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A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy

  • Nobuo Sanjo
  • Yurie Nose
  • Yukiko Shishido-Hara
  • Saneyuki Mizutani
  • Yoshiki Sekijima
  • Hitoshi Aizawa
  • Toru Tanizawa
  • Takanori Yokota
Original Communication

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.

Keywords

Progressive multifocal leukoencephalopathy CD4:CD8 ratio Regulatory plasma cell IRIS JC virus PML 

Notes

Acknowledgements

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.

Author contributions

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.

Funding

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.

Ethical standard

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.

Supplementary material

415_2018_9140_MOESM1_ESM.tif (218 kb)
Supplementary Figure 1. Medical history chart of treatment for underlying diseases in each patient until the onset of PML. Medications, radiation, intravenous cyclophosphamide, intravenous injection of immunoglobulin, and steroid pulse therapy for the underlying disease in each patient are indicated as black rectangles, thin arrows, thick arrows, a white arrow, and triangles, respectively, in each lane. Labels are indicated as month/year. R-CHOP: combination therapy of rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, and prednisolone; DEX: dexamethasone; PSL: prednisolone; IVCY: intravenous cyclophosphamide; IVIg: intravenous injection of immunoglobulin; CPA: oral administration of cyclophosphamide (TIF 217 KB)

References

  1. 1.
    Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687CrossRefPubMedGoogle Scholar
  2. 2.
    Berenguer J, Miralles P, Arrizabalaga J, Ribera E, Dronda F, Baraia-Etxaburu J, Domingo P, Marquez M, Rodriguez-Arrondo FJ, Laguna F, Rubio R, Lacruz Rodrigo J, Mallolas J, de Miguel V, Group GS (2003) Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 36:1047–1052CrossRefPubMedGoogle Scholar
  3. 3.
    Berger JR (2010) Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 33:969–983CrossRefPubMedGoogle Scholar
  4. 4.
    Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A (2013) PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 80:1430–1438CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bossolasco S, Calori G, Moretti F, Boschini A, Bertelli D, Mena M, Gerevini S, Bestetti A, Pedale R, Sala S, Sala S, Lazzarin A, Cinque P (2005) Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 40:738–744CrossRefPubMedGoogle Scholar
  6. 6.
    Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, Simon K, Frisque RJ, Gorelik L (2009) Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 53:1840–1849CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Buckanovich R, Liu G, Stricker C, Luger S, Stadtmauer E, Schuster S, Duffy K, Tsai D, Pruitt A, Porter D (2002) Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin’s lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy. Ann Hematol 81:410–413CrossRefPubMedGoogle Scholar
  8. 8.
    Bygbjerg IC, Svenson M, Theander TG, Bendtzen K (1987) Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes. Int J Immunopharmacol 9:513–519CrossRefPubMedGoogle Scholar
  9. 9.
    Carotenuto A, Scalia G, Ausiello F, Moccia M, Russo CV, Saccà F, De Rosa A, Criscuolo C, Del Vecchio L, Brescia Morra V, Lanzillo R (2017) CD4/CD8 ratio during natalizumab treatment in multiple sclerosis patients. J Neuroimmunol 309:47–50CrossRefPubMedGoogle Scholar
  10. 10.
    Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9:438–446CrossRefPubMedGoogle Scholar
  11. 11.
    Clifford DB, Nath A, Cinque P, Brew BJ, Zivadinov R, Gorelik L, Zhao Z, Duda P (2013) A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurolvirol 19:351–358CrossRefGoogle Scholar
  12. 12.
    Clifford DB, Yiannoutsos C, Glicksman M, Simpson DM, Singer EJ, Piliero PJ, Marra CM, Francis GS, McArthur JC, Tyler KL, Tselis AC, Hyslop NE (1999) HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52:623–625CrossRefPubMedGoogle Scholar
  13. 13.
    Delbue S, Branchetti E, Bertolacci S, Tavazzi E, Marchioni E, Maserati R, Minnucci G, Tremolada S, Vago G, Ferrante P (2009) JC virus VP1 loop-specific polymorphisms are associated with favorable prognosis for progressive multifocal leukoencephalopathy. J Neurovirol 15:51–56CrossRefPubMedGoogle Scholar
  14. 14.
    Delbue S, Elia F, Carloni C, Tavazzi E, Marchioni E, Carluccio S, Signorini L, Novati S, Maserati R, Ferrante P (2012) JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy. J Cell Physiol 227:3511–3517CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Du Pasquier RA, Schmitz JE, Jean-Jacques J, Zheng Y, Gordon J, Khalili K, Letvin NL, Koralnik IJ (2004) Detection of JC virus-specific cytotoxic T lymphocytes in healthy Individuals. J Virol 78:10206–10210CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gheuens S, Bord E, Kesari S, Simpson DM, Gandhi RT, Clifford DB, Berger JR, Ngo L, Koralnik IJ (2011) Role of CD4 + and CD8 + T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with Immune reconstitution inflammatory syndrome. J Virol 85:7256–7263CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gray F, Bazille C, Adle-Biassette H, Mikol J, Moulignier A, Scaravilli F (2005) Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 11(Suppl 3):16–22CrossRefPubMedGoogle Scholar
  18. 18.
