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From Epidemiology and Genetics to Diagnostics, Outcome Measures, and Novel Treatments in Autoimmune Bullous Diseases

2014; Elsevier BV; Volume: 134; Issue: 9 Linguagem: Inglês

10.1038/jid.2014.171

1523-1747

Ralf J. Ludwig, Luca Borradori, Luis A. Díaz, Takashi Hashimoto, Michael Hertl, Saleh Ibrahim, Marcel F. Jonkman, Yasuo Kitajima, Dédée F. Murrell, Enno Schmidt, Hiroshi Shimizu, John R. Stanley, David T. Woodley, Detlef Zillikens,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

The International Pre IID 2013 Satellite Meeting on Autoimmune Bullous Diseases (AIBDs) was held in Lübeck, Germany, from 6th to 7th May 2013, preceding the International Investigative Dermatology (IID) meeting in Edinburgh, UK. This Satellite Meeting followed the tradition of the IID-associated symposia on AIBDs in Kyoto (1993), Salzburg (1998), and Otsu (2008). In total, 180 international researchers and clinicians attended the meeting. Plenary lectures covered the following topics: (i) epidemiology and genetics of AIBDs; (ii) diagnosis and novel disease entities; (iii) cell biology of desmosomes and disease pathways; (iv) cell biology of hemidesmosomes and disease pathways; and (v) outcome measures and novel treatments. In the exhibit of posters, approximately 60 abstracts were presented. The meeting was flanked by two satellite symposia. Importantly, the meeting provided ample time for interactive discussions, critical analyses of the progress achieved to date, and the identification of questions that still needed to be resolved. Here, two speakers independently indicated a sharp increase in bullous pemphigoid (BP) incidence in various European regions. Moreover, increased mortality rates as well as an association with neurological diseases were noted (Langan et al., 2008Langan S.M. Smeeth L. Hubbard R. et al.Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study.Br Med J. 2008; 337: a180Crossref PubMed Scopus (459) Google Scholar). In addition to this epidemiological research, unraveling the genetic predisposition of AIBDs will aid in future clinical decision making and facilitate personalized medical care. The results of the first genome-wide association study (GWAS) in pemphigus vulgaris patients were presented. The study, which was recently published in this journal, led to the identification of ST-18 as a susceptibility gene in pemphigus vulgaris (Sarig et al., 2012Sarig O. Bercovici S. Zoller L. et al.Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris.J Invest Dermatol. 2012; 132: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). In addition to GWAS, functional and metagenomic genetic studies are expected to provide further insights into AIBD pathogenesis. As an example of a functional study, a strong association was reported between allelic and copy number variations in human Fc gamma receptor genes and an increased susceptibility to AIBD. This study was paralleled by investigations on the impact of these variations on neutrophil function in vitro. As an example of a metagenomic study, data on gene interactions, microbiota, and autoimmune disease susceptibility were presented, which subsequently have also been published (Srinivas et al., 2013Srinivas G. Möller S. Wang J. et al.Genome-wide mapping of gene-microbiota interactions in susceptibility to autoimmune skin blistering.Nat Comm. 2013; 4: 2462Crossref PubMed Scopus (68) Google Scholar). A new terminology for AIBD was discussed focusing on both the target antigen and autoantibody isotype. This classification is based on our growing understanding of the molecular biology of AIBD, including the identification of novel autoantigens (Dainichi et al., 2009Dainichi T. Kurono S. Ohyama B. et al.Anti-laminin gamma-1 pemphigoid.Proc Natl Acad Sci USA. 2009; 106: 2800-2805Crossref PubMed Scopus (131) Google Scholar). In addition, novel methods for serological AIBD diagnosis, such as biochip mosaic-based and bioplex-based techniques, were discussed. Furthermore, the practical importance of differentiating epidermolysis bullosa acquisita (EBA) from other sub-epidermal AIBDs, such as BP, using direct immunofluorescence microscopy of the patient’s skin and determining the fluorescence pattern (e.g., either “n-serrated” or “u-serrated) was demonstrated with audience participation (Terra et al., 2013Terra J.B. Meijer J.M. Jonkman M.F. et al.The n- versus u-serration is a learnable criterion to differentiate pemphigoid from epidermolysis bullosa acquisita in direct immunofluorescence serration pattern analysis.Br J Dermatol. 2013; 169: 100-105Crossref PubMed Scopus (42) Google Scholar). Regarding pemphigus, the characterization of anti-desmoglein antibodies generated by phage display from pemphigus patients was presented. This powerful technique facilitates a detailed analysis of the B-cell immune response, exemplified by following the B-cell response in pemphigus patients over several years. Using this technique, it was demonstrated that autoreactive B-cell clones persist over a long period of time. Furthermore, generation of an autoimmune B-cell response to Dsg 3 relies on somatic mutations in response to an unrelated antigen (Di Zenzo et al., 2012Di Zenzo G. Di Lullo G. Corti D. et al.Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface.J Clin Invest. 2012; 122: 3781-3790Crossref PubMed Scopus (128) Google Scholar). Interestingly, various Dsg 3-specific T cells not only contribute to the generation of an anti-Dsg 3 IgG response but also directly cause interface dermatitis in vivo (Takahashi et al., 2011Takahashi H. Kouno M. Nagao K. et al.Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice.J Clin Invest. 2011; 121: 3677-3688Crossref PubMed Scopus (66) Google Scholar). In addition, an environmental, non-infectious agent (sand fly salivary antigen) may drive the generation of autoimmunity in pemphigus in endemic pemphigus foliaceus (Qian et al., 2012Qian Y. Jeong J.S. Maldonado M. et al.Cutting edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen.J Immunol. 2012; 189: 1535-1539Crossref PubMed Scopus (69) Google Scholar). Evidence for the pathogenicity of non-desmoglein-specific autoantibodies (e.g., autoantibodies directed against desmocollin 3) in pemphigus was summarized and discussed in detail (Rafei et al., 2011Rafei D. Muller R. Ishii N. et al.IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion.Am J Pathol. 2011; 178: 718-723Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar; Kalantari-Dehaghi et al., 2013Kalantari-Dehaghi M. Anhalt G.J. Camilleri M.J. et al.Pemphigus vulgaris autoantibody profiling by proteomic technique.PLoS ONE. 2013; 8: e57587Crossref PubMed Scopus (77) Google Scholar). This session also focused on the involvement of signaling molecules in the pathogenesis of pemphigus vulgaris (e.g., the Dsg3-p38MAPK adhesion receptor complex, which has been identified as a potential drug target in the treatment of pemphigus; Spindler et al., 2013Spindler V. Rotzer V. Dehner C. et al.Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering.J Clin Invest. 2013; 123: 800-811PubMed Google Scholar). In addition, the role of apoptosis in pemphigus was widely discussed: on one hand, the evidence for Fas ligand involvement in the pathogenesis of blister formation in pemphigus was provided. On the other hand, data from skin biopsies from pemphigus patients do not support apoptotic involvement. Furthermore, in contrast with Dsg 3 antibodies, Dsg 1 antibodies were shown to induce widening between keratinocytes by diminishing desmosome size and number and altering plakoglobin distribution. These observations support the desmoglein non-assembly depletion hypothesis as a dominant mechanism for acantholysis in pemphigus foliaceus (Oktarina et al., 2011Oktarina D.A. van der Wier G. Diercks G.F. et al.IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis.Br J Dermatol. 2011; 165: 552-562Crossref PubMed Scopus (54) Google Scholar). The actin-binding protein adducin may also control blistering in pemphigus as it was reported to regulate Dsg 3 protein expression. The mechanisms involved in blister formation in pemphigoid disease were a focus of this session. Novel data from the BP neonatal mouse model (Liu et al., 1993Liu Z. Diaz L.A. Troy J.L. et al.A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.J Clin Invest. 1993; 92: 2480-2488Crossref PubMed Scopus (543) Google Scholar) indicate that blister induction completely depends on IL-1 signaling, particularly IL-1β and inflammasome activation. In dermatitis herpetiformis, epidermal transglutaminase (TG3) diffuses from human epidermis into the upper dermis. The subsequent binding of anti-TG3 IgA initiates the blistering cascade in dermatitis herpetiformis. Furthermore, the pathogenic relevance of anti-IgE antibodies and cleavage site–specific antibodies in BP were discussed. Convincing evidence was presented for the contribution of anti-BP180 IgE in the pathogenesis of BP, which is mediated by Fc-receptor-independent effects (Messingham et al., 2011Messingham K.N. Srikantha R. Degueme A.M. et al.FcR-independent effects of IgE and IgG autoantibodies in bullous pemphigoid.J Immunol. 2011; 187: 553-560Crossref PubMed Scopus (64) Google Scholar) and the regulation of eosinophil functions. In contrast, the pathogenic relevance of cleavage site–specific autoantibodies, as studied in the COL17-humanized mouse model of BP (Nishie et al., 2007Nishie W. Sawamura D. Goto M. et al.Humanization of autoantigen.Nat Med. 2007; 13: 378-383Crossref PubMed Scopus (240) Google Scholar), needs to be further evaluated. In addition to targeting blister-inducing mechanisms in pemphigoid, the pathways involved in blister resolution, such as Flightless I, may also be used as novel treatments (Kopecki et al., 2013Kopecki Z. Ruzehaji N. Turner C. et al.Topically applied flightless I neutralizing antibodies improve healing of blistered skin in a murine model of epidermolysis bullosa acquisita.J Invest Dermatol. 