Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage

The role of focal brain damage as a trigger for autoimmune inflammation in multiple sclerosis (MS) is unclear. In this study we examine mechanisms by which experimental autoimmune encephalomyelitis (EAE) is enhanced by focal brain damage. EAE was produced in Lewis rats by footpad inoculation; focal brain damage, in the form of a cortical cryolesion (cryolesion-EAE), was in duced 8 days post-inoculation (d.p.i.). The distribution of inflammation an d chemokine production in cryolesion-EAE and EAE-only were compared. Inflam mation in the brain, measured by immunocytochemistry for T lymphocytes (W3/ 13) and microglial activation (MHC class II -OX6), was significantly enhanc ed in cryolesion-EAE 11-15 d.p.i. (p < 0.01-0.05) but by 20-40 d.p.i., equa ted with EAE-only. Inflammation in cryolesion-EAE related to breakdown of t he blood-brain barrier (BBB) at the site of the cryolesion and also to the corticospinal tracts and thalamus, reflecting the afferent and efferent neu ronal connections with the cryolesioned cortex. Semiquantitative RT/PCR dot -blot hybridization assay showed a 6-fold increase in mRNA for specific che mokines in the brain in cryolesion-EAE at 9 d.p.i. (MCP-1) and 11 d.p.i. (M CP-1 and MCP-5) with no significant increase in RANTES, GRO-<alpha>, or MIP -1 alpha. By 14 d.p.i., the levels of MCP-1 and MCP-5 mRNA equated with EAE -only animals. These results suggest that enhancement and location of autoi mmune inflammation in the brain following focal cortical injury initially i nvolve chemokines such as the macrophage chemoattractants MCP-1 and MCP-5, and the activities of afferent and efferent neuronal connections with the s ite of damage. By analogy, similar factors may modulate or reactivate autoi mmune inflammation in MS.