Immune signature in pemphigus and its potential for therapeutic JAK inhibition

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dc.contributor.advisor Ghoreschi, Kamran (Prof. Dr.)
dc.contributor.author Holstein, Julia
dc.date.accessioned 2021-10-29T12:57:23Z
dc.date.available 2021-10-29T12:57:23Z
dc.date.issued 2023-06-30
dc.identifier.uri http://hdl.handle.net/10900/120276
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1202761 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-61649
dc.description.abstract Pemphigus vulgaris and pemphigus foliaceus are rare bullous autoimmune diseases of the skin and mucous membranes mediated by autoreactive antibodies directed against the desmosomal cadherins desmoglein (Dsg)1 and Dsg3. Binding of these antibodies leads to acantholysis, the loss of cell-cell adhesion between keratinocytes and thus manifests in blisters and erosions of the skin and mucosa in patients suffering from pemphigus. Previous data indicate that T helper type 2 (Th2) cells and related cytokines play a major role in disease initiation and manifestation, yet the contribution of other T cell subsets remains unclear and evidence is emerging for the involvement of Th17 cell subsets and associated cytokines in pemphigus pathogenesis. To address this issue, the cytokine signature in lesional skin of pemphigus patients was determined by whole transcriptome sequencing and quantitative real-time PCR (qPCR). Further, the distribution of Th and follicular T helper (Tfh) cells in peripheral blood from pemphigus patients with different disease activity stages was analyzed by flow cytometry. Transcriptome analysis identified a broad spectrum of cytokines and chemokines, including interleukins (IL), as well as other immune mediators differentially expressed in lesional pemphigus skin compared to healthy skin samples. Most importantly, an IL-17A-dominated immune signature and an upregulation of the IL-17A signaling pathway were revealed in the skin of pemphigus patients. The dominance of IL-17A and associated cytokines was further validated by qPCR. Moreover, flow cytometry analyses demonstrated elevated levels of IL 17A-producing Th17, Th17.1, Tfh17 and Tfh17.1 cells in the blood of patients with active pemphigus disease. Of note, levels of Th17, Tfh17 and Tfh17.1 cell subsets positively correlated with the levels of circulating Dsg3 reactive memory B cells in active patients. Follow-up experiments by the collaborating partners in Marburg identified Tfh17 cells as the primary inducers of Dsg-specific antibody production by B cells. These findings demonstrate that Tfh17 cells are substantially implicated in pemphigus pathogenesis and offer novel therapeutic approaches, for instance with small molecules targeting cytokine signal transduction of cells involved in disease initiation and manifestation. In the next step, such small compounds aiming to block Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated signal transduction were investigated for their ability to interfere with various signaling cascades initiated by cytokines in CD4+ Th cells. In particular, compounds targeting JAK3 were assessed and compared with the clinically established pan-JAK inhibitor Tofacitinib. In this setting, four of the five inhibitors tested were able to selectively block JAK3-mediated signal transduction without affecting other JAKs. Furthermore, the compounds abrogated the signaling cascade activated by IL-21, a cytokine crucial for Tfh cell differentiation and autoantibody formation. Immunohistochemical staining revealed STAT1 and STAT3 activation in epidermal keratinocytes of perilesional pemphigus skin. Blockade of JAK1 as well as JAK3 in primary human epidermal cells resulted in a protective effect towards cell sheet fragmentation of keratinocyte monolayers in dispase-based dissociation assays. Taken together, these findings indicate a potentially beneficial effect of JAK inhibition in patients suffering from pemphigus and provide the basis for further investigations regarding the therapeutic application of JAK inhibitors in clinical practice. en
dc.description.abstract Dissertation ist gesperrt bis zum 30.06.2023 !! de_DE
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podno de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=en en
dc.subject.classification Pemphigus , Autoimmunität de_DE
dc.subject.ddc 500 de_DE
dc.subject.other T-Zelle de_DE
dc.subject.other IL-17 de_DE
dc.subject.other IL-17 en
dc.subject.other Keratinozyten de_DE
dc.subject.other Keratinocytes en
dc.subject.other T cell en
dc.title Immune signature in pemphigus and its potential for therapeutic JAK inhibition en
dc.type Dissertation de_DE
dcterms.dateAccepted 2021-10-04
utue.publikation.fachbereich Biochemie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.source Teile publiziert in: J Allergy Clin Immunol 147(6), 2358-2369 (2021) de_DE
utue.publikation.noppn yes de_DE

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