Interferon-gamma expression in periventricular leukomalacia in the human brain

Periventricular leukomalacia (PVL), the major lesion underlying cerebral palsy in survivors of prematurity, is characterized by focal periventricular necrosis and diffuse gliosis of immature cerebral white matter. Causal roles have been ascribed to hypoxiaischemia and maternal-fetal infection, leading to cytokine responses, inflammation, and oligodendrocyte cell death. Because interferon-gamma (IFN-gamma) is directly toxic to immature oligodendrocytes, we tested the hypothesis that it is expressed in PVL (N = 13) compared to age-adjusted controls (N = 31) using immunocytochemistry. In PVL, IFN-gamma immunopositive macrophages were clustered in necrotic foci, and IFN-gamma immunopositive reactive astrocytes were present throughout the surrounding white matter (WM). The difference in the number of IFN-gamma immunopositive glial cells/high power field (IFN-gamma score, Grades 0-3) between PVL cases (age-adjusted mean 2.59+/-0.25) and controls (age-adjusted mean 1.39+/-0.16) was significant (p<0.001). In the gliotic WM, the IFN-gamma score correlated with markers for lipid peroxidation, but not nitrative stress. A subset of premyelinating (04+) oligodendrocytes expressed IFN-gamma receptors in PVL and control cases, indicating that these cells are vulnerable to IFN-gamma toxicity via receptor-mediated interactions. In PVL, IFN-gamma produced by macrophages and reactive astrocytes may play a role in cytokine-induced toxicity to premyelinating oligodendrocytes as part of a cytokine response stimulated by ischemia and/or infection.