Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury

Abstract

Traumatic spinal cord injury (SCI) in mammals causes widespread glial activation and recruitment to the CNS of innate (e.g. neutrophils, monocytes) and adaptive (e.g. T and B lymphocytes) immune cells. To date, most studies have sought to understand or manipulate the post-traumatic functions of astrocytes, microglia, neutrophils or monocytes. Significantly less is known about the consequences of SCI-induced lymphocyte activation. Yet, emerging data suggest that T and B cells are activated by SCI and play significant roles in shaping post-traumatic inflammation and downstream cascades of neurodegeneration and repair. Here, we provide neurobiologists with a timely review of the mechanisms and implications of SCI-induced lymphocyte activation, including a discussion of different experimental strategies that have been designed to manipulate lymphocyte function for therapeutic gain.

Figure 1

SCI triggers production of antibodies specific for systemic and CNS antigens. (A) Sera from naïve (n=5; lanes 1-5), sham (n=4; lanes 6-9) or SCI mice at 14 (n=5; lanes 10-14) or 42 days post-injury (n=5; lanes 15-19) were used to probe homogenized CNS proteins. Lane 20 was probed with a commercial anti-MBP antibody (1:40,000) and lane 21 with serum (1:200) from a mouse immunized 35d previously with 200 μg guinea-pig MBP in adjuvant. Quantitation of mean band intensity in each lane within a group is shown and reveals marked induction of anti-CNS antibodies at 42 dpi vs. naïve, sham and 14 dpi groups (OD ± SEM at the bottom of each column; *** p< 0.001 vs naive, **p < 0.01 vs sham, *p < 0.05 vs dpi 14, ANOVA with Tukey's post test; mean binding in samples from sham or uninjured mice were not different from zero; t-test). (B-G) Sera were used to probe HEp-2 (B-D) and Crithidia luciliae (E-G) substrate slides (for anti-nuclear and anti-DNA antibodies, respectively). Sera from SCI B cell knockout (BCKO, B&E) and uninjured (C&F) mice fail to show anti-nuclear or anti-DNA binding. In contrast, sera from SCI C57BL/6 mice (D&G) reveal strong binding to nuclear antigens and DNA. High power (inset in D) shows labeling consistent with binding to nuclear membranes, nucleosomes and/or centromeres. (H) Sera from SCI mice indicate possible binding to neuronal glutamate receptors [∼110 kD; compare anti-GluR2/3 positive-control labeling (lane 1) with SCI (dpi 42) sera labeling in lane 2]. Pre-injury sera failed to bind neuronal antigens (lane 3; arrow). Scale = 25 μm (B-G). (I) Gene chip data shows upregulation of selected genes encoding autoreactive immunoglobulins within the mouse SCI contusion site. Data are expressed relative to genes found in the spinal cord of mice given laminectomy (sham) surgery but no SCI. (A-H reprinted with permission from The Journal of Neurochemistry, November 2006, Volume 99(4), pg 1073-1087.)