William H Robinson1, 2, 3, 4, Paulo Fontoura1, Byung J Lee1, 2, Henry E Neuman de Vegvar1, 3, Jennifer Tom1, 2, Rosetta Pedotti1, Carla D DiGennaro1, 2, Dennis J Mitchell1, Derek Fong1, 2, Peggy P-K Ho1, Pedro J Ruiz1, Emanual Maverakis5, David B Stevens6, Claude C A Bernard7, Roland Martin8, Vijay K Kuchroo9, Johannes M van Noort10, Claude P Genain11, Sandra Amor12, Tomas Olsson13, Paul J Utz2, 4, 14, Hideki Garren4, 14 & Lawrence Steinman1, 4, 14
The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.