Research Agenda

In line with the research focus on autoimmune bullous skin diseases at the Department of Dermatology, our division has specialized on the transition from basic research into the clinic. Research is centered around the diagnosis and the development of novel treatment options for autoimmune blistering diseases.

An addition animal studies about the pathogenesis and modulation of bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita are performed. Furthermore, the pathogenetic importance of patient autoantibodies is investigated in different in-vitro systems. We are also involved in the establishment of new autoantibody detection systems. Another focus of the working group is the preparation of clinical studies.

We closely cooperate with our partner on the campus including the Comprehensive Center for Inflammation Medicine (CCIM) as well as the working groups of Prof. R. Ludwig (LIED), Prof. S. Ibrahim (LIED), Prof. H. Busch (LIED), Prof. C. Sadik (Dermatology), Prof. J Westermann (Anatomy) and Prof. J. Köhl (Immunology).

Current projects

Biomarker

Our overall goal is the development of new test systems for the detection of autoantibodies in autoimmun bullous skin diseases. The test systems will be used to improve the diagnosis of these diseases, including the use of new target antigens, but also the optimization of existing detection systems in terms of effectiveness, cost reduction and automation.
Another aim is the identification of biomarkers that describe clinical subgroups within the disease group that differ in respect of prognosis and treatment.

Recent Publications:
  1. Goletz S, Probst C, Komorowski L, Schlumberger W, Fechner K, van Beek N, Holtsche MM, Recke A, Yancey KB, Hashimoto T, Antonicelli F, Di Zenzo G, Zillikens D, Stöcker W, Schmidt E. Sensitive and specific assay for the serological diagnosis of anti-laminin 332 mucous membrane pemphigoid. Br J Dermatol 2019, 180: 149-56.
  2. Holtsche MM Goletz S, van Beek N, Zillikens D, Benoit S, Harman K, Walton S, English J, Sticherling M, Chapman Levell ANJ, Groves R, Williams HV, König IR, Schmidt E. Prospective study in bullous pemphigoid: Association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score. Br J Dermatol 2018, 179: 918-24.
  3. van Beek N, Dähnrich C, Johannen N, Lemcke S, Goletz S, Hübner F, Di Zenzo G, Dmochowski M, Drenovska K, Geller S, Horn M, Kowalewski C, Medenica L, Murrell DF, Patsatsi A, Uzun S, Vassileva S, Zillikens D, Schlumberger W, Schmidt E. Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases.J Am Acad Dermatol. 2017 May;76(5):889-894
  4. Van Beek N, Lütmann N, Hübner F, Recke A, Karl I, Schulze FS, Zillikens D, Schmidt E. Correlation of serum levels of IgE autoantibodies against BP180 with bullous pemphigoid disease activity. JAMA Dermatol. 2017 Jan 1; 153(1):30-38
  5. Mindorf S, Dettmann I, Krüger S, Fuhrmann T, Rentzsch K, Ingolf K, Probst C, Komorowski L, Fechner K, van Beek N, Lemcke S, Sárdy M, Bangert C, Benoit S, Hashimoto T, Zillikens D, Pas H, Jonkman M, Stöcker W, Schmidt E. Routine detection of serum anti-desmocollin autoantibodies is only useful in patients with atypical pemphigus. Exp Dermatol 2017, 26: 1267-70.
  6. Recke A, Oei A, Hübner F, Fechner K, Graf J, Hagenah J, May C, Woitalla D, Salmen A, Zillikens D, Gold R, Schlumberger W, Schmidt E. Parkinson’s disease and multiple sclerosis are not associated with autoantibodies against structural proteins of the dermal-epidermal junction. Br J Dermatol 2016, Aug; 175(2): 407-9
  7. Sadik C, Pas HH, Bohlmann MK, Mousavi S, Benoit S, Sárdy M, Terra JB, Lima AL,. Hammers CM, van Beek N, Bangert C, Zillikens D, Schmidt E. Value of BIOCHIP technology in the diagnosis of pemphigoid gestationis. Acta Dermatol Venereol (Stockh.) 2017 Jan 4; 97(1):128-130
  8. Schmidt E. Increasing the diagnostic sensitivity for mucous membrane pemphigoid by detection of salivary autoantibodies (commentary). Br J Dermatol 2016, 174: 956-57.

