Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease This information is current as Anne M. Ercolini and Stephen D. Miller of September 29, 2021. J Immunol 2006; 176:3293-3298; ; doi: 10.4049/jimmunol.176.6.3293 http://www.jimmunol.org/content/176/6/3293 Downloaded from References This article cites 89 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/176/6/3293.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 29, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease1 Anne M. Ercolini and Stephen D. Miller2 Many disorders of the CNS, such as multiple sclerosis myelination reflect the diversity of clinical manifestations in (MS), are characterized by the loss of the myelin sheath humans. Although none are exact replicates of the human dis- surrounding nerve axons. MS is associated with infiltra- ease, they share many similarities and have provided insight into tion of inflammatory cells into the brain and spinal cord, the pathobiology of the human diseases they model. which may be the primary cause of demyelination or which may be induced secondary to axonal damage. Both Experimental autoimmune encephalomyelitis (EAE) the innate and adaptive arms of the immune system have EAE is a frequently studied autoimmune model of MS. EAE is Downloaded from been reported to play important roles in myelin destruc- induced in mice by active priming with whole myelin proteins tion. Numerous murine demyelinating models, both vi- or specific myelin peptide epitopes in adjuvant; the specific my- rus-induced and/or autoimmune, are available, which re- elin epitopes able to induce EAE varies with the strain of mouse used. Demyelination and paralytic episodes are associated with flect the clinical and pathological variability seen in ϩ infiltration of myelin-specific inflammatory Th1 CD4 T cells human disease. This review will discuss the immuno- http://www.jimmunol.org/ into the CNS (7). EAE can also be induced by adoptive transfer pathologic mechanisms involved in these demyelinating ϩ of myelin-specific CD4 T cells, confirming the importance of disease models. The Journal of Immunology, 2006, 176: T cells in disease induction (8). The symptoms of EAE in mice 3293–3298. are varied and mimic different clinical manifestations seen in human MS (9). Disease can be monophasic, involving an acute he axons of many vertebrate neurons are surrounded by paralytic episode followed by complete recovery; relapsing-re- a myelin sheath, which increases the speed at which the mitting, which involves multiple cycles of attack interspersed by T axon can conduct electrical impulses. Numerous in- full or partial recovery; or chronic, where disease symptoms of flammatory and metabolic disorders of the nervous system re- the initial attack either stabilize at peak levels or gradually by guest on September 29, 2021 sult in loss of the myelin sheath, with symptoms ranging from worsen over time. In the monophasic and relapse-remitting speech and visual disturbances to paralysis. Many of these dis- forms, recovery from disease is associated with clearance of in- orders are associated with immune infiltrates into the nervous flammatory infiltrates from the CNS. Susceptibility to either system, normally considered to be an immunologically privi- the monophasic or relapse-remitting subtypes has been mapped leged site. These inflammatory infiltrates may be the primary to distinct genetic loci (10). Similarly, studies suggest that these cause of the demyelination; alternatively, infiltrates may amass two MS disease subtypes are genetically distinct entities (11, 12). at sites of prior injury and contribute to progressive tissue dam- A primary hallmark of the relapsing-remitting and chronic age. Multiple sclerosis (MS) is the most prevalent human de- subtypes of EAE is the phenomenon of epitope spreading, myelinating disease of the CNS (1). The loss of myelin in MS is which is the diversification of the initial immune response, sec- thought to be autoimmune in nature because it is associated ondary to acute myelin destruction, to include reactivity to en- ϩ with elevated levels of CD4 T cells specific for the major my- dogenous CNS determinants (13). In EAE, spreading can occur elin proteins (2–4), as well as with the presence of myelin-spe- to different epitopes within the same myelin protein used to cific Abs (5, 6). initiate the disease (intramolecular spreading) or to epitopes Genetic and environmental factors (particularly exposure to within a different myelin protein (intermolecular spreading). virus or bacterial infections) are postulated to interact to varying For example, there is a sequential and hierarchical order of degrees depending on disease type to initiate autoimmune de- epitope spreading seen in the relapse-remitting disease of SJL myelination. The many described murine models of CNS de- mice primed with PLP139–151 (myelin proteolipid protein) Department of Microbiology-Immunology and Interdepartmental Immunobiology Cen- 2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of ter, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: [email protected] Received for publication November 28, 2005. Accepted for publication December 13, 2005. 3 Abbreviations used in this paper: MS, multiple sclerosis; CSF, cerebrospinal fluid; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; HI-TMEV, Haemophi- The costs of publication of this article were defrayed in part by the payment of page charges. lus influenzae-TMEV; i.c., intracerebral; MBP, myelin basic protein; MHV, murine hep- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. atitis virus; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; PLP, Section 1734 solely to indicate this fact. proteolipid protein; SFV, Semliki Forest virus; SV, Sindbis virus; TMEV, Theiler’s murine 1 This work was supported in part by National Institutes of Health Grants NS026543, encephalomyelitis virus; TMEV-IDD, TMEV-induced demyelinating disease. NS030871, NS023349, NS040460, and NS048411; National Multiple Sclerosis Society Research Grant RG-3489-A-6-2; and Myelin Repair Foundation Grant SM MRF-02. A.M.E. is supported by NMSS Postdoctoral Fellowship Grant FG-1596-A-1. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 3294 BRIEF REVIEWS: IMMUNE-MEDIATED CNS DEMYELINATION ϩ ϩ (14). The first relapse is associated with Th1-type CD4 T cell APCs to Th1-type CD4 T cells (37). Proinflammatory cyto- reactivity to PLP178–191 and the second to MBP84–104 (myelin kines released by these T cells recruit monocytes and macro- basic protein). Myelin destruction during the acute disease ep- phages into the CNS, which cause damage to myelin. This sub- isode creates an inflammatory environment, leading to the in- sequent release of myelin Ags and uptake by APCs lead to the ϩ filtration of peripheral myeloid dendritic cells (DCs) to the emergence of myelin-specific CD4 T cells. Initial studies CNS, which locally present endogenously acquired myelin showed that immune responses to TMEV were detectible 5–7 ϫ epitopes to naive T cells (15). In both SJL and (SWR SJL)F1 days postinfection but that reactivity to myelin did not appear EAE models, tolerance to the primary spread epitope after in- until after the onset of clinical symptoms (30–35 days postin- duction of EAE prevented relapses and/or disease progression fection) (15, 38–40). Thus, the chronic phase of TMEV-IDD (16, 17). However, using a mouse transgenic for a single mye- is autoimmune caused by epitope spreading from viral determi- lin-specific TCRs, Jones et al. (18) showed that disease relapses nants to self-myelin determinants. Tolerance to multiple mye- could occur in the absence of reactivity to spread epitopes. lin proteins after virus infection significantly inhibits TMEV- Epitope spreading has been shown in mice double transgenic IDD, which demonstrates the importance of the myelin- for human TCR and MHC class II molecules associated with specific immune response in disease progression (41). In SJL susceptibility to MS (19, 20). The ability to clearly assess the mice, reactivity appears to multiple myelin epitopes starting role of epitope spreading in MS is hampered somewhat by the with the immunodominant epitope PLP139–151 and spreading at heterogeneity of the disease and time