    Harel A, Horng S, Gustafson T, Ramineni A, Farber RS, Fabian M (2018) Successful treatment of progressive multifocal leukoencephalopathy with recombinant interleukin-7 and maraviroc in a patient with idiopathic CD4 lymphocytopenia. J NeuroVirolGoogle Scholar
  19. 19.
    Huang D, Cossoy M, Li M, Choi D, Taege A, Staugaitis SM, Rehm S, Ransohoff RM (2007) Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients. Ann Neurol 62:34–39CrossRefPubMedGoogle Scholar
  20. 20.
    Kobayashi Z, Akaza M, Numasawa Y, Ishihara S, Tomimitsu H, Nakamichi K, Saijo M, Morio T, Shimizu N, Sanjo N, Shintani S, Mizusawa H (2013) Failure of mefloquine therapy in progressive multifocal leukoencephalopathy: report of two Japanese patients without human immunodeficiency virus infection. J Neurol Sci 324:190–194CrossRefPubMedGoogle Scholar
  21. 21.
    Lykken JM, DiLillo DJ, Weimer ET, Roser-Page S, Heise MT, Grayson JM, Weitzmann MN, Tedder TF (2014) Acute and chronic B cell depletion disrupts CD4+ and CD8+ T cell homeostasis and expansion during acute viral infection in mice. J Immunol 193:746–756CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Martin JD, King DM, Slauch JM, Frisque RJ (1985) Differences in regulatory sequences of naturally occurring JC virus variants. J Virol 53:306–311PubMedPubMedCentralGoogle Scholar
  23. 23.
    Mauri C, Menon M (2015) The expanding family of regulatory B cells. Int Immunol 27:479–486CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Metz I, Radue EW, Oterino A, Kumpfel T, Wiendl H, Schippling S, Kuhle J, Sahraian MA, Gray F, Jakl V, Hausler D, Bruck W (2012) Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy. Acta Neuropathol 123:235–245CrossRefPubMedGoogle Scholar
  25. 25.
    Nishiyama S, Misu T, Shishido-Hara Y, Nakamichi K, Saijo M, Takai Y, Takei K, Yamamoto N, Kuroda H, Saito R, Watanabe M, Tominaga T, Nakashima I, Fujihara K, Aoki M (2018) Fingolimod-associated PML with mild IRIS in MS: A clinicopathologic study. Neurol Neuroimmunol Neuroinflamm 5:e415CrossRefPubMedGoogle Scholar
  26. 26.
    Okada Y, Sawa H, Endo S, Orba Y, Umemura T, Nishihara H, Stan AC, Tanaka S, Takahashi H, Nagashima K (2002) Expression of JC virus agnoprotein in progressive multifocal leukoencephalopathy brain. Acta Neuropathol 104:130–136CrossRefPubMedGoogle Scholar
  27. 27.
    Pavlovic D, Patel MA, Patera AC, Peterson I (2018) T cell deficiencies as a common risk factor for drug associated progressive multifocal leukoencephalopathy. Immunobiology 223:508–517CrossRefPubMedGoogle Scholar
  28. 28.
    Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M, for the Progressive Multifocal Leukeoncephalopathy C (2015) Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord 8:255–273CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Pedersen BK, Bygbjerg IC, Theander TG, Andersen BJ (1986) Effects of chloroquine, mefloquine and quinine on natural killer cell activity in vitro. An analysis of the inhibitory mechanism. Allergy 41:537–542CrossRefPubMedGoogle Scholar
  30. 30.
    Sanjo N, Kina S, Shishido-Hara Y, Nose Y, Ishibashi S, Fukuda T, Maehara T, Eishi Y, Mizusawa H, Yokota T (2016) Progressive multifocal leukoencephalopathy with balanced CD4/CD8 T-cell infiltration and good response to mefloquine treatment. Intern Med 55:1631–1635CrossRefPubMedGoogle Scholar
  31. 31.
    Shah R, Bag AK, Chapman PR, Curé JK (2010) Imaging manifestations of progressive multifocal leukoencephalopathy. Clin Radiol 65:431–439CrossRefPubMedGoogle Scholar
  32. 32.
    Shishido-Hara Y (2010) Progressive multifocal leukoencephalopathy and promyelocytic leukemia nuclear bodies: a review of clinical, neuropathological, and virological aspects of JC virus-induced demyelinating disease. Acta Neuropathol 120:403–417CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shishido-Hara Y, Higuchi K, Ohara S, Duyckaerts C, Hauw J-J, Uchihara T (2008) Promyelocytic leukemia nuclear bodies provide a scaffold for human polyomavirus JC replication and are disrupted after development of viral inclusions in progressive multifocal leukoencephalopathy. J Neuropathol Exper Neurol 67:299–308CrossRefGoogle Scholar
  34. 34.
    Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9:425–437CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Taoufik Y, Gasnault J, Karaterki A, Pierre Ferey M, Marchadier E, Goujard C, Lannuzel A, Delfraissy JF, Dussaix E (1998) Prognostic value of JC virus load in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Infect Dis 178:1816–1820CrossRefPubMedGoogle Scholar
  36. 36.
    Weber F, Goldmann C, Krämer M, Kaup FJ, Pickhardt M, Young P, Petry H, Weber T, Lüke W (2001) Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 49:636–642CrossRefPubMedGoogle Scholar
  37. 37.
    Weissert R (2011) Progressive multifocal leukoencephalopathy. J Neuroimmunol 231:73–77CrossRefPubMedGoogle Scholar
  38. 38.
    Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77:4911–4927CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Neurology and Neurological ScienceTokyo Medical and Dental University Graduate School of Medical and Dental SciencesTokyoJapan
  2. 2.Department of Anatomic PathologyTokyo Medical UniversityTokyoJapan
  3. 3.Department of Internal Medicine (Neurology)Tokyo Metropolitan Bokutoh HospitalTokyoJapan
  4. 4.Department of Medicine (Neurology and Rheumatology)Shinshu University School of MedicineNaganoJapan
  5. 5.Department of NeurologyTokyo Medical UniversityTokyoJapan
  6. 6.Department of PathologyTokyo Metropolitan Bokutoh HospitalTokyoJapan

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