Publications by authors named "Rüdiger Eming"

81 Publications

Autoreactive Peripheral Blood T Helper Cell Responses in Bullous Pemphigoid and Elderly Patients With Pruritic Disorders.

Front Immunol 2021 25;12:569287. Epub 2021 Mar 25.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated with recombinant BP180 proteins (NH- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.
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http://dx.doi.org/10.3389/fimmu.2021.569287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027500PMC
March 2021

Pemphigus: a critical review on clinical subtypes, pathogenesis, diagnostics and established and novel therapeutics.

G Ital Dermatol Venereol 2020 Dec 14. Epub 2020 Dec 14.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

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http://dx.doi.org/10.23736/S0392-0488.20.06790-5DOI Listing
December 2020

Immunophenotyping in pemphigus reveals a T17/T17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

J Allergy Clin Immunol 2020 Nov 20. Epub 2020 Nov 20.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Background: T2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear.

Objective: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus.

Methods: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of T cell and folliclular helper (T) cell subsets was analyzed by flow cytometry. Finally, the capacity of T and T cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments.

Results: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17 T17, T17, and T17.1 cells. Notably, levels of T17 and T17 cells correlated with levels of Dsg-specific CD19CD27 memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T17 cells. Coculture experiments revealed T17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.

Conclusion: Our findings show that T17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2020.11.008DOI Listing
November 2020

Alternative splicing of the TNFSF13B (BAFF) pre-mRNA and expression of the BAFFX1 isoform in human immune cells.

Gene 2020 Nov 4;760:145021. Epub 2020 Aug 4.

Department of Neurology, Philipps-University Marburg, Marburg, Germany; F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address:

Human B cell activating factor (TNFSF13B, BAFF) is a tumor necrosis factor superfamily member. Binding its unique receptor (TNFRSF13C, BAFF-R) mediates gene expression and cell survival in B cells via activation of NFκB pathway. Furthermore, there is data indicating a role in T cell function. A functionally inhibitory isoform (ΔBAFF) resulting from the deletion of exon 3 in the TNFSF13B pre-RNA has already been reported. However, data on the complexity of post-transcriptional regulation is scarce. Here, we report molecular cloning of nine TNFSF13B transcript variants resulting from alternative splicing of the TNFSF13B pre-mRNA including BAFFX1. This variant is characterized by a partial retention of intron 3 of the TNFSF13B gene causing the appearance of a premature stop codon. We demonstrate the expression of the corresponding BAFFX1 protein in Jurkat T cells, in ex vivo human immune cells and in human tonsillar tissue. Thereby we contribute to the understanding of TNFSF13B gene regulation and reveal that BAFF is regulated through a post-transcriptional mechanism to a greater extent than reported to date.
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http://dx.doi.org/10.1016/j.gene.2020.145021DOI Listing
November 2020

Amyopathic and anti-TIF1 gamma-positive dermatomyositis: analysis of a monocentric cohort and proposal to update diagnostic criteria.

Eur J Dermatol 2020 Jun;30(3):279-288

Department of Dermatology and Allergology.

Dermatomyositis (DM) is a group of autoimmune diseases characterized by a variable degree of skin symptoms and myopathy. An amyopathic form of DM (ADM) has been described, and more recently, an anti-TIF-1 gamma-positive subtype, characterized by poikiloderma and associated with a relatively high risk of cancer. To characterise a cohort of DM patients. A cohort of 29 DM patients was followed between January 2004 and March 2019, and investigated for clinical characteristics, pathological features based on electromyography and MRI, laboratory data, and auto-antibody profile. Based on the investigations, DM was shown to be heterogeneous. However, we identified a subgroup of anti-TIF-1 gamma-positive patients who all shared heliotrope erythema. Furthermore, we observed a positive correlation between serum glutamicoxaloacetic transaminase (GOT) and creatine kinase (CK) concentrations in patients with anti-TIF-1 gamma antibodies, which is not found in patients with anti-MDA-5 antibodies. Based on the findings of this study, we propose an update of the Sontheimer et al. diagnostic criteria to improve the sensitivity of diagnosis for ADM. In addition, we describe a significant association between serum GOT and CK levels in DM patients with anti-TIF-1 gamma antibodies, and further highlight the significance of heliotrope rash as a clinical hallmark for this particular subset of patients.
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http://dx.doi.org/10.1684/ejd.2020.3766DOI Listing
June 2020

The polymorphous spectrum of dermatomyositis: classic features, newly described skin lesions, and rare variants.

