Blistering diseases Blistering diseases Sarolta Kárpáti

SEMMELWEIS UNIVERSITY, BUDAPEST

Technology Transfer in Diagnostic Pathology, 5th Central European Regional Meeting

May 1, 2010, Siófok

Blistering diseases

• Autoimmune blistering

• Differential: – inherited blistering– inherited blistering– bacterial infection induced blistering

Blistering diseases

• Blisters

• Erosions

• Crusted erosions

• Erythema (redness) ± blisters

• Urticariform or exsudatív, erythematous plaques• Urticariform or exsudatív, erythematous plaques

• Pigmented or depigmented macules (healed symptoms)

AU b listering 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– IgA class– in newborn: transplacentar IgG

• Dermatitis herpetiformis– IgA related -– more patients (Hungary)– gluten induced autoimmunity - diet is necessary

Desmosomal molecules

Plakophillin

Cell membrane

Pemphigus vulgaris: mucosal and skin blisters

„epitope spreading ”

desmoglein 3

desmoglein 1

desmoglein 3

Somatic diversity of autoantibodies

Recombination

Hypermutation

Double a utoimmunity to desmosomal and hemidesmosomal adhesion molecules with double splitformation

D- IZ HD -BM Tumor association:

PARANEOPLASTIC PEMPHIGUS

Plaque proteins: DP I, II, Plectin, BP230, envoplak in, periplakin

Cell membrane

BM zone

Laminin 1,2

P200= gamma 1 chain

NC16A domain

Michael Hertl

Detlef Zillikens

Why BP

• itchy?• associated with eosinophilic reaction in the skin

and circulation?and circulation?

Answer for many questions:

IgE autoantibodies

• BP : Autoantibodies of IgG or IgE or IgA c lass to structure proteins of thehemidesmosomes, BP180 (Collagen XVII) and BP230

• IgE autoantibody binding– complement activation,

– mast cell degranulation

– accumulation of inflammatory cells (eosinophiles, mast cells, – accumulation of inflammatory cells (eosinophiles, mast cells, neutrophils)

• proteases, split and blisterformation

Iowa City, Janet Fairley

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

Indication of Rituximab (anti-CD20 AB) 2009, JID

Paraneoplastic

pemphigus

Pemphigus vulgaris

Pemphigus foliaceus

Epidermolysis bullosa acquisita

Mucose membrane pemphigoid

Bullous pemphigoidBullous pemphigoid

Rituximab 4x375 mg/m2

Glucocorticoids + immunsuppressive drugs

(azathioprin +mycophenolat mofetil)

in children and under age 18 --- lack of experience

PNP could be an exception

– Rituximab - CD20

– CD22,

– CD19,

– CD40-CD40L,

– B cell activating factor belonging to the TNF family (BAFF) – B cell activating factor belonging to the TNF family (BAFF)

– A proliferation-inducing ligand (APRIL).

Autoimmune blistering diseases

– Histology

– Skin deposited autoantibodies (IgG or IgA) detected by

immunfluorescens histology

– Detection of circulating antibodies by indirect immunofluorescence or

by ELISA by ELISA

Etiology

• Unknown

• Triggering factors

– Drugs (drug induced diseases)

– Tumors (e.g. paraneoplastic pemphigus) – Tumors (e.g. paraneoplastic pemphigus)

– Infective agents

• (e.g. folgo selvagem- endemic pemphigus foliaceus)

1. Intraepidermal: EB simplex (EBS)

2008 consensus classification: 4 major EB types

2. Intra-lamina lucida: junctional EB (JEB)

Suprabasal EBS Basal EBS

BK

BM

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BK

BM

D

BK

BM

D

3. Sub-lamina densa: dystrophic EB (DEB)

4. Mixed: Kindler syndrome (KS)

Fine JD et al. J Am Acad Dermatol 2008; 58: 931-50

D

BK

BM

D

BK

BM

D

BK

BM

D

BK

BM

D

Inherited blistering diseases: prognosis

• Pitfalls

– Late start: blister formation: days or weeks after

deliverydelivery

– Late progression of „mild” symptoms

– Early severe symptoms show regression

What is wrong?

What is missing?

Inherited blistering diseases

• Make your differencial

• Clinical impressions may be wrong

• Let organize at a specialist • Let organize at a specialist

– skin histology

– „antigen mapping”

– ultrastructure

You need

• EB specialist in histology- protein analysis

• Clinical genetician

• Mutation analysis- if verified:

– Prenatal testing from villous samples– Prenatal testing from villous samples

• by IF

• by mutation analysis

• preimplantation mutation analysis

• (circulating foetal cells)

You need

• Special EB centers for correct diagnosis,

mutation analysis

Dermatitis herpetiformis

• Skin disease

– TG3 is the autoantigen

of skin IgA

– circulating IgA type TG3

autoantibodies

• Gluten sensitive

enteropathy

• TG2 is the autoantigen of the

small bowel

• circulating IgA type TG2 autoantibodies

– antibodies

• circulating IgA type TG2

autoantibodies

– IgA anti-jejunal antibodies

binding to the jejunum

– disease specific small

bowel IgA staining pattern

Challenge = clinical symptoms

Differential diagnosis

» DH with classical skin symptoms

» DH with atypical skin symptoms

» + skin symptoms of associated diseases

Semmelweis UniversityDept. Dermato-Venerology and

Dermatooncology, Budapest

Klaudia PreiszPalma SillóMercedes MrazánAnnamária Glász-Bóna

Antal Blazsek

University of Cologne II. Istitute forBiochemistry

ats Paulsson, Neil Smyth, Barbara Merkl

Dept. Dermatology

Thomas Krieg

University Freiburg, Dept. Dermatology

Leena Bruckner TudermanIstván Kósnai, (Miklós Sárdy)

Márta Csikós

Dept. Gastroenterology and Pediatrics

Tamás Zágoni

Erika Tomsits

Leena Bruckner Tuderman

Kurume University, Dept. Dermatology Japan

Takashi Hashimoto,