SUMMARY
We exploited genetic information to assess non-genetic influences in autoimmunity. We isolated gene modules whose products physically interact with environmental exposures related to autoimmunity, and analyzed their nominal statistical evidence of association with autoimmune and non-autoimmune diseases in genome-wide association studies (GWAS) data. Epstein Barr virus (EBV) and other Herpesviruses interactomes emerged as specifically associated with multiple sclerosis (MS), possibly under common regulatory mechanisms. Analyses of MS blood and brain transcriptomes, cytofluorimetric studies of endogenous EBV-infected lymphoblastoid lines, and lesion immunohistochemistry, confirmed a dysregulation of MS-associated EBV interactors, suggesting their contribution to CD40 signaling alterations in MS. These interactors resulted enriched in modules from inherited axonopathies-causing genes, supporting a link between EBV and neurodegeneration in MS, in accord with the observed transcriptomic dysregulations in MS brains. They were also enriched with top-ranked pharmaceutical targets prioritized on a genetic basis. This study delineates a disease-specific influence of herpesviruses on MS biology.
Competing Interest Statement
Mechelli R., Renato U., Rinaldi V., Bellucci G., Angelini D.F., Guerrera G., Bigi R., Fornasiero A., Ferraldeschi M., Romano S., Buscarinu MC., Srinivasan S, Anastasiadou E., Trivedi P., Di Silvestre D., Mauri P., De Candia P., Battistini L., D Alfonso S., Magliozzi R. and Ristori G. declare no conflict of interest. Centonze D. is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme e Teva Pizzolato Umeton R. is supported by the National MS Society. Farina C. received research support from Merck-Serono, Teva, Novartis. Uccelli A. has received consulting honoraria including as part of advisory board and/or speaker fees from Sanofi Genzyme, Roche, Biogen, Novartis, TEVA and Merck. Matarese G. reports receiving research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, and Roche Reynolds R. received research support from the UK MS Society and MedImmune and has received speaker honoraria from Roche and Novartis. Salvetti M. received research support and consulting fees from Biogen, Merck-Serono, Novartis, Roche, Sanofi, Teva
Footnotes
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