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Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4 + T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity., Competing Interests: L.K. received compensation for serving on Scientific Advisory Boards for Genzyme and Novartis; received speaker honoraria and travel support from Novartis, Merck Sorono, and CSL Behring; and receives research support from Novartis and Biogen Idec. C.C.G. received speaker honoraria and travel expenses for attending meetings from Genzyme (2014), Novartis Pharma GmbH (2011), and Bayer Health Care (2014). N.S. received speaking honoraria from Novartis and Biogen and travel expenses from Biogen. S.G.M. received honoraria for lecturing and travel expenses for attending meetings and financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Omniamed, Novo Nordisk, Sanofi-Aventis, and Teva. T.K. received honoraria for lectures from Novartis and Biogen Idec Canada and served as a consultant for Genzyme Corporation. H.W. received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis, and Sanofi Aventis; received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, Glaxo Smith Kline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis, and Sanofi Aventis; received compensation as a consultant from Biogen Idec, Merck Serono, Novartis, and Sanofi Aventis; and received research support from Bayer Vital, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi Aventis Germany, and Sanofi US.

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2%of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation. [ABSTRACT FROM AUTHOR]