T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases

Recent evidence has highlighted the fact that axon injury is an important c omponent of multiple sclerosis pathology. The issue of whether a CNS antige n-specific immune response is required to produce axon injury remains unres olved. We investigated the extent and time course of axon injury in a roden t model of a delayed-type hypersensitivity (DTH) reaction directed against the mycobacterium bacille Calmette-Guerin (BCG). Using MRI, we determined w hether the ongoing axon injury is restricted to the period during which the blood-brain barrier is compromised. DTH lesions were initiated in adult ra ts by intracerebral injection of heat-killed BCG followed by a peripheral c hallenge with BCG. Our findings demonstrate that a DTH reaction to a non-CN S antigen within a CNS white matter tract leads to axon injury. Ongoing axo n injury persisted throughout the 3-month period studied and was not restri cted to the period of blood-brain barrier breakdown, as detected by MRI enh ancing lesions. We have previously demonstrated that matrix metalloproteina ses (MMPs) are upregulated in multiple sclerosis plaques and DTH lesions. I n this study we demonstrated that microinjection of activated MMPs into the cortical white matter results in axon injury. Our results show that axon i njury, possibly mediated by MMPs, is immunologically non-specific and may c ontinue behind an intact blood-brain barrier.