Functional Activation of Myelin-Specific T Cells by Virus-Induced Molecular Mimicry Julie K. Olson, Todd N. Eagar and Stephen D. Miller This information is current as J Immunol 2002; 169:2719-2726; ; of September 26, 2021. doi: 10.4049/jimmunol.169.5.2719 http://www.jimmunol.org/content/169/5/2719 Downloaded from References This article cites 34 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/169/5/2719.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Functional Activation of Myelin-Specific T Cells by Virus-Induced Molecular Mimicry1 Julie K. Olson, Todd N. Eagar, and Stephen D. Miller2 Molecular mimicry is the process by which T cells activated in response to determinants on an infecting microorganism cross-react with self epitopes, leading to an autoimmune disease. Normally, infection of SJL/J mice with the BeAn strain of Theiler’s murine encephalomyelitis virus (TMEV) results in a persistent CNS infection, leading to a chronic progressive, CD4؉ T cell-mediated demyelinating disease. Myelin damage is initiated by T cell responses to virus persisting in CNS APCs, and progressive demy- elinating disease (50 days postinfection) is perpetuated by myelin epitope-specific CD4؉ T cells activated by epitope spreading. We developed an infectious model of molecular mimicry by inserting a sequence encompassing the immunodominant myelin epitope, proteolipid protein (PLP) 139–151, into the coding region of a nonpathogenic TMEV variant. PLP139-TMEV-infected mice ؉ developed a rapid onset paralytic inflammatory, demyelinating disease paralleled by the activation of PLP139–151-specific CD4 Downloaded from Th1 responses within 10–14 days postinfection. The current studies demonstrate that the early onset demyelinating disease induced by PLP139-TMEV is the direct result of autoreactive PLP139–151-specific CD4؉ T cell responses. PLP139–151-specific CD4؉ T cells from PLP139-TMEV-infected mice transferred demyelinating disease to naive recipients and PLP139–151-specific tolerance before infection prevented clinical disease. Finally, infection with the mimic virus at sites peripheral to the CNS induced early demyelinating disease, suggesting that the PLP139–151-specific CD4؉ T cells could be activated in the periphery and traffic to the CNS. Collectively, infection with PLP139–151 mimic encoding TMEV serves as an excellent model for molecular mimicry http://www.jimmunol.org/ :by inducing pathologic myelin-specific CD4؉ T cells via a natural virus infection. The Journal of Immunology, 2002, 169 2719–2726. utoimmune diseases have been suggested to be initiated ular mimicry in autoimmune disease, the evidence was indirect in and perpetuated as a result of virus infections. Three that autoreactivity was not induced as a direct consequence of A possible mechanisms have been suggested for initiating infection. Recently, several reports have provided more direct ev- autoimmune disease following virus infection: bystander activa- idence of infection-induced molecular mimicry by showing that tion, molecular mimicry, and epitope spreading (reviewed in Ref. infection with HSV type I leads to the development of herpes 1). Molecular mimicry is the process by which cross-reactive T stromal keratitis, an inflammatory eye disease (10), and that a by guest on September 26, 2021 cells are generated during a virus infection that recognizes both Theiler’s virus variant engineered to encode a molecular mimic of viral and self epitopes (2). Over the past decade, evidence for a an encephalitogenic proteolipid protein epitope (PLP139–151)3 role of molecular mimicry in the initiation of autoimmune diseases could induce demyelinating disease upon infection (11). has resulted from a number of approaches. Initial molecular mim- Multiple sclerosis (MS) is a CD4ϩ T cell-mediated autoimmune icry studies showed that transgenic mice expressing virus proteins demyelinating disease affecting humans that has a suspected virus in the context of self tissues developed autoimmune disease fol- etiology (12). Theiler’s murine encephalomyelitis virus (TMEV)- lowing infection with the corresponding virus (3, 4). Previous induced demyelinating disease serves as a relevant mouse model studies