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01-02-2019 | Original Communication

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

Authors: Nobuo Sanjo, Yurie Nose, Yukiko Shishido-Hara, Saneyuki Mizutani, Yoshiki Sekijima, Hitoshi Aizawa, Toru Tanizawa, Takanori Yokota

Published in: Journal of Neurology | Issue 2/2019

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.

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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 439:682–687CrossRefPubMed

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 36:1047–1052CrossRefPubMed

Berger JR (2010) Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 33:969–983CrossRefPubMed

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 80:1430–1438CrossRefPubMedPubMedCentral

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 40:738–744CrossRefPubMed

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 53:1840–1849CrossRefPubMedPubMedCentral

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 81:410–413CrossRefPubMed

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 9:513–519CrossRefPubMed

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 309:47–50CrossRefPubMed

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 9:438–446CrossRefPubMed

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 19:351–358CrossRef

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 52:623–625CrossRefPubMed

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 15:51–56CrossRefPubMed

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 227:3511–3517CrossRefPubMedPubMedCentral

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 78:10206–10210CrossRefPubMedPubMedCentral

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 85:7256–7263CrossRefPubMedPubMedCentral

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):16–22CrossRefPubMed

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 NeuroVirol

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 62:34–39CrossRefPubMed

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 324:190–194CrossRefPubMed

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 193:746–756CrossRefPubMed

22.

Martin JD, King DM, Slauch JM, Frisque RJ (1985) Differences in regulatory sequences of naturally occurring JC virus variants. J Virol 53:306–311PubMedPubMedCentral

23.

Mauri C, Menon M (2015) The expanding family of regulatory B cells. Int Immunol 27:479–486CrossRefPubMedPubMedCentral

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 123:235–245CrossRefPubMed

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:e415CrossRefPubMed

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 104:130–136CrossRefPubMed

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 223:508–517CrossRefPubMed

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 8:255–273CrossRefPubMedPubMedCentral

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 41:537–542CrossRefPubMed

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 55:1631–1635CrossRefPubMed

31.

Shah R, Bag AK, Chapman PR, Curé JK (2010) Imaging manifestations of progressive multifocal leukoencephalopathy. Clin Radiol 65:431–439CrossRefPubMed

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 120:403–417CrossRefPubMedPubMedCentral

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 67:299–308CrossRef

34.

Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9:425–437CrossRefPubMedPubMedCentral

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 178:1816–1820CrossRefPubMed

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 49:636–642CrossRefPubMed

37.

Weissert R (2011) Progressive multifocal leukoencephalopathy. J Neuroimmunol 231:73–77CrossRefPubMed

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 77:4911–4927CrossRefPubMedPubMedCentral

Title: A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy
Authors: Nobuo Sanjo
Yurie Nose
Yukiko Shishido-Hara
Saneyuki Mizutani
Yoshiki Sekijima
Hitoshi Aizawa
Toru Tanizawa
Takanori Yokota
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 2/2019
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-018-9140-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Objective

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

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