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REVIEW AUTOANTIBODIES IN TRAUMATIC BRAIN INJURY AND CENTRAL NERVOUS SYSTEM TRAUMA Q1 M. RAAD, a E. NOHRA, b N. CHAMS, a M. ITANI, g

of autoantibodies to CNS insult is still not fully characterized. It is being suggested that there may be an analogy of CNS autoantibodies secretion with the pathophysiology of autoimmune diseases, in which case, understanding and defining the role of autoantibodies in brain injury paradigm (SCI and TBI) may provide a realistic prospect for the development of effective neurotherapy. In this work, we will discuss the accumulating evidence about the appearance of autoantibodies following brain injury insults. Furthermore, we will provide perspectives on their potential roles as pathological components and as candidate markers for detecting and assessing CNS injury. Ó 2014 Published by Elsevier Ltd. on behalf of IBRO.

F. TALIH, c* S. MONDELLO d AND F. KOBAISSY e,f* a Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

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b Department of Surgery, Division of General Surgery, American University of Beirut, Lebanon

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c Department of Psychiatry, American University of Beirut Medical Center, Beirut, Lebanon

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d

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e

Faculty of Medicine, Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon

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f Department of Psychiatry, Center for Neuroproteomics and Biomarkers Research, University of Florida, Gainesville, FL, USA

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g Faculty of Medicine, Saint George University of London, Nicosia, Cyprus

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Abstract—Despite the debilitating consequences and the widespread prevalence of brain trauma insults including spinal cord injury (SCI) and traumatic brain injury (TBI), there are currently few effective therapies for most of brain trauma sequelae. As a consequence, there has been a major quest for identifying better diagnostic tools, predictive models, and directed neurotherapeutic strategies in assessing brain trauma. Among the hallmark features of brain injury pathology is the central nervous systems’ (CNS) abnormal activation of the immune response post-injury. Of interest, is the occurrence of autoantibodies which are produced following CNS trauma-induced disruption of the blood–brain barrier (BBB) and released into peripheral circulation mounted against self-brain-specific proteins acting as autoantigens. Recently, autoantibodies have been proposed as the new generation class of biomarkers due to their longterm presence in serum compared to their counterpart antigens. The diagnostic and prognostic value of several existing autoantibodies is currently being actively studied. Furthermore, the degree of direct and latent contribution

Department of Neurosciences, University of Messina, Messina, Italy

Key words: autoantibodies, humoral immune response, traumatic brain injury, spinal cord injury, biomarkers, CNS Q3 trauma, immune system. 22

Contents Introduction The immune response after CNS injury Autoantibodies as biomarkers The contribution of B cells to secondary CNS injury Neurotherapeutic approaches through B cell manipulation Conclusion References

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*Corresponding authors. Address: American University of Beirut Medical Center, PO Box 110236, Cairo Street, 1107 2020 Beirut, Lebanon. Tel: +961-1-350000x5650; fax: +961-1-749209 (F. Talih). Address: 4000 SW 23[rd] Street, Apt 5-204, Gainesville, FL 32608, USA. Tel: +961-01-350000x4805 (F. Kobeissy). E-mail addresses: [email protected] (F. Talih), fi[email protected] (F. Kobaissy). Abbreviations: ACR, acetylcholine receptor; BBB, blood–brain barrier; BDPs, break down products; CSF, cerebrospinal fluid; GFAP, glial fibrillary acid protein; IgM, immunoglobulin M; MBP, myelin basic protein; NMDA, N-methyl-D-aspartate; SCI, spinal cord injury; TBI, Q2 traumatic brain injury; UCH-L1, ubiquitin carboxy-terminal hydrolase L1. http://dx.doi.org/10.1016/j.neuroscience.2014.08.045 0306-4522/Ó 2014 Published by Elsevier Ltd. on behalf of IBRO. 1

