Current concepts of autoimmune bullous diseases Advances in pathogenesis. Luca Borradori

Transcription

1 Current concepts of autoimmune bullous diseases Advances in pathogenesis Luca Borradori Dept. of Dermatology Inselspital, University Hospital of Berne Switzerland

2 Autoimmune bullous diseases Bullous pemphigoid

3 Autoimmune bullous diseases Bullous pemphigoid

4 Autoimmunbullöse Erkrankungen Pemphigus vulgaris

5 Autoimmune blistering diseases of the skin 1. Heterogeneous group of diseases with substantial clinical overlap associated with blistering of skin and/or mucosae 2. Humoral and cellular autoimmune response to disease-specific target antigens 3. Targeted auto-antigens: molecular components of adhesion complexes critical for skin integrity (and beyond ) 4. The same targeted antigens are defective in distinct inherited skin diseases associated with skin fragility, blistering (e.g. epidermolysis bullosa group), palmoplantar keratoderma, or ectodermal dysplasia

6 Major adhesion complexes in epidermis and other stratified epithelia as disease targets of autoimmune bullous disease Desmosomes Cell-cell adhesion complexes Hemidesmosomes Junctional adhesion complexes Kottke MD et al. J Cell Science 2006

7 Autoimmune bullous diseases: major groups 1. Diseases with intraepidermal blistering Loss of cell-cell adhesion Pemphigus group 2. Diseases with subepidermal blistering Dermo-epithelial dysadhesion Pemphigoid group Mucous membrane pemphigoid Epidermolysis bullosa acquisita (Dermatitis herpetiformis) 3. Diseases with mixed type of blistering Paraneoplastic pemphigus (PNP)

8 Bullous pemphigoid - Key points 1. Most frequent autoimmune subepidermal bullous disease in Europe Elderly affected Rarely in childhood 2. Subepidermal blistering with a dermal neutrophilic and eosinophilic infiltrate 3. Linear deposits of IgG and/or C3 along the epidermal basement membrane zone 4. Autoantibodies and autoreactive T cell response to BP180 and BP230, two components of hemidesmosomes DIF Di Zenzo G et al. Clin Dermatol :3-16.

9 BP180 BP180 et BP230, the target antigens of pemphigoids, are components of hemidesmosomes BASAL KERATINOCYTE PLECTIN a6 6 4 BP230 BP Auto-Abs TARGETS Laminin 332 ANCHORING FILAMENTS Collagen VII ANCHORING FIBRILS

10 BP autoantibodies Are BP recognize autoantibodies multiple directed antigenic sites against on BP180 both BP180 (and BP230) and BP230 pathogenic? Di Zenzo & Borradori, Clin Dermatol 2011 BP180 BP230 Intracellular Domain (ICD) Extracellular Domain (ECD) NH 2 Globular head Rod Globular repeats B C COOH NH 2 COOH FP-3A FP-7 NC16A Collagen 15 ECD LAD-1 C-terminus rbp55 F G BP230-C N1 N2 N3 C1 C2 BP230-N BP230-C1

11 Pathogenic role of anti-bp180 autoantibodies Transplacentar passage of anti-bp180 autoantibodies in gestational pemphigoid causes transient blistering in the newborn

12 Demonstration of pathogenic activity of anti-bp180 auto-antibodies in murine models: previous limitations Human anti-bp180 auto-abs fail to react with mouse BP180 and do not reproduce bullous pemphigoid in a passive transfer mouse model Liu Z et al. J Clin Invest 1993; 92: Need for better models to assess the role of anti-bp180 auto-abs

13 Generation of BP180-humanized mice (mbp180 -/- hbp180 +/+ ) (1) Inactivation of BP180 gene Transgenic expression of human BP180 mbp180 -/- hbp180 +/+ mbp180 +/- Crossing TG-hBP180 mbp180 -/- mbp180 -/-,hubp180 +/+ human BP180 murine BP180 Nishie W et al. Nature Med. 2007;11: Humanized mice to test the pathogenicity of human anti-bp180 auto-antibodies

14 BP180-humanized mice injected with either purified anti-bp180 auto-abs or with a mab to human BP180 (NC16A) develop a BP-like phenotype Erythema and subepidermal blistering Anti-BP180 IgG auto-antibodies are pathogenic Separation in the lamina lucida IgG auto-abs fixation at the DEJ Nishie W et al. Nature Med. 2007;11: ; Li Q et al. J Immunol 2010; 185:

15 Blistering by human anti-bp180 abs depends on complement and neutrophils in a humanized BP180-NC16A mouse model Liu Z et al. J Autoimm 2008; 31: Mice depleted of neutrophils develop no blistering with pathogenic abs F(ab ) 2 fragments of anti-bp180 abs fail to trigger blistering in injected mice Murine C3 Murine C3

16 Both B cells and CD4-positive T cells are required for disease initiation Immunization with recombinant human BP180 Role of B and T cells in disease development: active mouse model for bullous pemphigoid Ujiie H et al. J Immunol 2010;184; Ujiie H et al. J Immunol 2010;184; in an active mouse model for bullous pemphigoid Spleen (T cells & B cells etc.) Transfer humbp180 -/- No tolerance against human BP180 Rag2 -/- Hum BP180 +/+

