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Subproject 2

T-cell-dependent regulation of autoreactive B cells in pemphigus

Summary

There is compelling evidence from experimental mouse models of PV including the HLA-transgenic mouse that the pathogenesis of PV is dependent on the interplay of T and B cells. For instance, the generation of Dsg3-specific, pathogenic IgG auto-ab requires activation of autoreactive B cells which is initiated by autoreactive T cells. In this project different subpopulations of T cells (Th, Tf and Treg cells) as well as B cells will be studied both ex vivo in patients with PV and in mice by determining the expression of surface receptors, transcription factors, signaling molecules and cytokine secretion. To functionally address T/B cell interaction, the impact of Th and Tf cell subsets on activation of autoreactive B cells and auto-ab formation will be investigated. In parallel, the developmental stages of peripheral B cell populations will be studied in patients with active or remittent PV. Furthermore, PV patients in remission will be followed longitudinally to determine whether changes in distinct B cell subsets are associated with a clinical relapse of PV and whether this is accompanied by altered T cell function. The proposed experiments in PV patients and in animal models will thus allow i) to better understand the T/B cell interaction in PV pathogenesis, ii) to characterize the disease-relevant T cell subsets and the prominent B cell phenotype iii) and to identify new targets for treatment of PV. Furthermore, data of this project will help to define time-points at which interventional strategies may prevent the relapse of PV.

Contact

Charité - Universitätsmedizin Berlin
Prof. Dr. Kamran Ghoreschi
Projectleader TP2
Charitéplatz 1
D-10117 Berlin
Tel +49 30 450 518 062
Fax +49 30 450 518 911

E-Mail: kamran.ghoreschi@charite.de

Philipps University Marburg
Dr. Christian Möbs
Projectleader TP2
Klinik für Dermatologie und Allergologie
Philipps-Universität Marburg
Baldingerstraße
D-35043 Marburg
Tel +49 6421 58 61405
Fax +49 6421 58 64824

E-Mail: moebs@med.uni-marburg.de

Philipps University Marburg
Prof. Dr. Wolfgang Pfützner
Co-leader TP2
Klinik für Dermatologie und Allergologie
Philipps-Universität Marburg
Baldingerstraße
D-35043 Marburg
Tel +49 6421 58 62488
Fax +49 6421 58 62883 

E-Mail: Wolfgang.Pfuetzner@med.uni-marburg 

• Inhalt ausklappen Inhalt einklappen Publications of Project 2Publications of Project 2

  Holstein J, Solimani F, Baum C, Meier K, Pollmann R, Didona D, Tekath T, Dugas M, Casadei N, Hudemann C, Polakova A, Matthes J, Schäfer I, Yazdi AS, Eming R, Hertl M, Pfützner W, Ghoreschi K, Möbs C. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. J Allergy Clin Immunol. 2020 Nov 20:S0091-6749(20)31624-9. doi: 10.1016/j.jaci.2020.11.008.
  
  Gualtieri B, Solimani F, Hertl M, Buhl T, Möbs C, Pfützner W. Interleukin 17 as a therapeutic target of acute generalized exanthematous pustulosis (AGEP). J Allergy Clin Immunol Pract. 2020 Jun;8(6):2081-2084.e2. doi: 10.1016/j.jaip.2020.01.045. Epub 2020 Jan 31.
  
  Solimani F, Pollmann R, Schmidt T, Schmidt A, Savai R, Zheng X, Mühlenbein S, Pickert J, Eubel V, Möbs C, Eming R, Hertl M. Therapeutic targeting of Th17/Tc17 cells leads to clinical improvement of lichen planus. Front Immunol 2019. 10; doi:10.3389/ fimmu.2019.01808.
  
  Solimani F, Maglie R, Pollmann R, Schmidt T, Schmidt A, Ishii N, Tackenberg B, Pickert J, Kirschbaum A, Eming R, Hashimoto T, Hertl M. Thymoma-associated paraneoplastic autoimmune multiorgan syndrome – from pemphigus to lichenoid dermatitis. Front Immunol 2019. 10; doi.org/10.3389/fimmu.2019.01413.
  
  Pollmann R, Walter E, Schmidt T, Waschke J, Hertl M, Möbs C, Eming R. Identification of Autoreactive B cell Subpopulations in Peripheral Blood of Autoimmune Patients with Pemphigus vulgaris. Front Immunol 2019. 10; doi: 10.3389/fimmu.2019.01375.
  
  Sabat R, Wolk K, Loyal L, Döcke WD, Ghoreschi K. T cell pathology in skin inflammation. Semin Immunopathol 2019. 41(3):359-377.
  
  Eckardt J, Eberle FC, Ghoreschi K. Diagnostic value of autoantibody titres in patients with bullous pemphigoid. Eur J Dermatol. 2018;28(1):3–12.
  
  Forster M, Chaikuad A, Dimitrov T, Döring E, Holstein J, Berger BT, Gehringer M, Ghoreschi K, Müller S, Knapp S, Laufer S. Development, optimization, and structure-activity relationships of covalent-reversibel JAK3 inhibitors based on a tryciclic imidazo[5,4-d]pyrrolo[2,3-b]pyridine scaffold. J Med Chem 2018. 61, 5350-5366.
  
  Welsch K, Holstein J, Laurence A, Ghoreschi K. Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. Eur J Immunol. 2017;47(7):1096–1107.