INTRODUCTION

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Traumatic brain injury (TBI) is a major health concern with an incidence of 1.7 million cases per year in the United States. TBI is characterized with long-term consequences and debilitating post-injury disabilities (Selassie et al., 2008; Wolf et al., 2009; Corrigan et al., 2010). TBI refers to a spectrum of focal and diffuse cerebral insults resulting from sudden shock, blunt or transmitted force, hypoxia, intoxication, and vascular injuries to the brain (Malkesman et al., 2013). The immediate phase of injury arises from direct mechanical injury; while the secondary latent phase arises from systemic biochemical and physiological changes involving excitotoxicity, energy failure, ischemia, cell death, edema, delayed axonal injury, and inflammation (Diamond et al., 2013; Malkesman et al., 2013). Importantly, TBI, and even mild injuries, have been linked to serious long-term complications, including

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chronic traumatic encephalopathy, neuropsychiatric and movement disorders and early onset dementia (AngoaPerez et al., 2014; Bazarian et al., 2014). Currently, there are few effective therapies targeted against the latent manifestations of TBI (Beauchamp et al., 2008; Loane and Faden, 2010; Maas et al., 2010; Wheaton et al., 2011) exacerbated by the fact that there are no diagnostic approaches that can identify those who will develop severe complications later. A better understanding of CNS trauma and its pathogenic processes are major components to develop improved diagnostic tools that allow for accurate disease characterization and phenotyping. These enhanced tools have a direct impact toward establishing novel targeted patient management and better neurotherapeutic strategies. Advanced prognostic capabilities, determination of injury severity and prediction of long-term complications are also required for better injury management. These advances may be provided by identifying accurate biological molecular signature markers, referred to as biomarkers. Biomarkers refer to detectable components liberated by tissues in a disease state, or better defined as biological parameters that are in an altered state different from those in a healthy individual (Raad et al., 2012). An ideal biomarker involves detection, diagnosis and prognosis of a disease state. The five phases proposed by the National Institute of Health in the evaluation of biomarkers are in sequence (NIH, 1998): (1) discovery using genomics or proteomics, (2) developing an assay that is portable and reproducible, (3) measuring sensitivity and specificity, (4) affirming the measurement in a large cohort, and (5) determining the risks and benefits of using the new diagnostic biomarker. The current available protein and gene biomarkers are now regarded as early generation biomarkers that suffer from several limitations, such as low specificities and sensitivities (Papa et al., 2013). Therefore, a search for a novel family of biomarkers in this field is essential; and currently, both microRNAs and autoantibodies are under investigation. In this review, we highlight the potential use of autoantibodies as candidate blood biomarkers discussing their potential roles in the secondary progression of CNS trauma and its underlying pathology.

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THE IMMUNE RESPONSE AFTER CNS INJURY

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After brain injury, the immune system is engaged acutely to contain the injured cells, and chronically to support spontaneous brain regenerative processes, including neovascularization, axonal sprouting, and neurogenesis (Peruzzotti-Jametti et al., 2014). The degree of recovery may be dependent on the success of these molecular mechanisms. Autoinflammation involves inflammasomes, multioligomeric proteins that initiate the innate immune response and an uncontrolled production of cytokines coupled with the activation of myeloid cell lineages (e.g., monocytes/ macrophages and neutrophils), and self-reactive lymphocytes. On the other hand, autoimmunity occurs due to activation or survival of self-reactive lymphocytes with enhanced synthesis of autoantibodies directed against

