Pathological CNS Autoimmune Disease Triggered by Traumatic Spinal Cord Injury: Implications for Autoimmune Vaccine Therapy

Abstract

Lymphocytes respond to myelin proteins after spinal cord injury (SCI) and may contribute to post-traumatic secondary degeneration. However, there is increasing evidence that autoreactive T-lymphocytes may also convey neuroprotection and promote functional recovery after CNS injury. To clarify the role of myelin autoreactive lymphocytes after SCI, we performed contusion injuries in the thoracic spinal cord of transgenic (Tg) mice in which >95% of all CD4+ T-lymphocytes are reactive with myelin basic protein (MBP). We observed significantly impaired recovery of locomotor and reflex function in Tg mice compared with non-Tg (nTg) littermates. Measures of functional impairment in Tg mice correlated with significantly less white matter at the injury site, and morphometric comparisons of injured Tg and nTg spinal cords revealed increased rostrocaudal lesion expansion (i.e., secondary degeneration) in Tg mice. Rostrocaudal to the impact site in SCI-nTg mice, demyelination was restricted to the dorsal funiculus, i.e., axons undergoing Wallerian degeneration. The remaining white matter appeared normal. In contrast, lymphocytes were colocalized with regions of demyelination and axon loss throughout the white matter of SCI-Tg mice. Impaired neurological function and exacerbated neuropathology in SCI-Tg mice were associated with increased intraspinal production of proinflammatory cytokine mRNA; neurotrophin mRNA was not elevated. These data suggest that endogenous MBP-reactive lymphocytes, activated by traumatic SCI, can contribute to tissue injury and impair functional recovery. Any neuroprotection afforded by myelin-reactive T-cells is likely to be an indirect effect mediated by other non-CNS-reactive lymphocytes. Similar to the Tg mice in this study, a subset of humans that are genetically predisposed to autoimmune diseases of the CNS may be adversely affected by vaccine therapies designed to boost autoreactive lymphocyte responses after CNS trauma. Consequently, the safe implementation of such therapies requires that future studies define the mechanisms that control T-cell function within the injured CNS.

Treatment with Immunosuppressants FTY720 and Tacrolimus Promotes Functional Recovery after Spinal Cord Injury in Rats

“…It was reported recently that SCI could trigger an autoimmune response to myelin basic protein (MBP) (Jones et al 2002). MBP immunizations exacerbated neurological deficits, demyelination, and / or neuronal survival / function in animals subjected to SCI.…”

Sensitization to Brain Antigens after Stroke is Augmented by Lipopolysaccharide

“…When the BBB is compromised by recurrent stroke or systemic inflammation, CNS autoreactive T cells could transit into brain and cause injury. This potential is illustrated by the fact that transgenic animals in which 495% of CD4 þ T cells express receptors specific for MBP experience less recovery after spinal cord injury than wild-type controls and that animals immunized to MBP are more likely to die after MCAO (Becker et al, 1997;Jones et al, 2002). Moreover, T lymphocytes obtained from animals shortly after spinal cord injury precipitate histopathologic changes similar to experimental allergic encephalomyelitis (EAE) when injected into naïve animals (Popovich et al, 1996).…”

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

“…Experimental studies are only now beginning to explore their function in spinal cord injury. CNS-reactive T-cells exacerbate axonal injury, demyelination, and functional loss after experimental spinal cord injury (51,82,83) . Moreover, mice with a transgenic T-cell receptor specific to myelin exhibit worse functional outcomes after spinal cord injury than mice of the same genetic background.…”

“…Moreover, mice with a transgenic T-cell receptor specific to myelin exhibit worse functional outcomes after spinal cord injury than mice of the same genetic background. This difference may be attributed to altered chemokine expression (55,82) .…”