A Virus-Induced Molecular Mimicry Model of Multiple Sclerosis

Abstract

Multiple sclerosis1 (MS) is an immune-mediated autoimmune demyelinating disease in humans. The initiating event in MS is unknown, but epidemiological evidence suggests that virus infections may be important and one possible mechanism for induction of infection-induced autoimmune disease is molecular mimicry. To test the ability of a virus encoding a self myelin mimic epitope to induce an autoimmune response, we have developed a mouse model wherein the immunodominant myelin epitope PLP_139–151, or mimics of this epitope, were inserted into a nonpathogenic variant of Theiler’s murine encephalomyelitis virus (TMEV). SJL mice infected with TMEV containing PLP_139–151 or a mimic of PLP_139–151 expressed by the protease IV protein of Haemophilus influenzae, sharing only 6/13 amino acids with the native epitope, developed an early-onset demyelinating disease associated with activation of CD4⁺ T cells reactive with PLP_139–151. We have used this molecular mimicry model to further address the requirements for mimic epitope processing and presentation during infection and the requirements for TCR recognition and MHC binding of mimic epitopes. We have also investigated whether molecular mimicry may require multiple infections, with either the mimic-encoding virus or an unrelated virus, to initiate autoimmune disease. Finally, we have asked whether a virus encoding a molecular mimic has to directly infect the target organ to induce autoimmune disease. Overall, this virus-induced molecular mimicry model has provided critical information regarding the mechanisms by which infection-induced molecular mimicry can induce autoimmune diseases.