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one or more of the individual’s own self proteins. Both pathways have been implicated in progression of secondary injury after CNS injury (Archelos and Hartung, 2000; Jones et al., 2005; Trivedi et al., 2006; de Rivero Vaccari et al., 2008; Diamond et al., 2009). Autoimmune recognition plays a pivotal role in tuning the strength of the immune activation by presenting and processing selfantigens. The nature and degree of activation determine whether the response is beneficial or detrimental to recovery (Trivedi et al., 2006). Importantly, both B and T lymphocytes appear to contribute to CNS injury and repair (Ankeny et al., 2006, 2009; Popovich and Longbrake, 2008). Ankeny et al. discussed the contribution of B-cell activation and its associated autoantibodies in the area of spinal cord injury (SCI) pathogenesis proposing new sites for neuro-therapeutic targeting for patients suffering from SCI (Ankeny et al., 2006, 2009; Ankeny and Popovich, 2009, 2010). B-lymphocytes involved in such pathogenesis are shown to develop from bone marrow and specifically from hematopoietic stem cells at its immature phase (Dalakas, 2008a,b). Upon the entrance of a ‘‘non-self’’ alien antigen, the immune system mounts an immune response where plasma cells, which are mature B-cells, are paired with T cells stimulation. Nonetheless, when the confronted antigen is a self or a host-derived (DNA, Peptide or protein), then the immune response elicited is called an autoimmune response (Ankeny et al., 2009). Typically, during the developmental stages, negative-selection abolishes highly reactive lymphocytes whereas, positive-selection keeps ‘‘sub-threshold’’ stimulation of lymphocytes that identify self/host antigens and increase sensitivity to alien antigens (Stefanova et al., 2002). This machinery of positive-selection has a crucial role in controlling the immune reaction and regulating it; nonetheless, when the threshold level is crossed then an abnormal condition of autoimmunity is elicited (Stefanova et al., 2002). When stimulation of its correlated antigens occurs, B-cells differentiate into antibody-secreting plasma cells and afterward into the long-lived antibody secreting plasma cells (Dalakas, 2008a,b). B-cells can play the role of antigen-presenting cells as well as antibody secreting cells (Waubant, 2008; Dalakas, 2008b). These activated B-cells make their way to the secondary lymphatic system, to the bone marrow, and to the CNS (Dalakas, 2008b). Recent studies have provided conflicting evidence about which immune mechanisms are beneficial and which are detrimental (Ankeny et al., 2006, 2009; Popovich and Longbrake, 2008). Some autoantibodies produced against CNS cells have been shown to be beneficial since they activate intracellular repair pathways (Wright et al., 2009). Furthermore, natural autoreactive monoclonal antibodies, especially the immunoglobulin M (IgM) isotype that are produced at early phases of immune response, may have some neurotherapeutic potential in CNS disease by promoting CNS protection and repair (Schwartz and Raposo, 2014). IgM antibodies are thought to enhance re-myelination, neurite growth and prevention of neuronal apoptosis as shown in mouse models of multiple sclerosis (Wright et al., 2009). In addition, these

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antibodies have exhibited neurotherapeutic effects in neurological diseases such as amyotrophic lateral sclerosis, stroke, SCI or secondary progressive multiple sclerosis (Wright et al., 2009; Diamond et al., 2013; Cheng and Chen, 2014). In contrast, in vivo models of SCI indicate that B cells and SCI-induced autoantibodies exacerbate tissue damage impairing neurological recovery post SCI (Ankeny et al., 2006, 2009). Antibodies against glutamate receptors were found in the sera of spinal cord injured mice (Ankeny et al., 2006) and have been shown to amplify CNS injury by promoting inflammation, ischemia and reperfusion injury via complement activation (Zhang et al., 2004). The interaction between the B/T cells and the presentation of neural antigens is perhaps best described in SCI and TBI studies. It is postulated that post-injury, naı¨ ve neuroantigen-reactive lymphocytes are activated by CNS antigens that drain into the peripheral lymphoid tissues (Diamond et al., 2013). In the pathophysiology of CNS injury, there is major damage retained by the blood– brain barrier (BBB) and its integrity contributing to the leakage of neural proteins into the cerebrospinal fluid (CSF) as well as protease activation leading to breakdown of protein substrates that may escape into peripheral circulation (Auer, 1979; Okonkwo et al., 2013; Hook et al., 2014). The immune mechanisms elicited in response to brain injury occur naturally and may recognize some of the neuronal specific proteins as antigens leading to the secretion of autoantibodies against them as discussed later (Shamrei, 1969; Lopez-Escribano et al., 2002; Stein et al., 2002; Sorokina et al., 2011). This is illustrated in Fig. 1. In one SCI study, T cells in the spleen and lymph nodes were shown to be sensitized against spinal cord proteins including myelin basic protein (MBP) (Popovich et al., 1996). In mice with T cells sensitized to MBP, SCI led to the expansion of MBP-reactive T cells, which moved to the CNS and augmented pathology (Jones et al., 2002). Of interest, a similar expansion of MBP-reactive T cells were shown to occur in SCI patients, where the levels of T cells recognizing MBP are elevated compared to controls (Kil et al., 1999). This comparison is similar to the recognition pattern observed in multiple sclerosis (Kil et al., 1999). Interestingly, neurological deficits and histopathological changes similar to those observed in experimental SCI were demonstrated in disease-free control mice when naı¨ ve T cells proliferating in disease models were transferred to these control mice (Popovich et al., 1996). Along the same line, in experimental mechanical injury model of SCI mice, both T and B lymphocytes were activated and expanded in lymphatic tissue (Ankeny et al., 2006; Popovich and Longbrake, 2008). Thus, both cells may be involved in the autoimmunity post neuronal injury. Ankeny et al. described that both B and T cells may infiltrate the injured spinal cord and form granulomas and germinal centers in the lymphoid tissue (Ankeny et al., 2006) and this may be a key factor in increasing autoantibody synthesis (Ankeny et al., 2009). After traumatic CNS injury, T-dependent, and perhaps T-independent, self-antigens elicit adaptive immune responses with important functional consequences