have also demonstrated that viral peptides sharing limited of MS due to numerous pathological and immunological similar- sequence homology with self myelin peptides could stimulate au- ities (13). Infection of susceptible SJL/J mice with the BeAn strain toreactive T cell clones isolated from patients with multiple scle- of TMEV results in a chronic progressive CD4ϩ T cell-mediated rosis (5, 6). Mimic epitopes have been identified in Borrelia burg- CNS demyelinating disease onsetting 30–35 days postinfection dorferi that may be involved in Lyme arthritis and neuroborreliosis and characterized by persistent infection of CNS microglia (14). using patient T cell clones (7, 8), and heart disease was shown to Myelin destruction is initiated by virus-specific CD4ϩ T cells that be induced by immunizing mice with a Chlamydia pneumoniae eventually lead to the activation of myelin-specific, autoreactive peptide that shared sequence homology with heart-muscle protein CD4ϩ T cells via epitope spreading, with responses to PLP139– (9). Although these studies provided support for a role of molec- 151 first detected at 50 days postinfection (15, 16). Therefore, TMEV-induced demyelinating disease is a highly relevant model for studying virus-initiated autoimmune disease. Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611 Recently, we developed a molecular mimicry model for initia- tion of autoimmune demyelination following virus infection with Received for publication March 22, 2002. Accepted for publication June 20, 2002. TMEV containing a self myelin epitope (11). Native or mimic The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance sequences of the immunodominant PLP139–151 epitope were in- with 18 U.S.C. Section 1734 solely to indicate this fact. serted into a nonpathogenic TMEV variant. Infection of SJL mice 1 This work was supported by U.S. Public Health Service National Institutes of Health Research Grants NS34819, NS30871, and AI/DK-51973, and National Multiple Scle- rosis Society Grant RG2275. 3 Abbreviations used in this paper: PLP, proteolipid protein; DTH, delayed-type hy- 2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department persensitivity; EAE, experimental autoimmune encephalomyelitis; i.c., intracerebral; of Microbiology-Immunology, Northwestern University Medical School, 303 East MBP, myelin basic protein; MS, multiple sclerosis; SI, stimulation index; SP, spleno- Chicago Avenue, Chicago, IL 60611. E-mail address: [email protected] cyte; TMEV, Theiler’s murine encephalomyelitis virus; WT, wild type. Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 2720 MYELIN-SPECIFIC AUTOIMMUNITY INDUCED BY VIRUS INFECTION with TMEV encoding native mouse PLP139–151, an altered pep- was determined with triplicate wells for each peptide concentration and tide ligand of PLP139–151, or a PLP139–151 mimic present in then expressed as cpm Ϯ SEM. The stimulation index (SI) was calculated the protease IV protein of Hemophilus influenzae induced a rapid by dividing cpm in experimental wells by the cpm in PBS-containing wells. For cytokine analysis, a duplicate set of proliferation wells was used to onset demyelinating disease associated with the induction of ϩ collect supernatants at 48 and 72 h. Supernatants were analyzed for IL-2, PLP139–151-specific CD4 T cell responses. The current studies IFN-␥, or IL-5 secretion by ELISA (Endogen, Cambridge, MA). were conducted to determine whether the early onset demyelinat- ing disease occurred directly through early activation of PLP139– Coupled cell tolerance 151-specific CD4ϩ T cells. The results show that the PLP139– 151-specific CD4ϩ T cells induced in PLP139-TMEV-infected Spleens were removed from naive mice and mechanically disrupted, and mice were encephalitogenic, as demonstrated by serial transfer of the RBCs were lysed. The splenocytes were incubated with ethylcarbodi- imide (150 mg/ 3.2 ϫ 108 cells) and peptide (1 mg/ml PLP139–151 or these T cells to naive mice, and that infection of mice with OVA 323–339) on ice, shaking periodically for 2 h. The coupled cells were PLP139-TMEV at sites peripheral to the CNS resulted in activa- washed and centrifuged to remove cell clumps. The single cell