17 Pathogenicity of anti-bp180 IgG autoantibodies : current model EPIDERMIS BLISTER FORMATION IL-8 DERMIS DERMAL VESSEL IgG 1 C3b 3 2 C5a 3 MC 3 3 IL-8 3 PMN 3 MF 3 6 Neutrophil elastase 4 6 MMP-9 4 PMN a1- proteinase inhibitor 5 MMP-9 Di Zenzo et al Production of autoantibodies, regulation by autoreactive T cells Complement activation - Neutrophil migration and activation Eosinophils and mast cells implicated (IgE autoantibodies) Secretion and/or activation of plasmin, MMPs and neutrophil elastase Damage of the dermo-epidermal junction

18 Pemphigus vulgaris / p. foliaceus - Key points 1. Autoimmune blistering diseases of the skin and/or mucosae Start usually in adulthood Association with certain HLA class II alleles P. foliaceus: endemic areas in Brazil and North Africa 2. Intraepidermal blister formation (acantholysis) 3. Immune response to desmoglein 3 and/or desmoglein 1 4. Desmogleins: components of cell-cell adhesion complexes, desmosomes Stanley & Amagai. NEJM 2006; 355:

19 Mice without dsg 3 develop a phenotype of PV and hair loss Dsg 3 -/- Dsg 3 -/- Role of dsg 3 promoting cell-cell adhesion in normal hair structure (anchorage of telogen hair) Koch PJ et al. JCB 1997; JCS 1998

20 Pemphigus auto-abs cause acantholysis and blistering in passive transfer studies in mice Auto-abs target epitopes on the N-terminus of dsg 3/1 within the cell adhesion surface region Weakly pathogenic abs (only if combined) cell Strongly pathogenic ab (alone) Intracellular domain Futei Y et al. J. Immunol Sekiguchi M et al. J. Immunol Tsunoda K et al. J. Immunol Kawasaki H et al. JID 2006

21 Steric hindrance hypothesis Strongly pathogenic antibodies in pemphigus react with the cell adhesion surface of desmogleins Electronic tomographic mapping of a desmosome Model of interaction of cadherins at the cell surface Cellular membrane 100 nm He W. et al. Science 2003: 302: 109 Getsios S. et al. Nat Rev. 2004; 5: 271

22 Pemphigus - Mechanisms of acantholysis Autoantibodies activate transmembrane signaling pathways leading to an impaired intercellular adhesion Desmosome disassembly (phosphorylation) Reorganization of the cytoskeleton actin and intermediate filaments Impaired differentiation with increased proliferation Activated pathways p38 MAPK Protein kinase C c.myc proto-oncogene src, cdk2, Seishima et al. 1995, Esaki et al Caldelari & Müller 2001, Williamson & Müller 2006, Cirillo et al. 2007, Grando et al. 2007, Jolly SP et al. 2010

23 Perspectives: pharmacologic therapy of pemphigus? PV IgG-mediated signaling activates p38 MAPK with p38 MAPK inhibitors, including KC-706, currently evaluated reorganization of the cytoskeleton Inhibition of p38mapk prevents clinical blistering PV IgG GTPase RhoA Phosph. Berkowitz P et al. JBC 2005 Berkowitz P et al. PNAS 2006 Waschke J et al., JCB 2006 Jolly PS et al JBC 2010

24 PV mouse model : interaction between antigen-specific B-T cells is required for disease development Immunization with rdsg3 Spleen (T cells & B cells etc.) Dsg3 -/- No tolerance against Dsg3 IgG deposition Transfer Rag2 -/- Dsg3 +/+ Acantholytic blister Takashi et al. J Immunol 2009 kindly provided by M. Amagai Erosions & hair loss

25 Hertl M et coll. Marburg

26 Rituximab mechanisms of action CD4+ T-Helper-cell IgG 1 Plasmacells IL-4, IL-5 IL-13 B-Cell 1. Depletion of CD20+ pre-b cells, B cells and memory B cells Reduction of anti-dsg antibodies (via BAFF increase?) 2. Reappearance of naive B cells with a normal repertoire 3. Reduction of dsg-specific autoreactive T cells important for B cell activation (B and T cell crosstalk) Mousquet et al. J Invest Dermatol 2008; Eming et al. J Invest Dermatol 2008, Dermatol 2009 Nagel et al. J Invest

27 Advances in pathogenesis in AIBD Take home messages and learning objectives 1. Group of rare diseases associated with autoantibodies directed against structural components of adhesion complexes, desmosomes and hemidesmosomes Targets of both acquired and inherited dermatoses 2. Advances in the understanding of mechanisms leading to blistering Bullous pemphigoid: inflammatorry cascade with activation of complement, inflammatory cells, and proteases Pemphigus: steric hindrance, dsg-depleted desmosomes, activation of signaling pathways