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. van Beek N, Dähnrich C, Johannsen 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
  2. 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
  3. Mindorf S, Dettmann I, Krüger S, Fuhrmann T, Rentzsch K , Karl I, 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 Aug 16.
  4. 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
  5. 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
  6. Schmidt E. Increasing the diagnostic sensitivity for mucous membrane pemphigoid by detection of salivary autoantibodies (commentary). Br J Dermatol 2016, 174: 956-57.
  7. Schmidt E, Goebeler M, Hertl M, Sárdy M, Sitaru C, Eming R, Hofmann S, Hunzelmann N, Kern JS, Kramer H, Orzechowski HD, Pfeiffer C, Schuster V, Sporbeck B, Sticherling M, Worm M, Zillikens D, Nast A. S2k Guidelines for diagnosis of pemphigus vulgaris / foliaceus and bullous pemphigoid. J Dtsch Dermatol Ges 2015, 13 713-727
  8. Van Beek N, Dohse A, Riechert F, Krull V, Recke A, Zillikens D, Schmidt E. Serum autoantibodies against the dermal-epidermal junction in patients with chronic pruritic disorders, elderly individuals, and blood donors prospectively recruited. Br J Dermatol 2014, 170: 943-7.

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 reviews:
  1. Holtsche MM, Zillikens D., Schmidt E; Mucous membrane pemphigoid, Hautarzt in press
  2. Vorobyev A, Ludwig R, Schmidt E. Clinical features and diagnosis of epidermolysis bullosa acquisita. Expert Rev Clin Immunol, 2017 Feb;13(2):157-169.
  3. Groves R, Schmidt E. Immunobullous diseases. In: Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D (Hrsg.). Rook's Textbook of Dermatology. 9th edition. Wiley Balckwell, 2016, 50.01-50-56
  4. Goletz S, Hashimoto T, Zillikens D, Schmidt E. Anti-p200 pemphigoid. J Am Acad Dermatol 2014, 71: 185-91.
  5. Schwieger-Briel A, Moellmann C, Mattulat B, Schauer F, Kiritsi D, Schmidt E, Sitaru C, Ott H, Kern JS. Bullous pemphigoid in infants: characteristics, diagnosis and treatment. Orphanet J Rare Dis. 2014; 9: 185.
  6. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013, 381: 320-32.
  7. Ludwig R, Kalies K, Köhl J, Zillikens D, Schmidt E. Emerging treatments for pemphigoid diseases. Trends Mol Med 2013, 19: 501-12.
  8. Schulze F, Kasperkiewicz M, Zillikens D, Schmidt E. Bullöses Pemphigoid. Hautarzt 2013, 64: 931-43.
  9. Hammers C, Lunardon L, Schmidt E, Zillikens D. Contemporary management of pemphigus. Exp Opin Orphan Drugs 2013, 1: 295-314.
  10. Hammers CM, Schmidt E, Zillikens D. Blasenbildende Autoimmunerkrankungen der Haut – diagnostische und therapeutische Aspekte. DMW, 139: 1473-77.
  11. Schmidt E, Zillikens D. Diagnosis and treatment of autoimmune blistering skin diseases. Dtsch Ärztebl Int 2011, 108: 399-405.

Preclinical studies on new therapies for bullous autoimmune skin 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

