The role of IL-17 signalling in autoimmunity

1 PhD project proposal in the IPP summer call 2019

Scientific Background

During evolution, the immune system has developed to protect mammals from environmental stress factors. It functions as a fine-tuned consortium of effector units and their suppressors. However, under certain pathologic conditions effector units may escape control and start to attack their own body using the same principles they acquired to eliminate pathogens. This leads to the development of autoimmune diseases, the list of which consists of many examples and multiple sclerosis (MS) being one of them. MS is the most frequent disorder among neurodegenerative diseases with largely unknown aetiology and, despite much progress in the treatment of symptoms, with no cure up to date.

To study the cellular and molecular mechanisms of MS pathology, we are routinely using an animal disease model termed experimental autoimmune encephalomyelitis (EAE). In mice, the disease is induced by stimulation of the immune system with protein fragments derived from the central nervous system (CNS). The current concept is based on a paradigm that particular immune cells, namely T cells, become autoreactive and attack directly and indirectly the components of the CNS. A major subpopulation of CD4 T cells, involved in the pathogenesis of EAE is termed Th17 cells. These cells secrete the messenger protein (cytokine) interleukin (IL) – 17. This cytokine is also a critical pathogenic molecule also in other autoimmune diseases studied in our lab, including psoriasis and colitis. The mechanism by which IL-17 induces pathogenicity in these autoimmune diseases is not clear.

PhD project proposal: The role of IL-17 signalling in autoimmunity     

As a genetic/immunology lab we will offer the applicant to develop new mouse strains, which will allow to trace cells that underwent cell-to-cell interaction, using well acknowledged Cre-recombinase-dependent systems. Mechanistically we aim to activate Cre-recombinase in target cells in a tissue-specific manner. In the frame of the current project, we would like to investigate how the target tissue in different autoimmune diseases respond to IL-17 signalling and look for common dominators in this response. For that, we will use the Cre/loxP system to delete the IL-17 receptor in the target tissue (El Malki et al., 2013). We generated mice where the endothelial cells of the blood brain barrier lack the IL-17R and mice where the keratinocytes in the skin lack this receptor and we will study how absence of IL-17 signalling affects the development of autoimmunity in the central nervous system and in the skin, respectively. Further, we will generate mice that lack the IL-17 receptor also in the gut, to study the role of this cytokine in gut inflammation. We will use a combination of genetic tools, microscopy, Next Generation Sequencing, including single cell sequencing, ATAC sequencing and proteomics, as well as high dimensional flow cytometry to study the body’s response to IL-17.

Publications relevant to the project

Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129:625-637.

Croxford AL, Karbach S, Kurschus FC, Wortge S, Nikolaev A, Yogev N, Klebow S, Schuler R, Reissig S, Piotrowski C, Brylla E, Bechmann I, Scheller J, Rose-John S, Wunderlich FT, Munzel T, von Stebut E, Waisman A. IL-6 Regulates Neutrophil Microabscess Formation in IL-17A-Driven Psoriasiform Lesions. J Invest Dermatol. 2014;134:728-735.

Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Moller-Hackbarth K, Bartsch HS, Sotlar K, Krebs S, Regen T, Blum H, Hemmer B, Misgeld T, Wunderlich TF, Hidalgo J, Oukka M, Rose-John S, Schmidt-Supprian M, Waisman A, Korn T. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol. 2017;18:74-85.

Mufazalov IA, Schelmbauer C, Regen T, Kuschmann J, Wanke F, Gabriel LA, Hauptmann J, Muller W, Pinteaux E, Kurschus FC, Waisman A. IL-1 signaling is critical for expansion but not generation of autoreactive GM-CSF+ Th17 cells. EMBO J. 2017;36:102-115.

El Malki K, Karbach SH, Huppert J, Zayoud M, Reissig S, Schuler R, Nikolaev A, Karram K, Munzel T, Kuhlmann CR, Luhmann HJ, von Stebut E, Wortge S, Kurschus FC, Waisman A. An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol. 2013;133:441-451.

Contact Details

Foto©: Jan Potente, AMSEL e.V.


Prof. Dr. Ari Waisman

University Medical Center Mainz
Institute for Molecular Medicine