2013; 133: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). After a review of the molecular organization within hemidesmosomes, the biology of type VII collagen (COL7) and its potential use as protein-based treatment in recessive dystrophic epidermolysis bullosa (RDEB) was discussed given that recombinant COL7 forms new anchoring fibrils in RDEB patients after intravenous injection (Wang et al., 2013Wang X. Ghasri P. Amir M. et al.Topical application of recombinant type VII collagen incorporates into the dermal-epidermal junction and promotes wound closure.Mol Ther. 2013; 21: 1335-1344Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Novel insights into the mechanisms leading to loss of tolerance in EBA were also presented: epidemiologic observations, HLA genotyping of EBA patients, and data from mouse models of this disease provide strong evidence for a genetic contribution. In addition, experimental data indicate that specific T-cell subsets and cytokines are involved in the initiation of the autoimmune response (Ludwig et al., 2013Ludwig R.J. Kalies K. Köhl J. et al.Emerging treatments for pemphigoid diseases.Trends Mol Med. 2013; 19: 501-512Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In this final session, the attendees discussed the importance of outcome measures for AIBDs (Daniel et al., 2012Daniel B.S. Hertl M. Werth V.P. et al.Severity score indexes for blistering diseases.Clin Dermatol. 2012; 30: 108-113Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar) to determine disease activity, thereby offering the possibility of comparing therapeutic outcomes among AIBD studies. In an extension of a previous study on the clinical and molecular effects of rituximab treatment in pemphigus vulgaris (Colliou et al., 2013Colliou N. Picard D. Caillot F. et al.Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response.Sci Transl Med. 2013; 5: 175ra30Crossref PubMed Scopus (172) Google Scholar), initial data were presented from a randomized controlled study comparing rituximab and corticosteroids to corticosteroids alone in pemphigus vulgaris patients. Use of veltuzumab, a humanized anti-CD20 mAb, was discussed as an alternative treatment option in rituximab-refractory pemphigus. The evidence of immunoapheresis in bullous diseases was summarized (Schmidt and Zillikens, 2013Schmidt E. Zillikens D. Pemphigoid diseases.Lancet. 2013; 381: 320-332Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar), and the outline of an ongoing prospective controlled multicenter trial of immunoapheresis in pemphigus patients was discussed. The final results from this study are expected by the end of 2015. Several hours were exclusively reserved for discussions of the posters (n=58). Poster prizes were awarded to Volker Spindler (Munich) for the work entitled ‘‘Peptide-mediated prevention of pemphigus skin blistering in mice’’ and to Yvonne Exner (Marburg) for her work entitled ‘‘IgG autoantibodies against carboxy-terminal epitopes of desmoglein 3 are pathogenic in vitro’’. On 6th May, over 30 conference participants met to discuss the future direction of AIBD genetic studies. The participants agreed that relatively small patient numbers and ethnic differences are the major challenges for AIBD genetic studies. To overcome these challenges, joint efforts have been made to bring together all existing and recruiting cohorts. This effort can be achieved within the framework of the International Autoimmune Blistering Diseases Genetics Consortium. Following the first GWAS in pemphigus vulgaris patients (Sarig et al., 2012Sarig O. Bercovici S. Zoller L. et al.Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris.J Invest Dermatol. 2012; 132: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), the participants expect results from additional GWAS in BP, mucous membrane pemphigoid, and pemphigus within the next 2–3 years. The participants also agreed that novel technologies, such as next-generation sequencing, will be the driving force behind the progress in this field in the next years. Collectively, the identification of susceptibility genes will aid in the development of novel compounds targeting the respective pathways. On 7th May, 35 registrants joined this 4th and final meeting in a series of international EBA consensus meetings cochaired by Dedee Murrell (Australia) and Victoria Werth (USA). Previous meetings were held at the AAD, SID, and EADV over the preceding 2 years. Definitions agreed upon at the previous meetings and the EBA disease area index (EBADAI) were reviewed and discussed. One challenge in the development of a disease extent tool for both EBA and mucous membrane pemphigoid is scoring ocular involvement. For practical reasons, it would be easier if dermatologists could score ocular involvement themselves. However, a simple scoring sheet could ideally be used by ophthalmologists to ensure accuracy. Two scoring systems for ocular involvement were presented and widely discussed (Munyangango et al., 2013Munyangango E.M. Le Roux-Villet C. Doan S. et al.Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid.Br J Dermatol. 2013; 168: 381-390Crossref PubMed Scopus (38) Google Scholar). We thank Melanie Prinz, Bianca Engel, and Stephanie Latif for secretarial assistance. We also thank the Deutsche Forschungsgemeinschaft (DFG ZI 439/10-1) for supporting this meeting.