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Fig. 1. Proposed molecular mechanism leading to autoantibody production in TBI and SCI. Post CNS Injury (TBI–SCI), the immune response involves the activation of the innate immune system to contain damaged cells and debris by the action of microglia, macrophages, natural killer cells, and the complement system (a) This involves the release of cytokines and inflammatory mediators (b) that increase vascular permeability and further disrupt the blood brain barrier (c). This is coupled with neural injury and release of neural specific proteins (d). These self CNS-derived proteins will be recognized by our B cells leading to the secretion of autoantibodies. The exact role of autoantibodies has been investigated as a potential diagnostic/prognostic biomarker, a neurotherapeutic target or as a mediator exacerbating injury pathogenesis.

(Popovich et al., 1996; Kil et al., 1999; Schwartz and Kipnis, 2001; Ankeny et al., 2006, 2009). The nature and diversity of these autoantigens are currently under investigation. Researchers have demonstrated that in TBI, regulatory T cells play an important role in CNS injury and in the removal of autoreactive antibodies postulating their protective functions (Walsh et al., 2014). In one study, TBI patients with T cells activated against myelin exhibited protective immunity and tended to have better prognosis than those with no T cell activation (Cox et al., 2006). Further research is needed to clarify these findings and to evaluate whether the production of autoantibodies in response to exposure to brain-specific proteins would have implications for biomarker development that carry important diagnostic and prognostic potentials in the management of patients with CNS trauma.

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AUTOANTIBODIES AS BIOMARKERS

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As discussed, the activation of immune mechanisms post CNS trauma involves the disruption of the BBB with exposure of brain-specific proteins (potential antigens) to the immune system along with break down products (BDPs). The breach in the BBB allows the self antigen/ immune cell interaction to occur activating the immune

