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After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( n NationMS = 946, n variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of BIONAT :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of MC1R :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS., Competing Interests: Competing interest statement: H.W. received honoraria and consultation fees from Bayer Healthcare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharma. K.L. is coinventor on patent no. US 2016/0158322 A1 entitled “NDP-MSH for treatment of inflammatory and/or neurodegenerative disorders of the CNS.” A.S. received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, none related to this work. R.G. serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. (Teva), Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva, Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases, and is on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva, Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this work. L.K. receives honoraria for lecturing and travel expenses for attending meetings from Biogen, Merck, Sanofi Genzyme, Novartis and Roche; her research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Interdisciplinary Center for Clinical Studies (IZKF) Muenster, Biogen, Merck, and Novartis. M.A.F. received honoraria for consultation and travel expenses from Biogen, Merck KGaA, Novartis, and Roche; his research is funded by the BMBF, DFG, Landesforschungsförderung Hamburg, Gemeinnützige Hertie-Stiftung, and Else Kröner-Fresenius-Stiftung. S.G.M. receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva; his research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, IZKF Muenster, German Foundation Neurology and Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. R.H. has received grant support from Biogen, Genzyme-Sanofi, Merck Serono, Novartis, Teva, and personal fees from Actelion, Biogen, Genzyme-Sanofi, Medday, Merck Serono, Novartis, Roche, and Teva. T.K. has received travel expenses and personal compensation from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche, and Biogen, as well as grant support from Bayer Schering AG, Novartis, and Chugai Pharma. U.Z. has received grants from DFG, BMBF, the European Research Council, Bristol Myers Squibb, Janssen Pharmaceuticals NV, Servier, and Biogen Idec, and personal consultation fees from Pfizer GmbH, Bayer Vital GmbH, and CorTec GmbH. F.Z. received funds for scientific consultation or research by DFG, BMBF, the Pharmaceutical Management Science Association, Novartis, Octapharma, Merck Serono, ONO Pharma, Biogen, Genzyme, Celgene, Roche, Sanofi Aventis. A.S.-M. received travel expenses and research support from Novartis. C.C.G. received speaker honoraria and travel expenses for attending meetings from Biogen, Euroimmun, Genzyme, MyLan, Novartis Pharma GmbH, and Bayer Health Care, none related to this study; her work is funded by Biogen, Novartis, the BMBF (01Gl1603A), the DFG (GR3946/3-1, SFB Transregio 128 A09), the European Union (Horizon2020, ReSToRE), the IZKF, and the Innovative Medizinische Forschung. D.B. receives lectures, congress invitation, board participation with Bayer, Biogen, Medday, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. B.T. received personal speaker honoraria and consultancy fees as a speaker and advisor from Alexion, Bayer Healthcare, Biogen, CSL Behring, GILEAD, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva, and UCB Pharma; his university received unrestricted research grants from Biogen-Idec, Novartis, Teva, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme, and UCB Pharma. F.T.B. has received, through his institution, grant support and/or travel reimbursement to attend scientific meetings from Actelion, Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva; he has received personal honoraria for speaking or advisory board activities from Actelion, Bayer, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; his research is funded, in part, by the DFG and the BMBF. C.W. has received institutional support from Novartis, Sanofi Genzyme, Biogen, and Roche. H.-P.H. has received fees for consulting, speaking, and serving on steering committees from Bayer Healthcare, Biogen, GeNeuro, MedImmune, Merck, Novartis, Opexa, Receptos Celgene, Roche, Sanofi Genzyme, CSL Behring, Octapharma, and Teva, with approval by the Rector of Heinrich-Heine University. H.T. received speaker honoraria from Bayer, Biogen, Fresenius, Genzyme, Merck, Novartis, Roche, Siemens, and Teva; he serves as section editor for the Journal of Neurology, Psychiatry, and Brain Research; H.T. and his institution receives research support from the BMBF, DMSG, Fresenius, Genzyme, Merck, and Novartis, none related to this work. A.B. has received personal compensation from Merck, Biogen, Bayer Vital, Novartis, Teva, Roche, Celgene, Alexion, and Sanofi Genzyme, and grants for congress trips and participation from Biogen, Teva, Novartis, Sanofi Genzyme, Celgene, and Merck, none related to this work. C.L. received an endowed professorship supported by the Novartis foundation, has received consulting and speaker’s honoraria from Biogen-Idec, Bayer Schering, Novartis, Sanofi Genzyme, and Teva; and has received research scientific grant support from Merck-Serono and Novartis. B.W. received research grants and/or honoria from Merck Serono, Biogen, Teva, Novartis, Sanofi Genzyme, Bayer Healthcare, Roche, and research grants from the Dietmar Hopp Foundation, the Klaus Tschira Foundation, the BMBF, and the DFG. U.K.Z. received honoraria for lecturing and/or travel expenses for attending meetings from Almirall, Alexion, Bayer, Biogen, Celgene, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, and Teva, as well as grant support from the BMBF and European Union, none related to this study; his research is funded by the BMBF, German Ministry of Economy, DFG, and European Union. S.B. has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Roche. M.S. has received honoraria for scientific lectures or consultancy from Alexion, Bayer Healthcare, Biogen, CSL Behring, Grifols, MedDay, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva; his institution received research support from Biogen, Sanofi-Genzyme, and Merck-Serono. R.A.L. received personal compensation from Celgene, Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche, and Biogen, as well as grant support from Novartis and Merck. F.W. served on the scientific advisory board of Genzyme, Merck Serono, and Novartis; he has received travel funding and/or speaker honoraria from Bayer, Biogen, Teva, Merck Serono, Novartis, and Pfizer; he is employed by Sana and received research support from the BMBF, Merck Serono, and Novartis. F.P. reported other support from Bayer, Novartis, Biogen-Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, Roche, and Shire outside the submitted work; he has a post as academic editor for PLoS One and is associate editor for Neurology: Neuroimmunology & Neuroinflammation; he has scientific advisory board membership for Novartis and consulting fees from Sanofi Genzyme, Biogen-Idec, MedImmune, Shire, and Alexion; and research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, the German Research Council, Werth Stiftung, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis of the United States. B.H. has served on scientific advisory boards for Novartis; he has served as data monitoring and safety committee member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; he holds part of two patents, one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. F.L. has served on the advisory board of Roche and received travel funding from Teva. M.M. received research support from Merck Serono and Novartis as well as travel expenses for attending meetings from Merck Serono. K.L.-H. has received research support (to Technische Universität München) from Novartis, honoraria from Novartis and F. Hoffmann-La Roche, and compensation for travel expenses from Merck Serono., (Copyright © 2021 the Author(s). Published by PNAS.)

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., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.