Spinal cord injury (SCI) activates immune cells that cause neuroinflammation and tissue destruction (secondary injury). To date, nearly all studies in this area have focused on the effects of macrophages and T cells. However, antibodies (Abs) that bind CNS proteins (autoantibodies) accumulate in SCI patients, demonstrating that B cells (Ab-producing immune cells) are also activated by SCI. Our preliminary studies show that mice given experimental SCI also show strong B cell activation and autoantibody (autoAb) production. However, the effect of this B cell activation is not known. The normal function of Abs is to bind and eliminate the cell or substance that they bind to--even if they bind self tissues. Indeed, in other autoimmune diseases (e.g., lupus and multiple sclerosis), autoAbs bind and kill neurons and/or myelin- forming oligodendrocytes. Thus, we predict that autoAbs may cause similar effects after SCI. We propose two specific aims to address this hypothesis.
In Aim 1, we will investigate the functional effects of Abs produced after SCI. Purified serum Abs from uninjured or SCI mice will be microinjected into the CNS of na?ve or SCI animals. Histological and immunohistochemical techniques will then be used to reveal Ab-mediated changes in neuron/glial survival, axon pathology and/or demyelination.
In Aim 2, we will evaluate the contributions of B cells to SCI degeneration by comparing post-SCI functional and anatomical outcome measures in normal mice and those devoid of B cells (B cell knockout, BCKO). Locomotor recovery and spinal reflex function as well as lesion morphometry, demyelination and neuron/axon survival will be examined to determine if the absence of B cells diminishes SCI-induced secondary injury. The presence of decreased dysfunction and neuropathology in BCKO mice will be interpreted as evidence that B cells enhance secondary injury after SCI. Collectively, the aims and experiments in this proposal will provide critical information about the contributions of antibody-producing B cells to the tissue damage caused by spinal cord injury. This information is essential because the B cell responses that occur in SCI patients may cause neuron and glial cell death. If so, then manipulating (specifically, inhibiting) B cell function may be useful as a therapy for these patients.
The aims and experiments in this proposal will provide critical information about the contributions of antibody-producing B cells to the tissue damage caused by spinal cord injury-a debilitating CNS disorder. This information is essential because the B cell responses that occur in spinally-injured patients may cause neuron and glial cell death. If so, then manipulating (specifically, inhibiting) B cell function may be useful as an acute and chronic therapy for these patients. ? ? ? ?
| Ankeny, D P; Popovich, P G (2009) Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury. Neuroscience 158:1112-21 |
| Ankeny, Daniel P; Guan, Zhen; Popovich, Phillip G (2009) B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J Clin Invest 119:2990-9 |
