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Molecular Mimicry Nervous System Autoimmune Disease by Induces The Journal of Immunology Viral Delivery of an Epitope from Haemophilus influenzae Induces Central Nervous System Autoimmune Disease by Molecular Mimicry1 J. Ludovic Croxford, Holly A. Anger, and Stephen D. Miller2 Multiple sclerosis (MS) is an autoimmune CNS demyelinating disease in which infection may be an important initiating factor. Pathogen-induced cross-activation of autoimmune T cells may occur by molecular mimicry. Infection with wild-type Theiler’s murine encephalomyelitis virus induces a late-onset, progressive T cell-mediated demyelinating disease, similar to MS. To deter- mine the potential of virus-induced autoimmunity by molecular mimicry, a nonpathogenic neurotropic Theiler’s murine enceph- alomyelitis virus variant was engineered to encode a mimic peptide from protease IV of Haemophilus influenzae (HI), sharing 6 of 13 aa with the dominant encephalitogenic proteolipid protein (PLP) epitope PLP139–151. Infection of SJL mice with the HI mimic-expressing virus induced a rapid-onset, nonprogressive paralytic disease characterized by potent activation of self-reactive ؉ PLP139–151-specific CD4 Th1 responses. In contrast, mice immunized with the HI mimic-peptide in CFA did not develop disease, ؉ associated with the failure to induce activation of PLP139–151-specific CD4 Th1 cells. However, preinfection with the mimic- expressing virus before mimic-peptide immunization led to severe disease. Therefore, infection with a mimic-expressing virus directly initiates organ-specific T cell-mediated autoimmunity, suggesting that pathogen-delivered innate immune signals may play a crucial role in triggering differentiation of pathogenic self-reactive responses. These results have important implications for explaining the pathogenesis of MS and other autoimmune diseases. The Journal of Immunology, 2005, 174: 907–917. t present, the mechanism(s) of initiation of multiple scle- mimicry between MBP96–102, a candidate autoantigen for MS, and rosis (MS),3 a CNS demyelinating disease considered to the U24 protein of human herpesvirus-6 (HHV-6; residues 4–10), be mediated by myelin-specific autoreactive CD4ϩ T a viral agent that may be associated with MS (11). A significant A ϩ cells, is unknown. Evidence from clinical and epidemiological number of CD4 T cells from MS patients could recognize either studies suggests that environmental factors, such as viruses, may MBP93–105 or a synthetic HHV-6 peptide compared with cells play an important role in the etiology of MS (1). Other CNS de- from normal healthy controls. Importantly, cross-activation by the myelinating diseases, both in humans and animals, are known to be HHV-6 peptide induced Th1 differentiation of the autoreactive T associated with viral infections (2–5). There is substantial evidence cells (11). that MS is an autoimmune disease, although normal, healthy in- Theiler’s murine encephalomyelitis virus (TMEV)-induced de- dividuals also possess peripheral T cells specific for the epitopes myelinating disease is a mouse model of MS mediated by CD4ϩ within the myelin Ags, myelin basic protein (MBP), myelin oli- cells, and characterized by a chronic-progressive paralytic course godendrocyte glycoprotein, and proteolipid protein (PLP) (6–8). in SJL/J mice (12, 13). TMEV is a natural neurotropic mouse However, the mechanism(s) underlying the activation of myelin- pathogen and intracerebral (i.c.) infection of mice with TMEV specific autoreactive T cells is unknown. One putative mechanism induces an initial virus-specific Th1 response that initiates by- for initiation of autoimmune demyelinating disease is molecular stander myelin destruction, with subsequent activation of self-re- mimicry, whereby autoreactive T cells are activated by epitopes active myelin epitope-specific CD4ϩ Th1 cells via epitope spread- from infectious agents that share structural or sequence homology ing (14–16). to self Ags (9, 10). A recent study has demonstrated molecular Although epitope spreading may explain how a persistent virus infection can lead to myelin-specific autoimmunity, the major pos- Department of Microbiology-Immunology, and Interdepartmental Immunobiology tulated mechanism for initiation of viral-induced autoimmunity is Center, Northwestern University Medical School, Chicago, IL 60611 molecular mimicry, although there is currently little direct evi- Received for publication March 16, 2004. Accepted for publication November dence to support this. Previous studies have used mimic sequences 8, 2004. from infectious pathogens, to modulate experimental autoimmune The costs of publication of this article were defrayed in part by the payment of page encephalomyelitis (EAE), or administered T cell lines specific for charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mimic epitopes to induce EAE (17–20). To provide more compel- 1 This work was supported in part by U.S. Public Health Service Grants NS-40460 ling evidence for the initiation of CNS autoimmunity via molec- and NS-23349. J.L.C. is