Abstract: Stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) cause irreversible damage to the nervous system. Although these are neurological disorders, pathology and loss of function also occur outside the nervous system and are often not easily explained by paralysis or impaired neural function. Emerging data indicate that much of the pathological sequelae that accompanies CNS trauma has characteristics of a self-directed immunological disease. Here, we outline those data, describing basic mechanisms of B cell activation and autoantibody synthesis after CNS injury. A summary of the anti-CNS autoantibodies that have been identified in humans and animals is provided along with a discussion of how autoantibodies may affect survival of neuronal and non-neuronal tissues and whether autoimmune reactions are feasible therapeutic targets after CNS trauma.
Mechanical trauma or prolonged ischemia in brain or spinal cord cause irreversible damage to neurons, glia, and endothelia leading to hemorrhage, demyelination, and necrotic cell death. Although these primary forms of central nervous system (CNS) injury are largely unavoidable, there is hope that the injurious consequences of secondary neurodegeneration can be minimized leading to enhanced recovery of neurological function. A large number of slowly progressing aberrant cellular and biochemical cascades have been implicated in causing secondary injury; however, effective therapies remain elusive. This is likely because stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) are neurological disorders in which pathology transcends the nervous system. Indeed, emerging data indicate that pathological sequelae that accompany CNS trauma have characteristics of a self-directed immunological disease.
Inflammatory reactions directed against self can be viewed as a continuum of autoinflammatory (self-directed tissue inflammation dominated by innate immune system) and autoimmune (loss of immunological tolerance with activation of self-directed adaptive immune responses) reactions (McGonagle and McDermott, 2006). The former involves the coordinated activation of inflammasomes and uncontrolled cytokine synthesis with robust activation of myeloid cell populations (e.g., neutrophils, monocytes/macrophages) and the latter activation of self-reactive lymphocytes with enhanced synthesis of autoantibodies. Each component has been implicated in progression of secondary injury after CNS injury and several reviews have been written on these subjects (Archelos and Hartung, 2000; de Rivero Vaccari et al., 2008; Diamond et al., 2009; Jones et al., 2005; Popovich and Longbrake, 2008; Trivedi et al., 2006). The focus of the present review is to provide a brief primer on mechanisms of B cell activation and autoantibody synthesis and then provide a theoretical framework for how these reactions are initiated after CNS injury and how they may positively and negatively affect survival of neuronal and non-neuronal tissues.
B Lymphocyte Activation and Autoantibody Synthesis
An introduction to B cell activation and antibody synthesis
B lymphocytes are critical players in adaptive immune responses. The activation and differentiation of naïve B cells occurs within follicles which are specialized microdomains of secondary lymphoid tissue (e.g., lymph nodes, spleen). There, B cells interact with T cells and follicular dendritic cells to orchestrate a complex activation sequence. Once activated, B cells can act as antigen-presenting cells (APCs) and sources of inflammatory cytokines, with both functions being essential for eliciting and coordinating interactions with T lymphocytes and other cells. Activated B cells also differentiate into antibody-producing plasma cells or memory cells. Plasma cells rapidly produce large amounts of antibodies (immunoglobulins, Ig) that bind to specific antigens while memory B cells persist indefinitely in bone marrow and secondary lymphoid tissues where they facilitate a rapid and more efficient immune response if the host is re-exposed to the inciting antigen. Antibodies bind to a range of antigens including proteins, carbohydrates, or lipid moieties found on pathogens. When antibodies are produced against host antigens, they are called autoantibodies.
Resting (naïve) B cells require two signals before they become activated (Archelos and Hartung, 2000; Harwood and Batista, 2010). The first signal is delivered via the B cell receptor (BCR) when it binds to antigen. B cells recognize and respond to soluble antigens and to those bound to the surface of APCs (Harwood and Batista, 2010). Most of what is known about BCR signaling was learned from biochemical assays using soluble antigens to trigger the BCR; however, recent data indicate that antigens bound to APCs are more efficient at activating B cells, in part because conformational changes associated with B cell binding to APCs help to recruit and cross-link BCR complexes in the B cell membrane (Carrasco and Batista, 2006). It is not known whether B cells are activated by neural antigens bound to APCs or in soluble form.