Eur J Dermatol 2020 Jun;30(3):229-242

Department of Dermatology and Allergology, Philipps-University, Marburg, Germany.

Dermatomyositis belongs to a group of rare autoimmune diseases characterized by a variable degree of skin symptoms and myopathy. The clinically diagnostic hallmarks of dermatomyositis are heliotrope rash, Gottron's papules and weakness of the proximal muscles. Along with pathognomonic, characteristic, and compatible cutaneous features, several uncommon and rare skin manifestations have been reported. In addition, new skin lesions have been described in dermatomyositis patients. Furthermore, rare clinical subtypes of dermatomyositis have been reported in the literature, including Wong-type dermatomyositis, characterised by the coexistence of dermatomyositis and pityriasis rubra pilaris with hyperkeratotic, erythematous, follicular confluent papules on the back of the hands along the bony prominences. In addition, plenty of autoantibody subsets have been recently described that are related to distinct clinical features and systemic involvement, such as anti-MDA5 autoantibodies. We reviewed the English- and German-language scientific literature using the key words "dermatomyositis", "autoantibodies", and "clinical features", alone or in combination, focusing on particular cutaneous symptoms and their association with defined autoantibody profiles. Furthermore, we focused on rare subtypes of dermatomyositis, unusual clinical features, and recently described skin lesions.
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http://dx.doi.org/10.1684/ejd.2020.3761DOI Listing
June 2020

[European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology].

Hautarzt 2020 Jul;71(7):542-552

Hautklinik, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Deutschland.

Background And Objectives: Treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe cases, the use of immunoglobulin is not generally based on data from randomized controlled trials usually required for evidence-based medicine. Since the indications for the use of IVIg are rare, it is unlikely that such studies will be available in the foreseeable future. Because first-line use is limited by the high costs of IVIg, the first clinical guidelines on the use of IVIg in dermatological conditions were established in 2008 and renewed in 2011.

Methods: The European guidelines presented here were prepared by a panel of experts nominated by the European Dermatology Forum (EDF) and European Academy of Dermatology and Venereology (EADV). The guidelines were developed to update the indications for treatment currently considered effective and to summarize the evidence for the use of IVIg in dermatological autoimmune diseases and TEN.

Results And Conclusion: The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.
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http://dx.doi.org/10.1007/s00105-020-04610-6DOI Listing
July 2020

Eine Reisedermatose mit Spätfolgen: marine Kontaktdermatitis durch Korallen mit verzögerter lichenoider Reaktion.

J Dtsch Dermatol Ges 2020 May;18(5):495-497

Klinik für Dermatologie und Allergologie, Universitätsklinikum Gießen und Marburg, Philipps Universität Marburg, Marburg.

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http://dx.doi.org/10.1111/ddg.14086_gDOI Listing
May 2020

S2k-Leitlinie zur Therapie des Pemphigus vulgaris/foliaceus und des bullösen Pemphigoids: 2019 Update.

J Dtsch Dermatol Ges 2020 May;18(5):516-527

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Dermatologie, Venerologie und Allergologie, Allergie-Centrum, Berlin, Deutschland.

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http://dx.doi.org/10.1111/ddg.14097_gDOI Listing
May 2020

S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update.

J Dtsch Dermatol Ges 2020 May;18(5):516-526

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology, Venereology und Allergy, Allergy Center, Berlin, Germany.

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http://dx.doi.org/10.1111/ddg.14097DOI Listing
May 2020

Travel-associated dermatosis with late sequelae: Coral contact dermatitis presenting with a lichenoid reaction.

