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Pathogenic antibodies are active participants in spinal cord injury
Gregory A. Dekaban and Sakina Thawer
BioTherapeutics Research Laboratory, Molecular Brain Research Group, Robarts Research Institute and Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
Address correspondence to: Gregory A. Dekaban, BioTherapeutics Research Laboratory, Molecular Brain Research Group, Robarts Research Institute, Rm 2-12, 100 Perth Drive, London, Ontario, N6A 5K8 Canada. Phone: (519) 663-5777 ext. 24241; Fax: (519) 391-5789; E-mail: dekaban@robarts.ca.
Find articles by Dekaban, G. in: JCI | PubMed | Google Scholar
BioTherapeutics Research Laboratory, Molecular Brain Research Group, Robarts Research Institute and Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
Address correspondence to: Gregory A. Dekaban, BioTherapeutics Research Laboratory, Molecular Brain Research Group, Robarts Research Institute, Rm 2-12, 100 Perth Drive, London, Ontario, N6A 5K8 Canada. Phone: (519) 663-5777 ext. 24241; Fax: (519) 391-5789; E-mail: dekaban@robarts.ca.
Find articles by Thawer, S. in: JCI | PubMed | Google Scholar
Published September 21, 2009 - More info
J Clin Invest. 2009;119(10):2881–2884. https://doi.org/10.1172/JCI40839.
© 2009 The American Society for Clinical Investigation
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Abstract
Traumatic injury to the mammalian spinal cord activates B cells, which culminates in the synthesis of autoantibodies. The functional significance of this immune response is unclear. Here, we show that locomotor recovery was improved and lesion pathology was reduced after spinal cord injury (SCI) in mice lacking B cells. After SCI, antibody-secreting B cells and Igs were present in the cerebrospinal fluid and/or injured spinal cord of WT mice but not mice lacking B cells. In mice with normal B cell function, large deposits of antibody and complement component 1q (C1q) accumulated at sites of axon pathology and demyelination. Antibodies produced after SCI caused pathology, in part by activating intraspinal complement and cells bearing Fc receptors. These data indicate that B cells, through the production of antibodies, affect pathology in SCI. One or more components of this pathologic immune response could be considered as novel therapeutic targets for minimizing tissue injury and/or promoting repair after SCI.
Authors
Daniel P. Ankeny, Zhen Guan, Phillip G. Popovich
Primary trauma to the CNS initiates a series of interrelated responses, including edema, excitotoxicity, and inflammation, that lead to secondary injury, resulting in further expansion of the initial lesion and additional loss of neurological function. The treatment of neuroinflammation in the context of both traumatic brain injury and spinal cord injury (SCI) still lacks a standard, universally accepted therapy that leads to improved neurological outcomes. There exists a clear, unmet medical need for an effective antiinflammatory treatment for the acute and chronic stages of traumatic brain injury and SCI arising in general civilian as well in injured military personnel populations. Currently, an important area of SCI research focuses on understanding the dual nature of post-SCI neuroinflammation. It can lead to increased damage to the neural tissue, yet it is an essential part of the wound healing process (1, 2). It is becoming increasingly clear that injury to the CNS results in alterations to the systemic immune system that in turn affect the competing pathogenic and wound healing processes evolving at the site of injury (3–5). The study reported by Ankeny et al. in this issue of the JCI (6) offers a new perspective on a poorly understood aspect of CNS inflammation in response to traumatic injury in mice, namely the impact of B cells and autoimmunity on neurological outcomes. This new understanding of SCI disease pathogenesis, if confirmed in humans, reveals avenues for the development of novel neuroprotective immunotherapies.
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SCI leads to pathogenic autoantibody production
The results presented in this issue by Ankeny et al. (6) clearly demonstrate that, in a mouse model of SCI, trauma of moderate severity at thoracic level 9 (T9) leads to a surprisingly robust B cell response that produces pathogenic antibodies. This important conclusion is supported by experiments demonstrating that spontaneous neurological recovery after injury was greatly improved in B cell–knockout mice compared with WT mice. Following SCI, coordinated stepping involving all four limbs was achieved in 88% of B cell–knockout mice but in only 35% of WT mice at the end of the nine-week observation period. Consistent with this improved functional recovery, the neuropathology observed in the B cell–knockout mice was also markedly less pronounced compared with WT animals. This suggests that, in WT mice that received an SCI, B cells play a role in the evolving inflammatory response that impedes neurological recovery. Importantly, passive transfer (injection) of purified pathogenic antibody into the spinal cord of WT mice under sterile conditions induced a similar type of neurotoxicity to that observed in mice with SCI. This confirmed that neurotoxic product of the SCI-induced B cell activation was likely pathogenic antibodies.