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response post TBI (Diamond et al., 2013). The BBB is a dynamic physiologic network of specialized capillary endothelial cells that separates the circulating blood from the brain restricting the passage of molecules and solutes and contributing to the brain’s immune privilege (Diamond et al., 2013). Its integrity can be compromised by several local and systemic factors including head trauma, activation of circulating leukocytes, and molecular mediators that affect vascular permeability (Marchi et al., 2014). Following injury, the permeability of the BBB injury is increased and results in the exposure of the brainspecific tissue to peripheral circulation and subsequently the leakage of these neural proteins to the periphery as shown in Fig. 1. In addition, the BBB disruption may facilitate the entry of environmental pathogens with the breakdown of natural barriers from other body districts, such as the skin, pelvis, extremities (Ankeny and Popovich, 2010), and the intestine (Liu et al., 2004; Bansal et al., 2009). These foreign molecules may sensitize the immune system by priming or reactivating memory B cells due to antigen mimicry (Ankeny and Popovich, 2010) or may enhance neuroinflammatory reaction post CNS injury by affecting the regulation of inflammation and its suppression vis-a`-vis the presence of these pathogens (Littman and Rudensky, 2010). These processes are also associated with an influx of peripheral neutrophils occurring following injury (Diamond et al., 2013). Concurrently, injury to neuronal and glial cells results in cellular activation and disintegration, leading to the release of brain-derived cell-type-specific proteins and their leakage into the blood stream, with a subsequent increase in the formation of autoantibodies against them (Diamond et al., 2013). Several antigens and their corresponding autoantibodies have been identified and characterized in the area of brain disorders including CNS injury as shown in Table 1. The presence of these autoantibodies may represent putative long-term biomarkers that may be correlated to injury severity as well disease prognostic indicators that may be the center

for potential neurotherapeutic targets as discussed later (see Fig. 1). Of note, S100B protein, released primarily by brain astrocytes, has its autoantibodies detected in a number of neurological disorders. In Alzheimer’s disease, antibodies against S100B were measured and were found to correlate with disease duration and severity with levels peaking at highest disease activity and decreasing in final stages of the disease (Gruden et al., 2007). As hypothesized by a recent study by Marchi et al., S100B is released primarily by brain astrocytes and is detected in patient sera after brain injury, where they cause an immune response associated with production of auto-antibodies. The study results show elevated levels of autoantibodies against S100B in football players after sub-concussive events and their association with functional and imaging data (Marchi et al., 2013). S100B protein appears to be specific for sports-related concussion, if measured at the 3 h post-injury, especially if compared to the individual’s baseline value (Bazarian et al., 2013; Kiechle et al., 2014). When used in conjunction with clinical data, S100B protein carries good prognostic value for survival and positive outcome (Lesko et al., 2014). S100B is in clinical use for the detection of intracranial bleeding in TBI (Kiechle et al., 2014). Based on these observations, S100B protein as well as its auto-antibodies have been hypothesized to be an expression of an autoimmune response that persists over time and may lead to different adverse outcomes, including prolonged postconcussive symptoms, early cognitive decline, chronic traumatic encephalopathy, and dementia of the Alzheimer type (Metting et al., 2012; Egea-Guerrero et al., 2013; Marchi et al., 2013; Thelin et al., 2013, 2014). Further research is needed to stratify the exact role of S100B autoantibodies as a specific marker for sportsrelated concussion and as a risk factor for the development of postconcussive symptoms, impaired recovery and long-term complications. In a recent study by Puvenna et al., the impact of sub-concussive head

Q5 Table 1. Lists the auto-antibodies that have been studied in association with traumatic brain injury Neural protein identified

Evidence

Strength of evidence

Significance

Time course (Serum)

Time course (CSF)

Beneficial or detrimental

Time for intervention

Reference

Anti-PL (phospholipid)

100 patients with microscopic examination of CSF 100 patients with microscopic examination of CSF 53 patients, in addition to rat models

Weak

Diagnostic marker and prognostic factor

N/A

Studied on 1st to 21st day

Likely detrimental

N/A

Ngankam et al. (2011)

Weak

Diagnostic marker and prognostic factor

N/A

Studied on 1st to 21st day

Detrimental

N/A

Ngankam et al. (2011)

Strong

Diagnostic marker and prognostic factor prognostic factor

1–10 days, likely longer

Studied at 24 h

Detrimental

N/A

Zhang et al. (2014)

1st year after trauma

N/A

Detrimental

At 6 months to 1 year

Goryunova et al. (2007))

Anti-BMP (basic myelin protein)

