Nobuo Sanjo1, Yurie Nose2, Yukiko Shishido-Hara3, Saneyuki Mizutani4, Yoshiki Sekijima5, Hitoshi Aizawa6, Toru Tanizawa7, Takanori Yokota2. 1. Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan. n-sanjo.nuro@tmd.ac.jp. 2. Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan. 3. Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan. 4. Department of Internal Medicine (Neurology), Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan. 5. Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan. 6. Department of Neurology, Tokyo Medical University, Tokyo, Japan. 7. Department of Pathology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
Abstract
OBJECTIVE: In the present study, we analyzed the inflammatory profiles of brain tissues obtained from patients with progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection to identify potential prognostic factors. METHODS: The study included seven patients (two men, five women) who had been pathologically diagnosed with PML, and all of whom were HIV negative. Fixed brain samples were analyzed via hematoxylin and eosin (HE) staining and Klüver-Barrera (KB) staining. We then performed immunohistochemistry (IHC) specific to JC virus capsid proteins (VP1 and VP2/3) and lymphocyte surface markers (CD4, CD8, CD138, and PD-1). RESULTS: The mean age at onset was 53.4, while the mean duration until biopsy/autopsy was 4.7 months. Four patients were included in the good prognosis (GP) group, while three were included in the poor prognosis (PP) group. Pathological analysis revealed a significantly larger number of CD4-positive T-cell infiltrations (P = .029) in the GP group, along with a preserved CD4:CD8 ratio. Larger numbers of CD138-positive plasma cells were also observed in the GP group (P = .029) than in the PP group. Linear regression analyses revealed a significant association between the numbers of CD138-positive plasma cells and PD-1-positive cells (R2 = 0.80). CONCLUSIONS: Viral loads in the cerebrospinal fluid, a controlled inflammatory response mediated by CD4- and CD8-positive T cells, and plasma cells are associated with PML prognosis. Our findings further indicate that regulatory plasma cells may regulate inflammatory T-cell activity via a PD-1/PD-L1 immuno-checkpoint pathway, thereby protecting the uninfected brain from excessive immune-mediated damage during an active JC virus infection.
OBJECTIVE: In the present study, we analyzed the inflammatory profiles of brain tissues obtained from patients with progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection to identify potential prognostic factors. METHODS: The study included seven patients (two men, five women) who had been pathologically diagnosed with PML, and all of whom were HIV negative. Fixed brain samples were analyzed via hematoxylin and eosin (HE) staining and Klüver-Barrera (KB) staining. We then performed immunohistochemistry (IHC) specific to JC virus capsid proteins (VP1 and VP2/3) and lymphocyte surface markers (CD4, CD8, CD138, and PD-1). RESULTS: The mean age at onset was 53.4, while the mean duration until biopsy/autopsy was 4.7 months. Four patients were included in the good prognosis (GP) group, while three were included in the poor prognosis (PP) group. Pathological analysis revealed a significantly larger number of CD4-positive T-cell infiltrations (P = .029) in the GP group, along with a preserved CD4:CD8 ratio. Larger numbers of CD138-positive plasma cells were also observed in the GP group (P = .029) than in the PP group. Linear regression analyses revealed a significant association between the numbers of CD138-positive plasma cells and PD-1-positive cells (R2 = 0.80). CONCLUSIONS: Viral loads in the cerebrospinal fluid, a controlled inflammatory response mediated by CD4- and CD8-positive T cells, and plasma cells are associated with PML prognosis. Our findings further indicate that regulatory plasma cells may regulate inflammatory T-cell activity via a PD-1/PD-L1 immuno-checkpoint pathway, thereby protecting the uninfected brain from excessive immune-mediated damage during an active JC virus infection.
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