Dissecting sex-specific mechanisms in T cell-mediated autoimmune neuroinflammation
The pro-inflammatory mechanisms driving the development and progression of multiple sclerosis (MS) show variations between males and females, that need to be considered in immunomodulatory therapy. In our previous project, we discovered the surface protein CD99 to be differentially expressed between male and female T cells in healthy individuals as well as MS patients and demonstrated its functional role in T cell activation and proliferation. In this project proposal, we aim to further disentangle sex differences in T cell-specific pro-inflammatory mechanisms with a focus on chronic neuroinflammation. We therefore created a single cell CITE-Seq dataset of T cells isolated from the central nervous system (CNS) of a preclinical model that depicts key sex differences observed in human MS. In a combined approach by also integrating data from human datasets, we will identify candidates mediating sex differences in pro-inflammatory T cell function that will be mechanistically analysed in vitro and in vivo. Decoding sex-specific aspects of autoimmune neuroinflammation holds the promise for a better pathophysiological understanding of MS and for an individualized, sex-specific therapy.
PROJECT-RELATED PUBLICATIONS
Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, Rothammer N, Tsvilovskyy V, Lorenz SM, Raich L, Bal LC, Vieira V, Wagner I, Bauer S, Glatzel M, Conrad M, Merkler D, Freichel M, Friese MA. (2024)
STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.
Cell. I 187:4043-4060.e30.
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Fischbach F, Richter J, Pfeffer LK, Fehse B, Berger SC, Reinhardt S, Kuhle J, Badbaran A, Rathje K, Gagelmann N, Borie D, Seibel J, Ayuk F, Friese MA, Heesen C, Kröger N. (2024)
CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.
Med. I 5:550-558.e2.
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Winschel I, Willing A, Engler JB, Walkenhorst M, Meurs N, Binkle-Ladisch L, Woo MS, Pfeffer LK, Sonner JK, Borgmeyer U, Hagen SH, Grünhagel B, Claussen JM, Altfeld M, Friese MA. (2024)
Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis.
Biol Sex Differ I 15:41
Winkler I, Engler JB, Vieira V, Bauer S, Liu YH, Di Liberto G, Grochowska KM, Wagner I, Bier J, Bal LC, Rothammer N, Meurs N, Egervari K, Schattling B, Salinas G, Kreutz MR, Huang YS, Pless O, Merkler D, Friese MA. (2023)
MicroRNA-92a-CPEB3 axis protects neurons against inflammatory neurodegeneration.
Sci Adv. I 9:eadi6855
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA. (2021)
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.
Med (NY) I 2:296-312.e8
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Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, and Gold SM. (2019)
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.
Cell Rep I 29:810-815.e4
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Engler JB, Heckmann FN, Jäger J, Gold SM, and Friese MA. (2019)
Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis.
J Immunol I 203:1743–1752
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Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, and Friese MA. (2019)
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Nat Neurosci I 22: 887-896
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Gold SM, Willing A, Leypoldt F, Paul F, and Friese MA. (2019)
Sex differences in autoimmune disorders of the central nervous system.
Semin Immunopathol I 41: 177–188
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Engler JB, Kursawe N, Solano ME, Patas K, Wehrmann S, Heckmann N, Lühder F, Reichardt HM, Arck PC, Gold SM, and Friese MA. (2017)
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy.
Proc Nat. Acad Sci USA I 114:E181–E190
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Ramien C, Taenzer A, Lupu A, Heckmann N, Engler JB, Patas K, Friese MA, and Gold SM. (2016)
Sex effects on inflammatory and neurodegenerative processes in multiple sclerosis.
Neurosci Biobehav Rev I 67:137–146
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Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, and Friese MA. (2016)
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation.
Sci Immunol I 1:eaaf8665
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Piédavent-Salomon M, Willing A, Engler JB, Steinbach K, Bauer S, Eggert B, Ufer F, Kursawe N, Wehrmann S, Jäger J, Reinhardt S, and Friese MA. (2015)
Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function.
Brain I 138(Pt 11):3263–74
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Dendrou CA, Fugger L, and Friese MA. (2015)
Immunopathology of multiple sclerosis.
Nat Rev Immunol I 15: 545–58
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