A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy
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.
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).
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).
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.
KeywordsProgressive multifocal leukoencephalopathy CD4:CD8 ratio Regulatory plasma cell IRIS JC virus PML
The authors thank Kazuo Nakamichi, Ph.D. in the Department of Virology 1 at the National Institute of Infectious Diseases for providing a part of patient data, Daisuke Ono and Hiroto Fujigasaki in the Department of Neurology at the Bokutoh Hospital for their cooperation. The authors also thank members of the PML Surveillance Committee in Japan, as well as the patients with PML and their families for providing important clinical information.
NS: study concept and design, acquisition, analysis and interpretation of data, statistical analysis, and drafting/revising the manuscript; YN: acquisition of data and drafting/revising the manuscript; YS-H: acquisition of data and drafting/revising the manuscript; SM: acquisition of data and drafting/revising the manuscript; YS: acquisition of data and drafting/revising the manuscript; HA: acquisition of data and drafting/revising the manuscript; TT: drafting/revising the manuscript; TY: drafting/revising the manuscript.
This work was supported by a Grant-in-Aid from the Research Committee of Prion Disease and Slow Virus Infection of the Ministry of Health, Labour, and Welfare of Japan (NS, YS-H); and a Grant-in-Aid from the Research Committee of Molecular Pathogenesis and Therapies for Prion Disease and Slow Virus Infection of the Ministry of Health, Labour, and Welfare of Japan (NS, YS-H). This work was, in part, supported by JSPS KAKENHI Grant Number 18K07397 (Y S-H).
Compliance with ethical standards
Conflicts of interest
The authors have NO affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.
The protocol followed ethical requirements and was approved by the Institutional Ethics Committee of Tokyo Medical and Dental University. This study was performed in accordance with the ethical standards laid down by the 2013 Declaration of Helsinki.
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