Immunopathogenesis of bullous pemphigoid

Our current knowledge about the pathogenesis of bullous pemphigoid (BP), the most common autoimmune bullous skin disease, is largely based on data obtained in the neonatal mouse model. Here, it was clearly shown that complement activation (in particular via the classical pathway) is essential, as well as the subsequent infiltration of inflammatory cells (e.g. neutrophils and macrophages) into the skin. The secretion of ROS and certain proteases (including neutrophil elastase and MMP-9) then results in the degradation of structural proteins of the dermal-epidermal junction zone, which clinically presents as blister. Some of these results have been reproduced in another model, in which human anti-BP180 IgG is injected into mice expressing the human BP180 molecule. However, many questions are still open and some may still be controversial. Therefore, we have recently established a passive mouse model of BP in adult mice that after injection of rabbit anti-BP180 IgG induces a skin disease that reflects the major clinical and immunopathological characteristics of the human disease.

Current projects explore the importance of the complement system, the differential regulation of Fcγ receptors, the role of IL17 and T cells and the glycosylation of autoantibodies in the adult mouse model of BP.

Recent Publications:
  1. Chakievska L, Holtsche MM, Künstner A, Goletz S, Petersen BS, Thaci D, Ibrahim SM, Ludwig RJ, Franke A, Sadik CD, Zillikens D, Hölscher C, Busch H, Schmidt E. IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. J Autoimmun 2019; 96: 104-12.
  2. Karsten CM, Beckmann T, Holtsche MM, Tillmann J, Tofern S, Schulze F, Heppe EN, Ludwig R, Zillikens D, König IR, Köhl J, Schmidt E. Tissue destruction in bullous pemphigoid can be complement-independent and may be mitigated by C5aR2. Front Immunol 2018, 9: 488.
  3. Schulze FS, Beckmann T, Nimmerjahn F, Ishiko A, Collin M, Köhl J, Goletz S, Zillikens D, Ludwig R, Schmidt E. FcgRIII and FcgRIV mediate tissue destruction in a novel adult mouse model of bullous pemphigoid. Am J Pathol 2014, 184: 2185-96.

Preclinical studies on new therapies for autoimmune blistering diseases

Various immunomodulators are currently being investigated in different in vitro and in vivo models. The following model systems are available:

In vitro

  • Keratinocyte degradation assay (pemphigus)
  • Dispase assay (pemphigus)
  • ROS-release assay (bullous pemphigoid)
  • Keratinocyte assay (bullous pemphigoid)

