: 24582475]
200. Tsuchiya H, Haga S, Takahashi Y, Kano T, Ishizaka Y, Mimori A. Identification of novel autoantibodies to GABAB receptors in patients with neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford). 2014;53:1219–1228. [PubMed: 24599914]
201. Uchida K, Stadtman E.R. Modification of histidine-residues in proteins by reaction with 4-hydroxynonenal. Proceedings of the National Academy of Sciences of the United States of America. 1992;89:4544–4548. [PMC free article: PMC49119] [PubMed: 1584790]
202. Ulvestad E, Williams K, Matre R, Nyland H, Olivier A, Antel J. Fc-receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets. J Neuropathol Exp Neurol. 1994;53:27–36. [PubMed: 8301317]
203. van Gent T, Heijnen C.J, Treffers P.D. Autism and the immune system. Journal of child Psychology and Psychiatry, and Allied Disciplines. 1997;38:337–349. [PubMed: 9232480]
204. Vargas D.L, Nascimbene C, Krishnan C, Zimmerman A.W, Pardo C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology. 2005;57:67–81. [PubMed: 15546155]
205. Veerhuis R, Nielsen H.M, Tenner A.J. Complement in the brain. Molecular Immunology. 2011;48:1592–1603. [PMC free article: PMC3142281] [PubMed: 21546088]
206. Vincent A, Bien C.G, Irani S.R, Waters P. Autoantibodies associated with diseases of the CNS: New developments and future challenges. Lancet Neurology. 2011;10:759–772. [PubMed: 21777830]
207. Vlajkovic S, Jankovic B.D. Experimental epilepsy in vitro: Neuromodulating activity of anti-brain autoantibodies from rats exposed to electroconvulsive shock. International Journal of Neuroscience. 1991;59:205–211. [PubMed: 1723059]
208. Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian A.A, Eghbalieh N. et al. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clinical and Diagnostic Laboratory Immunology. 2004;11:515–524. [PMC free article: PMC404567] [PubMed: 15138176]
209. Wang H, Munger K.L, Reindl M, O’Reilly E.J, Levin L.I, Berger T. et al. Myelin oligodendrocyte glycoprotein antibodies and multiple sclerosis in healthy young adults. Neurology. 2008;71:1142–1146. [PubMed: 18753473]
210. Wang K.K.W. Calpain and caspase: Can you tell the difference? Trends in Neurosciences. 2000;23:59–59. [PubMed: 10652545]
211. Wang Y.Z, Tian F.F, Yan M, Zhang J.M, Liu Q, Lu J.Y. et al. Delivery of an miR155 inhibitor by anti-CD20 single-chain antibody into B cells reduces the acetylcholine receptor-specific autoantibodies and ameliorates experimental autoimmune myasthenia gravis. Clinical and Experimental Immunology. 2014;176:207–221. [PMC free article: PMC3992033] [PubMed: 24387321]
212. Warren R.P, Foster A, Margaretten N.C. Reduced natural killer cell activity in autism. Journal of the American Academy of Child and Adolescent Psychiatry. 1987;26:333–335. [PubMed: 3597287]
213. Warren R.P, Singh V.K, Averett R.E, Odell J.D, Maciulis A, Burger R.A. et al. Immunogenetic studies in autism and related disorders. Molecular and Chemical Neuropathology. 1996;28:77–81. [PubMed: 8871944]
214. Waubant E. Spotlight on anti-CD20. International MS Journal/MS Forum. 2008;15:19–25. [PubMed: 18713565]
215. Whitney K.D, McNamara J.O. GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins. Journal of Neuroscience. 2000;20:7307–7316. [PMC free article: PMC6772766] [PubMed: 11007888]
216. Willenborg D.O, Prowse S.J. Immunoglobulin-deficient rats fail to develop experimental allergic encephalomyelitis. Journal of Neuroimmunology. 1983;5:99–109. [PubMed: 6194180]
217. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D.G, Van de Water J. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain, Behavior, and Immunity. 2009;23:64–74. [PMC free article: PMC2660333] [PubMed: 18706993]