  • Neonatale 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. 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 critically involves C5aR1 and reflects clinical and immunopathological characteristics of the human disease. J Invest Dermatol. 2017 Apr 26.
  2. Akbarzadeh R, Yu X, Vogl T, Ludwig RJ, Schmidt E, Zillikens D, Petersen F. Myeloid-related proteins-8 and -14 are expressed but dispensable in the pathogenesis of experimental epidermolysis bullosa acquisita and bullous pemphigoid J Dermatol Sci. 2016 Mar;81(3):165-72.
  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. Hirose M, Vafia K, Kalies K, Groth S, Westermann J, Zillikens D, Ludwig R, Collin M, Schmidt E. Enzymatic autoantibody glycan hydrolysis alleviates autoimmunity against type VII. J Autoimmun 2012, 39: 304-14.
  6. Spindler V, Rötzer V, Dehner C, Kempf B, Gliem M, Hartlieb E, Harms GS, Schmidt E, Waschke J. Tandem peptide blocks pemphigus vulgaris skin blistering in mice by preventing loss of desmoglein 3 binding and p38MAPK activation. J Clin Invest 2013, 123
  7. Vafia K, Groth S, Beckmann T, Hirose M, Dworschak J, Recke A, Ludwig R, Hashimoto T, Zillikens D, Schmidt E. Pathogenicity of autoantibodies in anti-p200 pemphigoid. PLoS One. 2012;7(7)
  8. 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 Feb 4;9(2).
  9. Dworschak J, Recke A, Freitag M, Ludwig R, Langenhan J, Kreuzer OJ, Zillikens D, Schmidt E. Mapping of B cell epitopes on desmoglein 3 in pemphigus vulgaris patients by the use of overlapping peptides. J Dermatol Sci 2012, 65: 102-9.
  10. Hirose M, Recke A, Beckmann T, Shimizu A, Ishiko A, Bieber K, Westermann J, Zillikens D, Schmidt E, Ludwig R. Repetitive immunization breaks tolerance to type XVII collagen and leads to bullous pemphigoid in mice. J Immunol 2011, 187: 1176-83.

Genetic markers in patients with bullous pemphigoid and pemphigus

Investigation of genetic susceptibility and the microflora of the skin.

Recent Publications:
  1. Miodovnik M, Künstner A, Langan EA, Zillikens D, Gläser R, Sprecher E, Baines JF, Schmidt E, Ibrahim SM. A distinct cutaneous microbiota pofile in autoimmune bullous disease patients. Exp Dermatol. 2017 Apr 18.
  2. Recke A, Vidarsson G, Ludwig R, Freitag M, Möller S, Vontheim R, Schellenberger J, Haase R, Hertl M, Zillikens D, König I, Schmidt E, Ibrahim S and the AIBD Genetic Study Group. Allelic and copy-number variations of FcyRs affect granulocyte funtion and susceptibility for autoimmune blistering dieases. J Autoimmun 2015,61:36-44
  3. Haase O, Alneebari 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 Apr;85(4):283-6..
  4. 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. 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
  2. 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.
  3. 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 Dec;136 (12):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 study

Recent publications
  1. Schmidt E. Rituximab as first-line treatment of pemphigus.  Lancet. 2017 May 20;389 (10083):1956-1958. IF 47.8
  2. 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 Apr 22;389 (10079):1630-1638
  3. 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, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone. Br J Dermatol. 2017 May 11
  4. Kasperkiewicz M, Süfke S, Schmidt E, Zillikens D. IgE-specific immunoadsorption for treatment of recalcitrant atopic dermatitis. JAMA Dermatology 2014, 150: 1350-51.
  5. Kasperkiewicz M, Schulze F, Meier M, van Beek N, Nitschke M, Zillikens D, Schmidt E. Case study of bullous pemphigoid patients treated with adjuvant immunoadsorption. J Am Acad Dermatol 2014, 71: 2018-20.
  6. Kasperkiewicz M, Shimanovich I, Meier M, Schumacher N, Westermann L, Kramer J, Zillikens D, Schmidt E. Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone, and azathioprine/ mycophenolate mofetil: a pilot study of 23 patients. Br J Dermatol 2012, 166: 154-60.
  7. Kasperkiewicz M, Shimanovich I, Ludwig R, Rose C, Zillikens D, Schmidt E. Rituximab for treatment-refractory pemphigus and pemphigoid: a case series of 17 patients. J Am Acad Dermatol 2011, 65: 552-8.
  8. Kasperkiewicz M, Schmidt E, Frambach Y, Rose C, Meier M, Nitschke M, Falk TM, Reich K, Ludwig R, Zillikens D. Improvement of treatment-refractory atopic dermatitis by immunoadsorption: A pilot study. J Allergy Clin Immun 2011, 127: 267-70.