Forschungsbericht

Third-party-funded project

Title:
Characterisation of autoantibodies to BP180/type XVII collagen: Correlation with the clinical phentype of autoimmune blistering diseases

Project management at the University of Würzburg:

Prof. Dr. med. Detlef Zillikens ,Tel: 0931-201-26710,Fax: 0931-201-26700,Mail: zillikens_d@klinik.uni-wuerzburg.de

Participating scientists:

Dr. med. Dr. rer.nat. Enno Schmidt ,Mail: schmidt_e@klinik.uni-wuerzburg.de
Dr. med. Iakov Shimanovich

Abstract:
Autoantibodies to hemidesmosomal constituents induce subepidemal blisters in the skin. An important component of hemidesmosomes is the 180 kD bullous pemphigoid antigen (BP180/type XVII collagen). Our studies addressed the question, if different autoantibody specifitities induce different clinical phenotypes in the patients. We produced overlapping recombinant peptides of the immunodominant NC16A region of the BP180 ectodomain und developd different ELISA systems to detect antibodies to BP180. Our results show that both the binding of autoantibodies to distinct epitopes on BP180 and the immunoglobulin subclass of the autoantibody determine disease expression. Diseases associated wit autoantibodies to BP180 include bullous pemphigoid, pemphigoid gestationis, lichen planus pemphigoides, linear IgA disease, and mucous membrane pemphigoid. Our results lead to a more precise classification of autoimmune subepidermal bullous diseases which should be helpful for developing better treatment strategies for the different diseases.

Key words:
    Type VII collagen
    BP180
    Pemphigoid

Projekt period: from 05.1999 to 04.2001

Funding institution:
Sonstige öffentliche Mittel ( Wilhelm Sander-Stiftung ) ,Granting date: 25.01.1999

Publications:

1. Zillikens D, Caux F, Mascaro JM, Wesselmann U, Schmidt E, Prost C, Callen JP, Bröcker EB, Diaz LA, Giudice GJ. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol 1999; 113: 117-121.. (xx). xx. (monograph)
2. Chimanovitch I, Schmidt E, Messer G, Döpp R, Partscht K, Bröcker EB, Giudice GJ, Zillikens D. IgG1 and IgG3 are the major immunoglobulin subclasses targeting epitopes within the NC16A domain of BP180 in pemphigoid gestationis. J Invest Dermatol 1999; 113: 140-142.. (xx). xx. (monograph)
3. Leverkus M, Schmidt E, Lazarova Z, Bröcker EB, Yancey KB, Zillikens D. Anti-epiligrin cicatricial pemphigoid: An underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases? Arch Dermatol 1999; 135: 1091-1098.. (xx). xx. (monograph)
4. Schmidt E, Obe K, Bröcker EB, Zillikens D. Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch Dermatol 2000; 136: 174-178.. (xx). xx. (monograph)
Rose C, Dieterich W, Bröcker EB, Schuppan D, Zillikens D. Circulating autoantibodies to tissue transglutaminase differentiate patients with dermatitis herpetiformis from those with linear IgA disease. J Am Acad Dermatol 1999; 41: 957-961.. (xx). xx. (monograph)
Zillikens D, Herzele K, Schmidt E, Chimanovitch I, Georgi M, Schumann H, Mascaro JM Jr, Diaz LA, Bruckner-Tuderman L, Bröcker EB, Giudice GJ. Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16A domain of BP180. J Invest Dermatol 1999; 113: 947-953.. (xx). xx. (monograph)
Kippes W, Schmidt E, Roth A, Rzany B, Bröcker EB, Zillikens D. Immunpathologische Befunde bei 115 Patienten mit bullösem Pemphigoid. Hautarzt 1999; 50: 866-872.. (xx). xx. (monograph)
Baier G, Zillikens D. Das vernarbende Pemphigoid. Eine wichtige Differentialdiagnose entzündlicher Schleimhautveränderungen. Laryngo-Rhino-Otol 1999; 78: 632-637.. (xx). xx. (monograph)
Schumann H, Baetge J, Tasanen K, Wojnarowska F, Schäcke H, Zillikens D, Bruckner-Tuderman L. The shed ectodomain of collagen XVII/BP180 is targeted by autoantibodies in different blistering skin diseases. Am J Pathol 2000;156: 685-695.. (xx). xx. (monograph)
12. Döpp R, Schmidt E, Chimanovitch I, Leverkus M, Bröcker EB, Zillikens D. IgG4 and IgE are the major immunoglobulin isotypes targeting the NC16A domain of BP180 in patients with bullous pemphigoid. J Am Acad Dermatol 2000; 42: 577-583.. (xx). xx. (monograph)
Chimanovitch I, Hamm H, Georgi M, Kroiss M, Stolz W, Apitz C, Bröcker EB, Zillikens D. Bullous pemphigoid of childhood: Autoantibodies target the same epitopes within the NC16A domain of BP180 as autoantibodies in bullous pemphigoid of adulthood. Arch Dermatol 2000; 136: 527-532.. (xx). xx. (monograph)
Kromminga A, Scheckenbach C, Georgi M, Hagl C, Arndt R, Christophers C, Bröcker EB, Zillikens D. Patients with bullous pemphigoid and linear IgA disease show a dual IgA and IgG autoimmune response to BP180. J Autoimmun 2000, 15: 293-300. (xx). xxx. (monograph)
Georgi M, Scheckenbach C, Kromminga A, Partscht K, Messer G, Bröcker EB, Zillikens D. Mapping of epitopes on the BP180 ectodomain targeted by IgA and IgG autoantibodies in patients with the lamina lucida-type of linear IgA disease. Arch Dermatol Res 2001; 293: 109-114.. (xxx). xx. (monograph)
Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, Fine JD, Foster CS, Ghohestani R, Hashimoto T, Hoang-Xuan T, Kirtschig G, Korman NJ, Lightman S, Lozada-Nur F, Marinkovich MP, Mondino BJ, Prost-Squarcioni C, Rogers RS, Setterfield JF, West DP, Wojnarowska F, Woodley DT, Yancey KB, Zillikens D, Zone JJ. The first international consensus on mucous membrane pemphigoid: Definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 2002; 138: 370-379. (xx). xx. (monograph)
Schachner M, Brieva JC, Jones JCR, Zillikens D, Skrobek C, Chan LS. Pemphigoid nodularis associated with autoantibodies to the BP180 NC16A domain and a hyperproliferative integrin profile. J Am Acad Dermatol 2001; 45: 747-754. (xx). xx. (monograph)
Schmidt E, Skrobek C, Kromminga A, Hashimoto T, Messer G, Bröcker EB, Yancey KB, Zillikens D. Cicatricial pemphigoid: IgA and IgG autoantibodies target epitopes on both intra- and extracellular domains of BP180. Br J Dermatol 2001; 145: 778-783.. (xx). xx. (monograph)
Shimanovich I, Skrobek C, Rose C, Nie Z, Hashimoto T, Bröcker EB, Zillikens D. Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180. J Am Acad Dermatol 2002; 47: 780-784.. (xx). xx. (monograph)
Kromminga A, Sitaru C, Meyer J, Arndt R, Schmidt E, Christophers E, Bröcker EB, Zillikens D. Cicatricial pemphigoid differs from bullous pemphigoid and pemphigoid gestationis regarding the fine specificity of autoantibodies to the BP180 NC16A domain. J Derm Sci 2002;28: 68-75. (xx). xx. (monograph)
Leverkus M, Georgi M, Nie Z, Hashimoto T, Bröcker EB, Zillikens D. Cicatricial pemphigoid with circulating IgA and IgG autoantibodies to the central portion of the BP180 ectodomain: Beneficial effect of adjuvant therapy with high dose intravenous immunoglobulin. J Am Acad Dermatol 2002; 46: 116-122. (xx). xx. (monograph)
chmidt E, Sitaru C, Schubert B, Wesselmann U, Kromminga A, Bröcker EB, Zillikens D. Subacute prurigo variant of bullous pemphigoid: Autoantibodies show the same specificity compared to classical bullous pemphigoid. J Am Acad Dermatol 2002; 47: 133-136. (xx). xx. (monograph)
Zillikens D. BP180 as the common autoantigen in blistering diseases with different clinical phenotypes. Keio J Med 2002; 51: 17-24. (xx). xx. (monograph)