The BCR is a complex composed of membrane-bound Ig that recognizes antigen and two transmembrane Igα/β signaling heterodimers. Antigen binding to Ig leads to BCR cross-linking and phosphorylation of immunoreceptor tyrosine activation motifs (ITAMs) by Lyn kinase. ITAM phosphorylation triggers formation of the signalosome, an assembly of kinases (e.g., Syk, phospholipase-Cγ2, phosphoinositide 3-kinase and Bruton’s tyrosine kinase, Vav) and adaptor molecules such as B cell linker (Blnk) that together coordinate intracellular signaling, antigen uptake, and the induction of gene expression (Harwood and Batista, 2010; Kurosaki et al., 2009). Endocytosed antigen is degraded by endosomal proteases and then antigen fragments are loaded onto major histocompatibility (MHC) class-II molecules. The resultant antigen-MHC complex is expressed on the surface where it is presented to helper T cells. If the antigen-MHC complex is recognized by a specific T-cell receptor (TCR), the “second signal” necessary to activate B cells is initiated. As B and T cells interact, CD40 on the surface of B cells binds with its ligand (CD40L) expressed on the T cell surface. This secondary signal and T cell cytokines together elicit isotype class switch recombination in B cells. Without signaling via CD40, B cells produce only IgM antibodies.
The development and activation sequences described above are specific for conventional B lymphocytes, also known as B-2 cells. In contrast, B-1 cells represent a distinct subclass of B lymphocytes with different developmental pathways and functions (Ghosn et al., 2011). B-1 cells are the first B cells produced in the fetus. In adult mammals, B-1 cells are localized primarily in the peritoneal and pleural cavities where they account for ~5% of the total B lymphocyte population. Unlike B-2 cells, which are continuously replenished by de novo synthesis in bone marrow, B-1 cells undergo self-renewal outside the bone marrow. B-1 cells primarily express surface IgM and respond to large polymeric carbohydrate antigens more efficiently than B-2 cells. As such, B-1 cells can be activated without signaling from T cells, but since somatic hypermutation is bypassed, the antibodies that are secreted by B-1 cells bind antigen with low affinity (Baumgarth, 2010).
An interesting but poorly understood aspect of B-1 cell development is that these cells undergo positive selection, i.e., despite their autoreactive potential, B-1 cells are not deleted during development. Instead, they survive and secrete a large repertoire of polyreactive germ-line encoded (natural) antibodies that bind various self-antigens including oxidized lipids and antigens expressed by apoptotic cells (e.g., annexin IV, phosphatidylcholine) (Baumgarth, 2010). The broad specificity of antibodies produced by B-1 cells may imply a role in acute tissue surveillance and maintenance of homeostasis; however, the number of B-1 cells increases in autoimmune diseases and the polyreactive autoantibodies they produce can exacerbate ischemic tissue damage (Duan and Morel, 2006; Zhang et al., 2004).
B Cell Activation and Generation of Autoantibodies After CNS Injury
Although there is evidence that autoimmune mechanisms contribute to pathology in animals and people who suffer from stroke, TBI, or SCI, there is no clear evidence that these disorders initiate a deleterious immune response because of specific genetic defects in immune function nor is it possible to predict disease severity or outcome based on a patient or animal’s major histocompatibility complex (MHC) haplotype. Still, the activation of neuroinflammatory cascades and subsequent onset of autoimmune reactions are a conserved feature of most forms of CNS trauma and neurological diseases including Parkinson’s disease, Alzheimer’s disease, subarachnoid hemorrhage, epilepsy, and autism (Table 1).
Common to all forms of traumatic or ischemic CNS injury is damage to the blood-brain or blood-spinal cord barriers (BBB/BSCB). A dysfunctional BBB/BSCB may also underlie autoimmune pathogenesis in traditional forms of neurodegeneration (e.g., Parkinson’s disease) (Carvey et al., 2009; Rite et al., 2007). The BBB/BSCB is comprised of a specialized network of endothelia and glia that limit cell and protein entry into the CNS from the circulation. When the BBB/BSCB is physically damaged (e.g., blunt trauma, penetrating lesion), recruitment and maintenance of immune cells is increased (Figure 1). This process is facilitated by factors released from activated glia and injured neurons (e.g., chemokines). Also, vascular injury can enhance egress of putative autoantigens from the CNS to secondary lymphoid tissue via blood and/or primitive lymphatics (Knopf et al., 1998). Although most antibodies and lymphocytes with autoreactive potential are held in check by complex mechanisms of central and peripheral tolerance (Basten and Silveira, 2010), their pathogenic potential can be unleashed when the BBB/BSCB is compromised.
