Functional genetics of sex differences in autoimmunity

Differences in the immune response between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect females. This has been documented for many autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune liver diseases – and for multiple sclerosis (MS). MS is the most common inflammatory disease of the central nervous system (CNS) and manifests in more than twice as many women, making sex one of the top risk factors for developing MS. Various factors can contribute to sex differences, such as hormones, genetic or epigenetic factors, which can influence immune cell function. However, it is unknown which genes are differentially expressed in females and males and could thereby contribute to sex differences in autoimmune incidence. To address that we conducted a gene expression analysis in female and male human spleen and blood. From 62 differentially expressed genes (DEGs) in the blood and 114 DEGs in the spleen, we selected DEGs that had associations with immune regulation. After successful validation of their differential expression in distinct immune cell subsets, we currently focus on mechanistic studies that might uncover sex-specific contributions to Tcell activation and transmigration. Thus, we hypothesize that sex determines expression of several immune-related genes resulting in different immune cell responses in females and males. This emerging sex-specific expression and functional differences could contribute to sexual disparity in autoimmunity, such as MS.

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 (N Y) 2:296-312.e8

read more

Ramien, C., E. C. Yusko, J. B. Engler, S. Gamradt, K. Patas, N. Schweingruber, A. Willing, S. C. Rosenkranz, A. Diemert, A. Harrison, M. Vignali, C. Sanders, H. S. Robins, E. Tolosa, C. Heesen, P. C. Arck, A. Scheffold, K. Chan, R. O. Emerson, M. A. Friese, and S. M. Gold. (2019)
T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis
Cell Rep 29: 810-815.e4

read more

Engler, J. B., N. F. Heckmann, J. Jäger, S. M. Gold, and M. A. Friese. (2019)
Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis
J Immunol 203: 1743–1752

read more

Schattling B., J. B. Engler, C. Volkmann, N. Rothammer, M. S. Woo, M. Petersen, I. Winkler, M. Kaufmann, S. C. Rosenkranz, A. Fejtova, U. Thomas, A. Bose, S. Bauer, S. Träger, K. K. Miller, W. Brück, K. E. Duncan, G. Salinas, P. Soba, E. D. Gundelfinger, D. Merkler, and M. A. Friese. (2019)
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis
Nat Neurosci 22: 887-896

read more

Gold, S. M., A. Willing, F. Leypoldt, F. Paul, and M. A. Friese. (2019)
Sex differences in autoimmune disorders of the central nervous system
Semin. Immunopathol 41: 177–188

read more

Engler, J. B., N. Kursawe, M. E. Solano, K. Patas, S. Wehrmann, N. Heckmann, F. Lühder, H. M. Reichardt, P. C. Arck, S. M. Gold, and M. A. Friese. (2017)
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy
Proc Nat. Acad Sci U. S. A 114: E181–E190

read more

Ramien, C., A. Taenzer, A. Lupu, N. Heckmann, J. B. Engler, K. Patas, M. A. Friese, and S. M. Gold. (2016)
Sex effects on inflammatory and neurodegenerative processes in multiple sclerosis
Neurosci Biobehav Rev. 67: 137–146

read more

Ufer, F., P. Vargas, J. B. Engler, J. Tintelnot, B. Schattling, H. Winkler, S. Bauer, N. Kursawe, A. Willing, O. Keminer, O. Ohana, G. Salinas-Riester, O. Pless, D. Kuhl, and M. A. Friese. (2016)
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Sci Immunol 1: eaaf8665

read more

Piédavent-Salomon M., A. Willing, J. B. Engler, K. Steinbach, S. Bauer, B. Eggert, F. Ufer, N. Kursawe, S. Wehrmann, J. Jäger, S. Reinhardt, and M. A. Friese. (2015)
Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function
Brain 138(Pt 11):3263–74

read more

Dendrou, C. A., L. Fugger, and M. A. Friese. (2015)
Immunopathology of multiple sclerosis
Nat Rev Immunol 15: 545–58

read more