title: Induction of encephalitis in rhesus monkeys infused with lymphocryptovirus-infected B-cells presenting MOG(34-56) peptide.
abstract: The overlapping epidemiology of multiple sclerosis (MS) and Epstein-Barr virus (EBV), the increased risk to develop MS after infectious mononucleosis (IM) and the localization of EBV-infected B-cells within the MS brain suggest a causal link between EBV and MS. However, the underlying mechanism is unknown. We hypothesize that EBV-infected B-cells are capable of eliciting a central nervous system (CNS) targeting autoimmune reaction. To test this hypothesis we have developed a novel experimental model in rhesus monkeys of IM-like disease induced by infusing autologous B-lymphoblastoid cells (B-LCL). Herpesvirus papio (HVP) is a lymphocryptovirus related to EBV and was used to generate rhesus monkey B-LCL. Three groups of five animals were included; each group received three intravenous infusions of B-LCL that were either pulsed with the encephalitogenic self peptide MOG(34-56) (group A), a mimicry peptide (981-1003) of the major capsid protein of cytomegalovirus (CMVmcp(981-1003); group B) or the citrullinated MOG(34-56) (cMOG(34-56); group C). Groups A and B received on day 98 a single immunization with MOG(34-56) in incomplete Freund's adjuvant (IFA). Group C monkeys were euthanized just prior to day 98 without booster immunization. We observed self-peptide-specific proliferation of T-cells, superimposed on similar strong proliferation of CD3(+)CD8(+) T-cells against the B-LCL as observed in IM. The brains of several monkeys contained perivascular inflammatory lesions of variable size, comprising CD3(+) and CD68(+) cells. Moreover, clusters of CD3(+) and CD20(+) cells were detected in the meninges. The only evident clinical sign was substantial loss of bodyweight (>15%), a symptom observed both in early autoimmune encephalitis and IM. In conclusion, this model suggests that EBV-induced B-LCL can elicit a CNS targeting inflammatory (auto)immune reaction.
authors: Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors: Krista G
authors: KG
authors: Haanstra
authors: Jacqueline A M
authors: JA
authors: Wubben
authors: Margreet
authors: M
authors: Jonker
authors: Bert A
authors: BA
authors: 't Hart
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology*; D049109:Cell Proliferation; D002490:Central Nervous System / Q000473:pathology; D002956:Citrulline / Q000276:immunology; D015331:Cohort Studies; D004660:Encephalitis / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D018143:Lymphocryptovirus / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D063308:Myelin-Oligodendrocyte Glycoprotein; D010455:Peptides; D002956:Citrulline
references: Eur J Immunol. 2012 Jan;42(1):217-27
references: 21928277
references: J Immunol. 2008 Feb 1;180(3):1326-37
references: 18209026
references: Lancet Neurol. 2008 Sep;7(9):841-51
references: 18703006
references: J Gen Virol. 2004 May;85(Pt 5):1301-1312
references: 15105547
references: J Neuroimmunol. 2007 Jan;182(1-2):135-52
references: 17126916
references: Annu Rev Immunol. 2005;23:683-747
references: 15771584
references: J Virol Methods. 1992 Sep;39(1-2):185-95
references: 1331148
references: J Exp Med. 2005 Sep 5;202(5):673-85
references: 16147978
references: Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):489-97
references: 11313007
references: J Neuroimmune Pharmacol. 2013 Jun;8(3):727-38
references: 23508625
references: JAMA. 2004 Apr 21;291(15):1875-9
references: 15100207
references: J Virol. 1981 Feb;37(2):821-6
references: 6261021
references: Trends Immunol. 2003 Mar;24(3):136-43
references: 12615209
references: J Neuroimmunol. 2005 Nov;168(1-2):1-12
references: 16023737
references: N Engl J Med. 2006 Mar 2;354(9):942-55
references: 16510748
references: J Immunol. 2010 Mar 15;184(6):2839-46
references: 20164413
references: Neurology. 2006 Dec 12;67(11):2063-5
references: 17159123
references: Immunol Rev. 2006 Jun;211:225-35
references: 16824131
references: J Neuropathol Exp Neurol. 2010 Apr;69(4):372-85
references: 20448482
references: Eur J Immunol. 2005 Nov;35(11):3240-7
references: 16224817
references: Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):569-79
references: 11313012
references: Immunol Res. 2002;25(3):201-17
references: 12018460
references: Brain. 2006 Feb;129(Pt 2):517-26
references: 16364958
references: Ann Neurol. 2007 Apr;61(4):288-99
references: 17444504
references: J Virol. 1998 Apr;72(4):3205-12
references: 9525646
references: Histol Histopathol. 2002 Oct;17(4):1293-310
references: 12371154
references: J Infect Dis. 2000 Apr;181(4):1462-6
references: 10762578
references: AJNR Am J Neuroradiol. 2009 Apr;30(4):716-21
references: 19147724
references: N Engl J Med. 2000 Aug 17;343(7):481-92
references: 10944566
references: Trends Immunol. 2009 Jun;30(6):243-8
references: 19428300
references: Cell. 1996 May 3;85(3):299-302
references: 8616884
references: J Cell Sci. 2000 Jul;113 ( Pt 14):2595-606
references: 10862717
references: Crit Rev Oncol Hematol. 2002 Dec;44(3):203-15
references: 12467961
references: PLoS Pathog. 2012;8(5):e1002715
references: 22615572
references: Infect Genet Evol. 2010 Jan;10(1):1-13
references: 19879975