Anti-GFAP (glial fibrillary acidic protein) Anti-NMDA and anti-AMPA

60 children

Moderate

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hits on neuronal injury and on BBB disruption in football players (Puvenna et al., 2014). For this purpose, markers of BBB disruption (serum beta 2-transferrin) and markers of brain injury including the brain-specific ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and S100B proteins were evaluated pre- and post-game and compared to positive controls. Of interest, low levels of S100B proteins were able to rule out mTBI while S100B levels correlated with TBI severity; this is in contrast to the diagnostic value of UCH-L1 which showed no correlation with mild TBI group as well as in football players (Puvenna et al., 2014). Of note, findings from this study complements the findings by Papa et al. where the authors showed that UCH-L1, in addition to other TBI markers correlated with brain injury severity; however this occurs in the severe TBI scenario rather in mild TBI insult (Papa et al., 2014). Taken together, this study may highlight the importance of using autoantibody of brain-specific proteins shed in periphery as a more sensitive marker than the autoantigen itself, an area that needs to be investigated in UCHL1 protein. Of note, S100B protein levels, however, are sensitive to age and race, and are affected by extracerebral sources of the protein which may limit accuracy, in particular its specificity (Bazarian et al., 2013). Another protein of interest which is associated with autoantibody synthesis is glial fibrillary acid protein (GFAP). 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). 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 7–10 days post injury and were of the immunoglobulin G (IgG) subtype (Zhang et al., 2014). Interestingly, these results were translated into an experimental model of rat TBI showing that human TBI autoantibodies co-localized in the injured rat brain and in primary rat astrocytes. These findings suggest that GFAP autoantibodies enter living astroglial cells compromising their survival (Zhang et al., 2014). GFAP has also been shown to be a biomarker of cerebral infarctions, head injuries and other conditions associated with reactive gliosis (Mori et al., 1978; Hayakawa et al., 1979). Furthermore, elevated levels of GFAP autoantibodies have been demonstrated in senile dementia as well as in vascular dementia (Mecocci et al., 1992). Interestingly, these disorders are characterized by cellular loss and neuronal damage sustained over long periods, and are associated with astrogliosis and high levels of GFAP in CNS (Bjorklund et al., 1985). Another candidate neural protein for autoantibody includes a7-subunit of acetylcholine receptor (ACR). ACR autoantibodies against several fragments ACR were assessed in children with different severities of cranio-cerebral trauma. Brain insult severity correlated directly with titers of a7-subunit as well as with the autoantibodies set against them in the first week of the insult (Sorokina et al., 2011). Sorokina et al. also came up with the hypothesis that an inflammatory reaction,

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together with disturbance of the BBB intensifies the leakage of glial proteins and of structural neuronal components in the circulation leading to the beginning of the abnormal immune reaction (autoantibodies) against them. In a separate but related neurological insults, autoantibodies have been also described; In encephalitis associated with severe status epilepticus, GABA receptor antibodies have been measured and identified as a potential target for directed therapy (Bien et al., 2012), while antibodies against N-methyl-D-aspartate (NMDA) receptors have been and associated with the cytotoxic cells activity against neuronal cells in paraneoplastic encephalitis. The contribution of cytotoxic T cells in response to these antibodies has also been described (Petit-Pedrol et al., 2014). We believe that assessing the levels of these autoantibodies in combination with other markers may yield valuable clinical information; however, further studies are necessary to correlate the pattern of expression against clinical outcomes at different time points post TBI. Autoantibody assessment after brain injury requires attention to the effects of age. Older individuals have more auto-reactive antibodies in general, and they have less regulatory T cells because of thymic regression but more circulatory T4 cells (Vadasz et al., 2013). Nonetheless, another study has shown that younger patients are more likely to produce auto-antibodies to neuronal antigens after brain injury (Cox et al., 2006). Of particular interest in children is the study of anti-NMDA receptor antibodies which appear to correlate with the development of seizure disorders post brain injury (Goryunova et al., 2007).