Ex vivo

  • Cryosection assay

In vivo

  • Neonatal mouse model for pemphigus
  • Passive mouse model for bullous pemphigoid/ mucous membrane pemphigoid
  • Passive mouse model for epidermolysis bullosa acquisita
  • Active mouse model for bullous pemphigoid
  • Active mouse model for epidermolysis bullosa acquisita
Recent Publications:
  1. Hofrichter M, Dworschak J, Langenhan J, Weiß F, Komorowski L, Zillikens D, Stöcker W, Probst C, Schmidt E*, Goletz S*. Immunoadsorption of anti-desmoglein 3-specific IgG abolishes the blister-inducing capacity of pemphigus vulgaris IgG in neonatal mice. Front Immunol 2018, 9: 1935. *equal contribution.
  2. Heppe EN, Tofern S, Schulze FS, Ishiko A, Shimizu A, Sina C, Zillikens D, Köhl J, Goletz S, Schmidt E. Experimental laminin 332 mucous membrane pemphigoid reflects clinical and immunopathological characteristics of the human disease and critically involves C5aR1. J Invest Dermatol 2017, 137: 1709-18.
  3. Sadeghi H, Lockmann A, Hund AC, Samavedam U, Pipi E, Vafia K, Hauenschild E, Kalies K, Pas HH, Jonkman MF, Iwata H, Recke A, Schön M, Zillikens D, Schmidt E*, Ludwig R*. Caspase-1-independent IL-1 release mediates blister formation in autoantibody-induced tissue injury through modulation of endothelial adhesion molecules. J Immunol, 2015 Apr 15;194(8):3656-63. *equal contribution.
  4. Schulze FS, Beckmann T, Nimmerjahn F, Ishiko A, Collin M, Köhl J, Goletz S, Zillikens D, Ludwig R, Schmidt E. FcgRIII and FcgRIV mediate tissue destruction in a novel adult mouse model of bullous pemphigoid. Am J Pathol 2014, 184: 2185-96.
  5. Yu X, Zheng J, Collin M, Schmidt E, Zillikens D, Petersen F. EndoS reduces the pathogenicity of anti-mCOL7 IgG through reduced binding of immune complexes to neutrophils. Plos One 2014, 9: e85317.
  6. Spindler V, Rötzer V, Dehner C, Kempf B, Gliem M, Hartlieb E, Harms GS, Schmidt E, Waschke J. Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering. J Clin Invest 2013, 123: 800-811

Genetic markers in patients with autoimmune bullous diseases

Investigation of genetic susceptibility and the microflora of the skin.

Recent Publications:
  1. Recke A, Konitzer S, Lemcke S, Freitag M, Sommer NM, Abdelhady M, Amoli MM, Benoit S, El-Chennawy F, Eldarouti M, Eming R, Gläser R, Günther C, Hadaschik E, Homey B, Lieb W, Peitsch WK, Pföhler C, Robati RM, Saeedi M, Sárdy M, Sticherling M, Uzun S, Worm M,  Zillikens D, Ibrahim S, Vidarsson G, Schmidt E, and the German AIBD Genetic Study Group. The p.Arg435His variation of IgG3 with high affinity to FcRn is associated with susceptibility for pemphigus vulgaris – analysis of four different ethnic cohorts. Front Immunol 2018, 9: 1788.
  2. Sadik C, Bischof J, van Beek N, Dieterich A, Benoit S, Sardy M, Worm M, Meller S, Gläser  R, Zillikens D, Homey B, Setterfield J, Minassian D, Schmidt E, Dart J, Ibrahim S. Genome-wide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid. Exp Dermatol 2017, 26: 1214-20.
  3. Miodovnik M, Künstner A, Langan E, Zillikens D, Gläser R, Sprecher E, Baines J*, Schmidt E*, Ibrahim S*. A distinct cutaneous microbiota profile in autoimmune bullous diseases patients. Exp Dermatol 2017, 26: 1221-27.
  4. Recke A, Vidarsson G, Ludwig R, Freitag M, Möller S, Vonthein R, Schellenberger J, Haase O, Görg S, Nebel A, Flachsbart F, Schreiber S, Lieb W, Gläser R, Benoit S, Sárdy M, Eming R, Hertl M, Zillikens D, König I, Schmidt E, Ibrahim S, and the German AIBD Genetic Study Group. Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibility for autoimmune blistering diseases. J Autoimmun 2015, 61: 36-44.
  5. Haase O, Alnebari R, Eldarouti MA, Abd El Hady M, Dorgham D, El-Nabarawy E, El Din Mahmoud SB, Mosaad El Sayed H, Darwish M, Abbas F, Salah S, Mosaad Y, El Chennawy F, Al Mongy S, Abdelaziz AM, Abd El Gaber S, Hertl M, Eming R, Recke A, Möller S, Schmidt E, Zillikens D, Ibrahim S. Association with HLA-DRB1 in Egyptian and German pemphigus vulgaris patients. Tissue Antigens 2015, 85: 283-86.
  6. Sarig O, Bercovici S, Zoller L, Goldberg I, Indelman M, Nahum S, Israeli S, Sagiv N, Martinez H, Katz O, Baum S, Barzilai A, Trau H, Murrell DF, Bergman R, Hertl M, Rosenberg S, Nöthen MM, Skorecki K, Schmidt E, Zillikens D, Darvasi A, Geiger D, Rosset S, Ibrahim SM, Sprecher E. A population-specific variant in ST18, encoding a pro-apoptotic molecule, predisposes to pemphigus vulgaris; J Invest Dermatol 2012, 132: 1798-805.

