B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

Abstract

IntroductionThe consequences of neuroinflammation caused by spinal cord injury (SCI) have been inferred mostly from the results of studies that manipulate the function or survival of neutrophils, monocytes/macrophages or T lymphocytes (T cells) (1-9). Less is known about the role played by antibody-producing B cells. In humans with SCI, elevated titers of myelin-reactive antibodies in serum and cerebrospinal fluid (CSF) suggest that SCI activates T and B cells that recognize CNS proteins (10-12). Using a clinically relevant murine model of SCI, we have shown that SCI induces a long-lasting B cell response, characterized by enhanced lymphopoiesis in bone marrow and spleen, with increased levels of circulating IgM and IgG antibodies (13). Activated B cells also accumulate in the injured spinal cord, in which they persist indefinitely (13). Accumulation of intraspinal B cells also is associated with de novo expression of mRNA that encodes a range of autoantibodies (14).Currently, the breadth of self/auto antigens recognized by SCIinduced antibodies is not known; however, some will bind CNS proteins and the potential exists for antibody-mediated neurodegeneration (10, 11, 13). Previously, we showed that microinjection of sera containing SCI antibodies into the intact CNS caused focal inflammation and neurotoxicity (13). Conversely, sera from SCI B cell-knockout mice (BCKO mice), which cannot make antibodies, was innocuous (13). Collectively, these data suggest that activated B cells contribute to the pathological sequelae of SCI, presumably via production of autoantibodies and activation of downstream inflammatory cascades. Here, we prove there is a causal role for B cells as effectors of post-SCI pathology. Specifically, we show that behavioral and anatomical indices of recovery from SCI are improved in BCKO mice and that B cell-mediated pathology is caused by the antibodies they produce. Indeed, antibodies purified from SCI mice cause axon and myelin pathology with transient impairment of motor function. Antibody-mediated pathology is dependent on activation of complement and cells bearing Fc-receptors in the spinal cord. Collectively, these data suggest that con-

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

“…Second, these findings demonstrate that the humoral immune system, via the action of endogenous antibodies, can actively promote wound healing in the absence of an overtly immunogenic stimulus, such as vaccination, by recognizing degenerating tissue as nonself. Interestingly, several weeks after spinal cord injury B-cell numbers increase in spleen and bone marrow suggesting that failure to clear CNS debris may trigger pathological B-cell activation (20,21). These data suggest the hypothesis that B-cell mediated autoimmune disease in the nervous system may in some cases arise from aberrations in a normally beneficial process-the clearance of myelin debris by endogenous antibodies.…”

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

“…In MS, neuronal antigens are readily detected in the CSF ), in CLN (van Zwam et al, 2009) and, as we show here within cells in the CSF. That such release of neuronal antigens may be pathogenic has been shown in adoptive transfer of antibodies from mice with spinal cord injury that on intraspinal injection into healthy mice cause hind limb paralysis (Ankeny et al, 2009). Naturally occurring antibodies that distinguish damaged tissue as non-self are required for the rapid and efficient removal of damaged axons and myelin after nerve crush (Vargas et al, 2010).…”

Pathogenic antibodies are active participants in spinal cord injury

“…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.…”

“…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.…”