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THE CONTRIBUTION OF B CELLS TO SECONDARY CNS INJURY

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Whether a cause–effect relationship, analogous to that observed in the chronic manifestations of systemic autoimmune diseases, exists in CNS trauma and its sequelae, is yet to be determined (Ankeny and Popovich, 2010). In post-CNS trauma, B cells and antibodies are believed to play a role in CNS inflammation in addition to the systemic disturbances (Ankeny and Popovich, 2010). Animal models lacking B cells had a better re-gain of locomotion in TBI models and reduced pathological manifestations when compared to controls with normal B cell function (Ankeny et al., 2009). In addition to the appearance of neural autoantibodies, levels of other autoantibodies known to be involved in systemic disease are increased after CNS injury, such as serum rheumatoid factor in SCI subjects (Petrova et al., 1993). However, this observation has yet to be confirmed in TBI. The type and amount of autoantibodies released following CNS injury may be related to lesion size, location, and molecular targets involved (Archelos and Hartung, 2000; Popovich and Longbrake, 2008; Ankeny and Popovich, 2010). Autoantibodies can hamper normal cellular function via binding to integral protein and surface receptors. Experimental studies have consistently shown that, in SCI, the complement system is activated and functional recovery is negatively affected (Abdul-Majid

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et al., 2002; Qiao et al., 2006; Ankeny et al., 2009). If these observations were to be confirmed in TBI, this knowledge could be translated into novel treatment strategies (e.g. Anti-auto Ab drug candidates or immunotherapy).

potentially improve our overall understanding of how the disruption of immune privilege of the CNS is triggered by trauma and the subsequent complex immune interactions that affect recovery.

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REFERENCES

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Accumulating data are suggestive of the integral role of the over-activated B cell in traumatic CNS injury exacerbating the initial systemic and neurological pathology, and contributing to impaired recovery (Ankeny et al., 2006, 2009). Drugs directed against B cell activation as well as B cell-depleting monoclonal antibodies including RituxanÒ (Rituximab) or OcrelizumabÒ or anti-CD20 drugs have been proposed as neurotherapeutic targets in autoimmune neurological disorders such as multiple sclerosis; several clinical trials are supportive of this approach (Waubant, 2008; Dalakas, 2008a; Dorner et al., 2009; Matsushita and Tedder, 2009). In this stage, it is still premature to predict whether patients with SCI will benefit from anti-CD20 treatment. Anti-CD20 acts on premature B cells that have not yet matured to produce antibodies. It may be effective in preventing de novo synthesis of more B cells that are self-reactive and may be beneficial if administered soon after the insult occurs. Drugs that interfere with B cell differentiation, such as agents that block a B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two key signaling molecules in the activation and differentiation of B cells, are also potential targets for therapy (Carson et al., 2009). One proposed approach to deliver these agents for assessing their efficacy would be to infuse them into animal models of CNS injury or with other neurological disorders either intraspinally or intracranially (Saltzman et al., 2013). This approach will test whether this treatment would presumably quench the autoinflammatory reactions, in particular the increase in autoantibodies. Of interest, one study assessed the sera of TBI patients on human leukemia cell lines cultured in vitro in the presence of sera collected from brain or systemic circulation (Lopez-Escribano et al., 2002). The leukemic cells had an increased rate of apoptosis. Therefore, apoptotic and necrotic cells in TBI may be potential sources of autoantigen presentation that may stimulate autoimmune responses (Lopez-Escribano et al., 2002). Therefore, the detection of any elevated serum antibody levels upon TBI presentation may help in the management and prediction of outcomes, as well as be of therapeutic advantage via chelation or suppression.

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CONCLUSION

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Taken together, the aforementioned autoantibody studies suggest that further rigorous experimental as well as clinical research is needed to assess whether autoantibodies may be used to diagnose CNS trauma, to predict the severity of the injuries, to define a therapeutic window for, and perhaps to provide a source for directed therapy. The mechanisms involved in the production and the function of autoantibodies in TBI will

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(Accepted 31 August 2014) (Available online xxxx)

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