Development of specific immunoadsorbers

Specific adsorbers are generated using recombinant BP180 NC16A (for BP, mucous membrane pemphigoid, pemphigoid gestationis)

Recent Publications:
  1. Hofrichter M, Dworschak J, Langenhan J, Weiß F, Komorowski L, Zillikens D, Stöcker W, Probst C, Schmidt E*, Goletz S*. Immunoadsorption of anti-desmoglein 3-specific IgG abolishes the blister-inducing capacity of pemphigus vulgaris IgG in neonatal mice. Front Immunol 2018, 9: 1935. *equal contribution.
  2. Mersmann M, Dworschak J, Ebermann K, Komorowski L, Schlumberger W, Stöcker W, Zilikens D, Probst C, Schmidt E. Immunoadsorber for specific apheresis of autoantibodies in the treatment of bullous pemphigoid. Arch Dermatol Res 2016, 308: 31-38
  3. Langenhan J, Dworschak J, Saschenbrecker S, Komorowski L, Schlumberger W, Stöcker W, Westermann J, Recke A, Zillikens D, Schmidt E, Probst C. Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. Exp Dermatol 2014, 23: 253-9.
  4. Meyersburg D, Schmidt E, Kasperkiewicz M, Zillikens D. Immunoadsorption in dermatology. Ther Apher Dial 2012, 16: 311-20.

Epidemiology of autoimmune bullous skin diseases

Determination of incidences, prevalence and clinical associations.

Recent publications:
  1. Hübner F, Recke A, Zillikens D, Lindner R, Schmidt E. Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany. J Invest Dermatol 2016, 136:2495-2498
  2. Schulze F, Neumann K, Recke A, Zillikens D, Linder R, Schmidt E. Malignancies in pemphigus and pemphigoid diseases. J Invest Dermatol 2015, 135: 1445-47.
  3. Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, Caux F, Marinovic B, Sinha A, Hertl M, Bernard P, Sirois D, Cianchini G, Fairley JA, Jonkman M, Pandya A, Rubenstein D, Zillikens D, Payne AS, Woodley D, Zambruno G, Aoki V, Pincelli C, Diaz L, Hall RP, Meurer M, Mascaro JM, Schmidt E, Shimizu H, Zone J, Swerlick R, Culton D, Mimouni D, Lipozencic J, Bincie B, Bystryn JC, Werth VP. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol 2012, 66: 479-85.
  4. van Beek N, Knuth- Rehr D, Altmeyer P, Assaf C, Babilas , Bayerl C, Benoit S, Dippel E, Effendy I, Eming R, Fischer M, Glaenz T, Gläser R, Goebeler M, Gollnick H, Götze S, Gross P, Hadaschik E, Herbst R, Hermes B, Homey B, Hunzelmann N, Jünger M, Kapp M, Kern JS, Körber A, Luger T, Mechtel D, Megahed M, Moll I, Peters KP, Pfeiffer C, Ring J, Röcken M, Sárdy M, Seitz C, Stadler R, Steinbrink K, Sticherling M, Szeimies RM, Tronnier M, Ulrich J, Vogt T, Wagner N, Welzel J, Wenzel J, Wozel G, Zouboulis CC, Zillikens D, Schmidt E. Diagnostic of autoimmune bullous diseases in German dermatology departments. J Dtsch Dermatol Ges 2012, 10: 492-99.
  5. Bertram F, Bröcker EB, Zillikens D, Schmidt E. Prospektive Untersuchung der Inzidenz blasenbildender Autoimmundermatosen in Unterfranken. J Dtsch Dermatol Ges 2009, 5: 434-40.