The autoreactive lymphocyte repertoire that accompanies neurological injury may also be comprised of memory T and B cells that had been activated previously by bacteria, virus, or other non-CNS self-antigens (Perry et al., 2003; Teeling and Perry, 2009). Indeed, lymphocytes with receptors that recognize pathogenic or systemic antigens (e.g., nucleic acids) can cross-react with CNS antigens (Figure 1). This concept of lymphocyte “polyspecificity,” previously referred to as molecular mimicry, could explain why anti-CNS T and B cell responses increase in animals and people with neurological disease. Memory lymphocytes could respond to CNS antigens directly or become re-activated by polyclonal stimuli including environmental pathogens or commensal bacteria that can translocate from the intestines into the circulation (Bansal et al., 2009; Liu et al., 2004). These endogenous bacteria could trigger polyclonal activation of B cells via toll-like receptors (TLRs) including TLR4 and RP105 (Akira et al., 2001; Medzhitov, 2001). Ligation of these receptors on B cells has been shown to exacerbate inflammatory disease (Kobayashi et al., 2008). Through these interactions, exogenous or endogenous microorganisms could amplify B cell responses, leading to enhanced neuroinflammatory reactions after CNS injury.
Pathological and Beneficial Consequences of Autoantibodies After CNS Injury
Numerous autoantigens have been identified that cause or exacerbate human neurological disease. For example, the presence of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-myelin basic protin (MBP) antibodies predicts relapses in multiple sclerosis (MS) patients (Berger et al., 2003; Olsson et al., 1990). After an acute first-ever stroke, mean levels of anti-neurofilament (NF) antibodies are elevated above baseline for many months after the insult (Bornstein et al., 2001). Similarly, levels of autoantibodies that bind to subunits (NR2A/2B) of the NMDA receptor increase significantly in people who suffer from transient ischemic attacks and acute ischemic strokes (Dambinova et al., 2003; Dambinova et al., 2002). In the majority of people who suffer from TBI or SCI, antibodies are produced that target gangliosides, myelin-associated glycoprotein (MAG), glutamate receptors, β-III tubulin, and nuclear antigens (Davies et al., 2007; Hayes et al., 2002; Lopez-Escribano et al., 2002; Prochazka et al., 1971; Skoda et al., 2006).
It is possible that if most autoantibodies produced after CNS injury are “natural” autoantibodies, they could bind CNS antigens without causing harm (Ehrenstein and Notley, 2010; Wright et al., 2009). B-1 cells synthesize natural IgM autoantibodies that bind multiple self-antigens with low affinity and these autoantibodies help clear aging and damaged cells and have anti-inflammatory functions (Baumgarth, 2010; Ehrenstein and Notley, 2010). Natural IgM autoantibodies also have been identified that can enhance remyelination and prevent neuronal apoptosis in animal models of MS (Vargas et al., 2010; Warrington and Rodriguez, 2010). Mechanistic studies indicate that by binding glycolipids and proteins on glia and neurons, natural autoantibodies trigger intracellular signaling pathways that promote protection and repair (Watzlawik et al., 2010; Wright et al., 2009). If this response is conserved across neurological disorders, it is of obvious benefit. However, independent research conducted in non-CNS tissues has shown that natural autoantibodies can exacerbate ischemia/reperfusion injury via a mechanism involving complement activation (Zhang et al., 2004). Clearly, further research is needed before the neurological significance of natural autoantibodies could be understood.
In mice and rats, spinal contusion injury triggers B and T cell expansion in spleen and lymph nodes coinciding with an increase in circulating IgG antibodies (Ankeny et al., 2006; Popovich et al., 2001). Thus, B-2 cells (rather than B-1 cells) and T lymphocytes are the predominant effectors of adaptive autoimmunity after SCI. Activated B and T cells also infiltrate and accumulate within the injured spinal cord where they form large cellular clusters that are reminiscent of germinal centers normally found in spleen and lymph nodes (Ankeny et al., 2006). These clusters may be important for increasing intraparenchymal antibody synthesis (Ankeny et al., 2009). Preliminary proteomics analyses indicate that >50 different self-proteins are targeted by SCI autoantibodies (unpublished data). Because many of these autoantigens exist throughout the body (e.g., actin, nuclear proteins), it may be appropriate to consider SCI as a trigger for CNS and systemic autoimmune disease. For example, an increase in autoantibodies that are able to bind both nuclear antigens (e.g., RNA/DNA) and glutamate receptors (Ankeny et al., 2006) could cause or exacerbate idiopathic cognitive deficits, renal problems, and reproductive sterility. All are secondary consequences of impaired neural function in people with SCI; autoimmune reactions may cause or exacerbate these pathological manifestations (Davidoff et al., 1992). Indeed, in patients with neuropsychiatric lupus, the polyspecific antibodies that bind DNA and NMDA receptors also cause kidney pathology and cortical neurodegeneration (DeGiorgio et al., 2001; Kowal et al., 2004).