This article (6) raises the question as to why B cells produce pathogenic antibodies when the SCI is in the lower half of the spinal cord (T9–T10). Yet, these same authors previously reported that when the SCI occurs at a higher level (T4–T5) profound immune suppression occurs, including that of B cell function (13). A likely explanation may lie in the fact that a high SCI disrupts the cholinergic antiinflammatory pathway by removing the sympathetic contribution (via the splenic nerves) due to injury to the intermediolateral column sympathetic fibers. This pathway plays a key role in regulating systemic inflammation (4). Further investigation is required to understand the underlying pathological mechanisms created by the loss of sympathetic control that results in immune suppression and whether this is a permanent feature of SCI located above T4/T5. Alternatively, the appearance of autoimmune neuropathogenic antibodies may only be delayed.
The presence of pathogenic antibodies in the spinal lesion is in part derived from systemic sources via a compromised blood–spinal cord barrier after injury. However, evidence was presented by Ankeny et al. (6) that B cell “follicle-like” structures were present in the lesion area, suggesting that local antibody production may be critical to the pathogenic outcome. Both activated B cells and plasma cells are present in these structures. The presence of B cell follicle-like structures in the diseased CNS is not unique to SCI but has been described in other CNS autoimmune diseases, including MS (9). The local SCI inflammatory environment likely would support the development of B cell follicle-like structures in two ways. Infiltrating monocyte/macrophages as well as the large number of proliferating astrocytes responding to the SCI likely could supply sufficient BAFF and APRIL to support B cell survival, proliferation, differentiation as well as follicle development (Figure 1). Secondly, SCI-induced neuroinflammation dysregulates an important immune regulatory mechanism known as the tryptophan–kynurenine pathway (14–17). The critical component of this tryptophan catabolic pathway is the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), which is primarily induced by IFN-γ but can be superinduced in the presence of TNF-α (14, 15). Both cytokines are present following SCI. IDO is a key regulator of tolerance and a preventer of autoimmunity (18, 19). IDO is expressed by activated microglia and infiltrating leukocytes (14). T cells, but not B cells, are particularly sensitive to the effects of IDO. The tryptophan metabolites generated by IDO, such as quinolinic acid, are well known neurotoxins and also render T cells, but not B cells, highly susceptible to apoptosis and other aspects of IDO-mediated regulation (4, 14, 17, 19). This alters the local cytokine environment to one that favors B cell autoimmunity and antibody production (17, 19) (Figure 1). Thus, within the SCI lesion, the local environment is conducive to the support of B cells and antibody production.
Figure 1B cells and an autoimmune response contribute to poor neurological outcome following SCI. After SCI, B cells, together with other leukocytes such as monocyte/macrophages (hMϕ) and T cells, infiltrate the lesion. Resident activated microglia, microglia-derived macrophages (mMϕ), and astrocytes, also surround and/or infiltrate the lesion. Infiltrating macrophages as well as proliferating astrocytes respond to the SCI by producing BAFF, lymphotoxin-β, and APRIL, which support B cell survival, proliferation, and differentiation as well as B cell follicle development. Follicle-like structures appear at the lesion area and house activated B cells and plasma cells. Additionally, the high levels of IFN-γ and TNF-α present at the SCI lesion will induce IDO expression, a key regulator of tolerance and a preventer of autoimmunity. IDO is expressed by activated microglia and infiltrating leukocytes. The toxic tryptophan metabolites generated by IDO render T cells but not B cells highly susceptible to apoptosis. This creates a cytokine environment that favors B cell autoimmunity and antibody production. Thus, within the SCI lesion, the local environment is conducive to the support of B cells and antibody production. Therapeutics such as blockers of BAFF, APRIL, or lymphotoxin-β; anti-CD20 monoclonal antibodies; and IVIG could prevent follicle-germinal center development, deplete B cells (but not plasma cells), and block the pathogenic activity of autoantibodies to neural antigens at the site of the SCI. These therapeutic agents could be used singly or in combination in order to obtain maximal benefit.
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