Clinical studies

Recent publications
  1. Hübner F, Kasperkiewicz M, Knuth-Rehr D, Shimanovich I, Hübner J, Süfke S, Muck P, Zillikens D, Schmidt E. Adjuvant tratment of severe/ refractory bullous pemphigoid with protein A immunoadsorption leads to rapid diseases control and decrease of anti-BP180 autoantibody levels. J Dtsch Dermatol Ges 2018, 16: 1109-18.
  2. Kasperkiewicz M, Mook SC, Knuth-Rehr D, Vorobyev A, Ludwig R, Zillikens D, Muck P, Schmidt E. IgE-selective immunoadsorption for severe atopic dermatitis. Front Med 2018, 5: 27.
  3. Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E, Chalmers JR, Childs M, Walton S, Harman K, Chapman A, Whitham D, Nunn AJ. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid – a pragmatic non-inferiority randomised controlled trial. Lancet 2017, 389: 1630-38.
  4. Sticherling M, Franke A, Aberer E, Gläser R, Hertl M, Pfeiffer C, Rzany B, Schneider S, Shimanovich I, Werfel T, Wilczek A, Zillikens D, Schmidt E. An open, multicenter, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone. Br J Dermatol 2017; 177: 1299-1305.30-38.
Recent reviews
  1. van Beek N, Zillikens D, Schmidt E. Therapie des Pemphigus. Hautarzt 2019, in press.
  2. Spindler V*, Eming R*, Schmidt E*, Amagai M, Grando S, Jonkman MF, Kowalczy AP, Müller EJ, Payne AS, Pincelli C, Sinha AA, Sprecher E, Zillikens D*, Hertl M*, Waschke J*. Mechanisms causing loss of keratinocyte cohesion in pemphigus. J Invest Dermatol 2018, 138: 32-37. *equal contribution
  3. van Beek N, Zillikens D, Schmidt E. Therapie des Pemphigus. Hautarzt 2019, in press.
  4. van Beek N, Zillikens D, Schmidt E. Diagnosis of autoimmune bullous diseases. J Dtsch Dermatol Ges 2018, 16: 1077-92.
  5. Witte M, Zillikens D, Schmidt E. Diagnosis of autoimmune blistering diseases. Front Med 2018, 5: 296.
  6. Holtsche M, Zillikens D, Schmidt E. Mucous membrane pemphigoid. Hautarzt 2018: 67-8
    Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L. Autoimmune subepidermal bullous diseases of the skin and mucosae: clinical features, diagnosis, and management. Clin Rev Allergy Immunol 2018, 54: 26-51.
  7. Goletz S; Zillikens D, Schmidt E. Structural proteins of the dermal-epidermal junction targeted by autoantibodies in pemphigoid diseases. Exp Dermatol 2017, 26: 1154-62.
  8. Vorobyev A, Ludwig R, Schmidt E. Clinical features and diagnosis of epidermolysis bullosa acquisita. Expert Rev Clin Immunol 2017, 13: 157-69. ol 2017, 26: 1154-62.
  9. Försti AK, Huilaja L, Schmidt E, Tasanen K. Neurological and psychiatric associations in bullous pemphigoid - more than skin deep? Exp Dermatol 2017, 26: 1228-34.17, 26: 1154-62.
  10. Schmidt E. Rituximab as first line therapy of pemphigus (translational comment). Lancet 2017, 389: 1956-58.
  11. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013, 381: 320-32.