The potential consequences of increased autoantibody synthesis after CNS injury are complex and may be affected by characteristics of the antibodies (e.g., isotypes, specificity, titer) and the lesion environment (injury location and severity, cofactors including time post injury and location of antibody deposition relative to the site of primary tissue damage) (Ankeny and Popovich, 2010; Archelos and Hartung, 2000; Popovich and Longbrake, 2008). As previously documented in other neurological autoimmune diseases, autoantibodies can impair cellular function by binding structural proteins and surface receptors. This alone may disrupt function but without causing overt pathology or cell loss. However, if antibody:antigen complexes activate complement or bind Fc receptors on myeloid and/or lymphoid cells, cell death and tissue pathology can occur. The recruitment and activation of complement and Fc receptor-bearing cells has been reported after traumatic SCI. In SCI mice, antibody and complement 1q (C1q) outline neuronal profiles in spared tissue and co-localize with regions of axonal injury and demyelination (Ankeny et al., 2009). Also, demyelination and inflammatory pathology are reduced and functional recovery is improved in SCI mice that are deficient in complement C3 (Qiao et al., 2006). When injected into intact spinal cord, antibodies purified from SCI mice cause pathology and neurological dysfunction; however, the destructive effects of SCI autoantibodies are attenuated when injected into mice deficient in complement C3 or Fc receptor γ chain (Ankeny et al., 2009). Together, these data help explain why recovery from SCI is improved and neuropathology is reduced in mice lacking B cells (Ankeny et al., 2009). Similar data confirming a pathological role for B cell activation and autoantibody synthesis after TBI or stroke/ischemic CNS injury are not currently available; however, complement activation has been implicated in each case (Leinhase et al., 2006; Mocco et al., 2006; Sewell et al., 2004; Ten et al., 2010).
Implications for Treatment and Prognosis of CNS Injury
The detection and identification of autoantibodies could have therapeutic and diagnostic value for traumatic CNS injury and various types of neurological disease. Most data indicate that CNS autoantibodies can cause tissue damage; therefore, strategies to remove or deplete autoantibodies or suppress B cell activation could be effective neuroprotective therapies (Martin and Chan, 2006). Although some B cell depleting monoclonal antibodies (e.g., Rituxan®, Ocrelizumab®) and fusion proteins or biologicals that regulate B-cell survival factors (e.g., BAFF and APRIL) have or are being tested as therapies for classical forms of autoimmune disease (Mackay et al., 2003), similar strategies have not been used to treat stroke, CNS injury, or neurodegenerative disease. In addition, the presence of specific autoreactive antibodies in patients offers an opportunity for early diagnosis of CNS diseases. For example, an increase in circulating levels of anti-cardiolipin (CL), anti-phospholipid (PL), and anti-β2-glycoprotein I (GPI) antibodies can help diagnose risk of stroke (Tanne et al., 1998; Urbanus et al., 2009). In the future, it may be possible to stratify the severity of injuries in a stroke, TBI, or SCI patient population based on their autoantibody profiles. Such an approach could be useful for predicting responders and non-responders for clinical trial design and perhaps for devising uniquely tailored treatment strategies. Indeed, a preponderance of a given autoantibody may help to predict changes in specific neurological functions and/or systemic pathologies.
Supported in part by NIH NS047175 and NS067260 and the Ray W. Poppleton Endowment.
The authors report no conflicts of interest.
Phillip G. Popovich, Ph.D., Center for Brain and Spinal Cord Repair, Department of Neuroscience, The Ohio State University Medical Center, 786 Biomedical Research Tower, 460 West 12th Avenue, Columbus, Ohio 43210, USA.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(60):395-402, May 2011.]