Sarolta Kárpáti - PuzzlePix · 2. Intra-lamina lucida: junctional EB (JEB) Suprabasal EBS Basal...
Transcript of Sarolta Kárpáti - PuzzlePix · 2. Intra-lamina lucida: junctional EB (JEB) Suprabasal EBS Basal...
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Blistering diseases Blistering diseases Sarolta Kárpáti
SEMMELWEIS UNIVERSITY, BUDAPEST
Technology Transfer in Diagnostic Pathology, 5th Central European Regional Meeting
May 1, 2010, Siófok
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Blistering diseases
• Autoimmune blistering
• Differential: – inherited blistering– inherited blistering– bacterial infection induced blistering
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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)
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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
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Desmosomal molecules
Plakophillin
Cell membrane
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Pemphigus vulgaris: mucosal and skin blisters
„epitope spreading ”
desmoglein 3
desmoglein 1
desmoglein 3
Somatic diversity of autoantibodies
Recombination
Hypermutation
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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
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Cell membrane
BM zone
Laminin 1,2
P200= gamma 1 chain
NC16A domain
Michael Hertl
Detlef Zillikens
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Why BP
• itchy?• associated with eosinophilic reaction in the skin
and circulation?and circulation?
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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
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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
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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
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– 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).
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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
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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)
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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
D
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
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Inherited blistering diseases: prognosis
• Pitfalls
– Late start: blister formation: days or weeks after
deliverydelivery
– Late progression of „mild” symptoms
– Early severe symptoms show regression
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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
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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)
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You need
• Special EB centers for correct diagnosis,
mutation analysis
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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
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Challenge = clinical symptoms
Differential diagnosis
» DH with classical skin symptoms
» DH with atypical skin symptoms
» + skin symptoms of associated diseases
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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,