Sarolta Kárpáti. Technology Transfer in Diagnostic Pathology, 5th Central European Regional Meeting May 1, 2010, Siófok

Transcription

1 Blistering diseases Sarolta Kárpáti SEMMELWEIS UNIVERSITY, BUDAPEST Technology Transfer in Diagnostic Pathology, 5th Central European Regional Meeting May 1, 2010, Siófok

2 Blistering diseases Autoimmune blistering Differential: inherited blistering bacterial infection induced blistering

3 Blistering diseases Blisters Erosions Crusted erosions Erythema (redness) ± blisters Urticariform or exsudatív, erythematous plaques Pigmented or depigmented macules (healed symptoms)

4 AU blistering diseases Pemphigus group: IgG pathogenic autoantibodies --- rare in newborn: transplacentar IgG IgA class Pemphigoid group in sensu latu most patients - IgG pathogenic autoantibodies IgA class in newborn: transplacentar IgG Dermatitis herpetiformis IgA related - more patients (Hungary) gluten induced autoimmunity - diet is necessary

5 Desmosomal molecules Plakophillin Cell membrane

6 Pemphigus vulgaris: mucosal and skin blisters epitope spreading desmoglein 1 desmoglein 3 Somatic diversity of autoantibodies Recombination Hypermutation

7 Double autoimmunity to desmosomal and hemidesmosomal adhesion molecules with double splitformation D- IZ HD -BM Tumor association: PARANEOPLASTIC PEMPHIGUS Plaque proteins: DP I, II, Plectin, BP230, envoplakin, periplakin

8 Cell membrane BM zone Laminin 1,2 P200= gamma 1 chain NC16A domain Michael Hertl Detlef Zillikens

9 Why BP itchy? associated with eosinophilic reaction in the skin and circulation?

10 Answer for many questions: IgE autoantibodies BP : Autoantibodies of IgG or IgE or IgA class to structure proteins of the hemidesmosomes, BP180 (Collagen XVII) and BP230 IgE autoantibody binding complement activation, mast cell degranulation accumulation ofinflammatory cells (eosinophiles, es mast cells, neutrophils) proteases, split and blisterformation Iowa City, Janet Fairley

11 Rituximab: chimeric monoclonal antibodies: murine Fab, human Fc CD 20 antigen expressed in B lymphocytes, in pre B Cells, pre-plasmacells not expressed in haematopoetic stemcells and in plasmacells depletion of memory B cells (pre- plasmacell stage), blocking AB production

12 Indication of Rituximab (anti-cd20 AB) 2009, JID Paraneoplastic pemphigus Pemphigus vulgaris Pemphigus foliaceus Epidermolysis bullosa acquisita Mucose membrane pemphigoid Bullous pemphigoid Glucocorticoids + immunsuppressive drugs (azathioprin +mycophenolat mofetil) Rituximab 4x375 mg/m2 in children and under age lack of experience PNP could be an exception

13 Rituximab -CD20 CD22, CD19, CD40-CD40L, B cell activating factor belonging to the TNF family (BAFF) A proliferation-inducing ligand (APRIL).

14 Autoimmune blistering diseases Histology Skin deposited autoantibodies (IgG or IgA) detected by immunfluorescens histology Detection of circulating antibodies by indirect immunofluorescence or by ELISA

15 Etiology Unknown Triggering factors Drugs (drug induced diseases) Tumors (e.g. paraneoplastic pemphigus) Infective agents (e.g. folgo selvagem-endemic pemphigus foliaceus)

16 2008 consensus classification: 4 major EB types 1. Intraepidermal: EB simplex (EBS) BK BK BM BM D Suprabasal EBS D 2. Intra-lamina lucida: junctional EB (JEB) Basal EBS BK BM D 3. Sub-lamina densa: dystrophic EB (DEB) BK BM D 4. Mixed: Kindler syndrome (KS) BK BM D BK BM D BK BM D Fine JD et al. J Am Acad Dermatol 2008; 58:

17 Inherited blistering diseases: prognosis Pitfalls Late start: blister formation: days or weeks after delivery Late progression of mild symptoms Early severe symptoms show regression

18 What is wrong? What is missing? Inherited blistering diseases Make your differencial Clinical impressions may be wrong Let organize at a specialist skin histology antigen mapping ultrastructure

19 You need EB specialist in histology-protein analysis Clinical genetician Mutation analysis-if verified: Prenatal testing from villous samples by IF by mutation analysis preimplantation mutation analysis (circulating foetal cells)

20 You need Special EB centers for correct diagnosis, mutation analysis

21 Dermatitis herpetiformis Skin disease TG3 is the autoantigen of skin IgA circulating IgA type TG3 autoantibodies antibodies Gluten sensitive enteropathy TG2 is the autoantigen of the small bowel circulating IgA type TG2 autoantibodies IgA anti-jejunal antibodies binding to the jejunum disease specific small bowel IgA staining pattern

22 Challenge = clinical symptoms Differential diagnosis» DH with classical skin symptoms» DH with atypical skin symptoms» + skin symptoms of associated diseases

23 Semmelweis University Dept. Dermato-Venerology and Dermatooncology, Budapest Klaudia Preisz Palma Silló Mercedes Mrazán Annamária Glász-Bóna Antal Blazsek István Kósnai, (Miklós Sárdy) Márta Csikós Dept. Gastroenterology and Pediatrics Tamás Zágoni Erika Tomsits University of Cologne II. Istitute for Biochemistry ats Paulsson, Neil Smyth, Barbara Merkl Dept. Dermatology Thomas Krieg University Freiburg, Dept. Dermatology Leena Bruckner Tuderman Kurume University, Dept. Dermatology Japan Takashi Hashimoto,