a fellow of the National Multiple Sclerosis Society (Post- ular mimicry, we asked whether CNS disease could be initiated by doctoral Research Fellowship Award FG-1456-A-1). infecting SJL mice with a neurotropic virus expressing a peptide 2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department mimic of the immunodominant PLP epitope (PLP139–151) derived of Microbiology-Immunology, Northwestern University Feinberg School of Medi- cine, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: s-d- from an infectious pathogen. [email protected] We demonstrate here a defined model of molecular mimicry, 3 Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic pro- wherein infection of SJL mice with a nonpathogenic variant of the tein; PLP, proteolipid protein; HHV-6, human herpesvirus-6; TMEV, Theiler’s mu- wild-type (WT)-TMEV (BeAn strain) expressing a mimic se- rine encephalomyelitis virus; EAE, experimental autoimmune encephalomyelitis; WT, wild type; HI, Haemophilus influenzae; i.c., intracerebral; DTH, delayed-type quence (Haemophilus influenzae (HI)574–586) derived from the hypersensitivity. protease IV protein of HI, a natural bacterial pathogen of mice, Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 908 MOLECULAR MIMICRY-INDUCED CNS AUTOIMMUNE DISEASE leads to early-onset demyelinating disease (21). This early-onset tutes of Health-approved Northwestern University Medical School animal clinical disease was associated with activation, proliferation, and facilities. All protocols were approved by the Northwestern University An- differentiation of PLP -specific autoreactive Th1 T cells. imal Care and Use Committee. Paralyzed mice were afforded easier access 139–151 to food and water. Furthermore, these data highlight the importance of studying mo- lecular mimicry in the context of an infectious pathogen, because Construction of the mimic-expressing virus immunization with the HI peptide emulsified in CFA failed 574–586 The cDNA encoding the BeAn strain of TMEV was modified by inserting to induce clinical disease. However, immunization of mice prein- ClaI sites at bp 1137 (Fig. 1A). This resulted in a 23-aa deletion in the fected with HI-BeAn with HI574–586/CFA induced a significantly leader sequence (L) of the BeAn genome. This virus was designated ⌬Cla- more severe clinical disease. This suggests that severe clinical dis- BeAn as described previously (21). Briefly, ClaI sites were introduced by ease, due to HI-BeAn-induced molecular mimicry, requires both PCR to the PLP cDNA at either end of a 30-aa sequence PLP130–159, which encompassed the immunodominant encephalitogenic PLP sequence the presence of the mimic sequence and the persistent stimulation 139–151 (Fig. 1B). A sequence from serine protease IV (HI ), naturally ex- of innate immune system by the pathogen. This model of molec- 574–586 pressed in HI, which shares 6 of 13 aa with PLP139–151 (Fig. 1B), was ular mimicry will allow potential mimic epitopes from other in- constructed by PCR mutagenesis of the PLP139–151 sequence to introduce fectious pathogens to be tested for their ability to induce autoim- amino acid substitutions at positions 139 (H3E), 140 (C3Q), 142 munity, and has important implications for the etiology and (G3V), 147 (H3L), 149 (D3A), 150 (K3P), and 151 (F3I). Follow- ing an enzyme restriction cut with ClaI, the 30-aa piece containing the pathogenesis of MS and other autoimmune diseases. HI574–586 sequence flanked by the original PLP sequences was inserted into the ClaI site in the ⌬Cla-BeAn virus cDNA. This was designated HI-BeAn Materials and Methods cDNA (Fig. 1A). As a negative control, an OVA sequence, OVA317–346, Mice encompassing the OVA323–339 epitope, with no homology to the PLP139–151 or ⌬ HI574–586 sequence (Fig. 1B), was inserted into the Cla-BeAn parental virus Five- to 6-wk-old female SJL mice were obtained from Harlan Sprague to yield OVA-BeAn (data not shown). Viral RNA was produced from the Dawley. Mice were housed under barrier conditions at the National Insti- cDNA through the T7 promoter and transfected into BHK-21 cells, resulting FIGURE 1. The construction of a PLP139–151 mimic expressing virus. A,AClaI insertion in the leader sequence (L) of cDNA encoding the TMEV BeAn strain 8386 resulted in a 23-aa deletion in the leader sequence of the parent virus (⌬Cla-BeAn). ClaI sites were in- troduced by PCR into the PLP cDNA at ei- ther end of a 30-aa sequence PLP130–159, which encompassed the immunodominant encephalitogenic PLP139–151 sequence. The PLP139–151 mimic sequence from the pro- tease IV protein of HI (HI574–586) was con- structed by PCR amino acid substitutions of the PLP139–151 sequence. The 30-aa sequence containing the HI574–586 sequence flanked by the PLP sequences was inserted into the ClaI site in the ⌬Cla-BeAn virus cDNA. This was designated HI-BeAn cDNA. Viral RNA was produced from the cDNA through the T7 pro- moter and transfected into BHK-21 cells re- sulting in the production of infectious virus. B, Peptide sequences of myelin and myelin mimic peptides.
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