Multiple Sclerosis: Pathogenesis and MR Imaging Features of T1 Hypointensities in Murine Model

Abstract

To prospectively determine how T1 hypointensities (T1 black holes) on brain magnetic resonance (MR) images are generated by the immune system by using a Theiler murine encephalitis virus-induced model of multiple sclerosis and high-field-strength MR imaging. All animal protocols and experiments were approved by the institutional animal care and use committee. Volumetric MR imaging studies were conducted at 7 T in six C57BL/6 mice and in immune differentiation marker (recombination activation gene [RAG]-1)-, immune cell (CD4, CD8)-, and immune effector molecule (Fas ligand, perforin)-deficient mice (six mice in each group) to determine which immune cell types and effector molecules lead to T1 hypointensities. The main outcome measure was the total T1 black hole volume per animal, as determined with volumetric analysis, and was analyzed statistically by using software. Compared with C57BL/6 mice, RAG-1-deficient mice showed a significant (P = .003) decrease in total T1 black hole volume, suggesting a clear role for the adaptive immune system. While CD4-deficient mice did not show a significant decrease in T1 black hole volume (P = .33), CD8-deficient mice did (P = .003). Perforin-deficient mice showed a significant reduction of T1 black hole volume (P = .002), whereas Fas ligand-deficient mice did not (P = .77). The data suggest that CD8 T cells utilizing perforin effector molecules are responsible for T1 black hole formation.