218. Wills S, Rossi C.C, Bennett J, Cerdenño V.M, Ashwood P, Amaral D.G. et al. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Molecular Autism. 2011a;2:5. [PMC free article: PMC3108923] [PubMed: 21521495]
219. Wills S, Rossi C.C, Bennett J, Martinez Cerdeno V, Ashwood P, Amaral D.G. et al. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Molecular Autism. 2011b;2:5. [PMC free article: PMC3108923] [PubMed: 21521495]
220. Winder C, Balouet J.C. The toxicity of commercial jet oils. Environmental Research. 2002;89:146–164. [PubMed: 12123648]
221. Wright B.R, Warrington A.E, Edberg D.E, Rodriguez M. Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Archives of Neurology. 2009;66:1456–1459. [PMC free article: PMC2796600] [PubMed: 20008649]
222. Xing G.Q, Ren M, Watson W.A, O’Neil J.T, Verma A. Traumatic brain injury-induced expression and phosphorylation of pyruvate dehydrogenase: A mechanism of dysregulated glucose metabolism. Neuroscience Letters. 2009a;454:38–42. [PubMed: 19429050]
223. Xing G.Q, Ren M, Watson W.D, O’Neill J.T, Verma A. Traumatic brain injury-induced expression and phosphorylation of pyruvate dehydrogenase: A mechanism of dysregulated glucose metabolism. Neuroscience Letters. 2009b;463:258–258. [PubMed: 19429050]
224. Yahya M.D, Pinnas J.L, Meinke G.C, Lung C.C. Antibodies against malondialdehyde (MDA) in MRL/lpr/pr mice: Evidence for an autoimmune mechanism involving lipid peroxidation. Journal of Autoimmunity. 1996;9:3–9. [PubMed: 8845052]
225. Yang L, Blumbergs P.C, Jones N.R, Manavis J, Sarvestani G.T, Ghabriel M.N. Early expression and cellular localization of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine. 2004;29:966–971. [PubMed: 15105666]
226. Younger D.S, Rowland L.P, Latov N, Hays A.P, Lange D.J, Sherman W. et al. Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Annals of Neurology. 1991;29:78–86. [PubMed: 1996882]
227. Yuan X.Q, Wade C.E. Neuroendocrine abnormalities in patients with traumatic brain injury. Frontiers in Neuroendocrinology. 1991;12:209–230. [PubMed: 11538874]
228. Zachou K, Oikonomou K, Renaudineau Y, Chauveau A, Gatselis N, Youinou P. et al. Anti-alpha actinin antibodies as new predictors of response to treatment in autoimmune hepatitis type 1. Alimentary Pharmacology and Therapeutics. 2012;35:116–125. [PubMed: 22050113]
229. Zahran W.E, Mahmoud M.I, Shalaby K.A, Abbas M.H. Unique correlation between mutated citrullinated vimentine IgG autoantibodies and markers of systemic inflammation in rheumatoid arthritis patients. Indian Journal of Clinical Biochemistry. 2013;28:272–276. [PMC free article: PMC3689334] [PubMed: 24426223]
230. Zhang M, Alicot E.M, Carroll M.C. Human natural IgM can induce ischemia/reperfusion injury in a murine intestinal model. Molecular Immunology. 2008;45:4036–4039. [PMC free article: PMC3230121] [PubMed: 18672288]
231. Zhang M, Takahashi K, Alicot E.M, Vorup-Jensen T, Kessler B, Thiel S. et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. Journal of Immunology. 2006;177:4727–4734. [PubMed: 16982912]
232. Zhang Z, Zoltewicz J.S, Mondello S, Newsom K.J, Yang Z, Yang B. et al. Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products. PloS One. 2014;9:e92698. [PMC free article: PMC3965455] [PubMed: 24667434]
233. Zheng W.R, Liu M.C, Hayes R.L, Wang K.K.W. Calpain and caspase mediated proteolysis of alpha II-spectrin and beta II-spectrin in rat cerebrocortical culture under oncotic, apoptotic and excitotoxic challenges. Journal of Neurotrauma. 2008;25:900–900.
234. Zolotova T.V, Grebeniuk I.E. [Serum level of anti-neurotrophine antibodies and activity of proteolytic enzymes in patients with sensorineural loss of hearing] Vestnik Otorinolaringologii. 2010:25–28. [PubMed: 21105340]