J Dtsch Dermatol Ges 2020 May 20;18(5):493-495. Epub 2020 Apr 20.

Department of Dermatology and Allergology, University Medical Center of Giessen and Marburg, Philipps University, Marburg, Germany.

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http://dx.doi.org/10.1111/ddg.14086DOI Listing
May 2020

Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis.

Int J Mol Sci 2020 Mar 21;21(6). Epub 2020 Mar 21.

Molecular and Cell Biology Laboratory, IDI-IRCCS, 00167 Rome, Italy.

Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of cancer. In this review, we described several paraneoplastic dermatoses and discussed extensively two paradigmatic ones, namely paraneoplastic pemphigus and paraneoplastic dermatomyositis.
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http://dx.doi.org/10.3390/ijms21062178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139382PMC
March 2020

Photodynamic therapy in oral lichen planus: A prospective case-controlled pilot study.

Sci Rep 2020 02 3;10(1):1667. Epub 2020 Feb 3.

Department of Periodontology, Philipps-University Marburg, Marburg, Germany.

Oral lichen planus (OLP) is a common, chronic relapsing inflammatory disorder of the mucous membranes, which causes major discomfort. Current treatment includes topical/systemic glucocorticoids, immune modulators and systemic immunosuppressants, which may lead to considerable side-effects. The aim of this study was to determine the clinical and immunological efficacy of photodynamic therapy (PDT) in OLP as an alternative, easy-to-use, safe and non-invasive treatment. Twenty patients with OLP were treated with PDT in a prospective case-controlled pilot-study. PDT was performed on the most extensive oral lesion in 4 sessions (day 1, 3, 7, 14). Peripheral blood and lesional T cells were analysed before (day 1) and after PDT treatment (day 28). PDT led to a statistically significant reduction of clinical parameters (lesion size, ABSIS, Thongprasom-score) and improvement of all evaluated quality-of-life (QOL) items. The clinical improvement was accompanied by a significant decrease of the relative number of CD4+ and CD8+ T cells in mucosal OLP-lesions. Furthermore, CXCL10 plasma levels were decreased and the number of activated peripheral CD4 + CD137+ and CD8 + CD137+ T cells and IL-17-secreting T cells was diminished. PDT treatment in OLP leads to lesion reduction and improvement of QOL, and induces local and systemic anti-inflammatory effects. The study identifies PDT as a novel therapeutic option in OLP.
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http://dx.doi.org/10.1038/s41598-020-58548-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997407PMC
February 2020

Polymorphisms in the Mitochondrial Genome Are Associated With Bullous Pemphigoid in Germans.

Front Immunol 2019 22;10:2200. Epub 2019 Nov 22.

Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany.

Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients ( = 180) and age- and sex-matched healthy controls ( = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP ( = 89) and control cohort ( = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data ( = 0.0017, = 0.0129, = 0.0076, and = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.
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http://dx.doi.org/10.3389/fimmu.2019.02200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883920PMC
October 2020

Therapeutic Targeting of Th17/Tc17 Cells Leads to Clinical Improvement of Lichen Planus.

Front Immunol 2019 31;10:1808. Epub 2019 Jul 31.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Lichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17 T cells leads to clinical improvement of mucosal and cutaneous LP lesions. A total of five patients with lichen planus were treated in a compassionate use trial with either secukinumab (anti-IL-17; 3 patients with acute and chronic recalcitrant muco-cutaneous LP), ustekinumab (anti-IL-12/IL-23; 1 patient with recalcitrant oral LP) or guselkumab (anti-IL-23; 1 patient with recalcitrant oral LP). The clinical course of the patients was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) reflecting both extent and severity of disease and functional sequelae of oral involvement for at least 12 weeks. The inflammatory infiltrate in lesional and post-lesional skin was analyzed by immunohistochemistry before and after treatment. Furthermore, the cytokine profile of peripheral blood T cells from the treated patients was assessed by flow cytometry and/or ELISpot assay. Treatment with secukinumab induced rapid and prolonged clinical amelioration of muco-cutaneous LP. Clinical improvement was accompanied by a strong reduction of the Th1 and Th17/Tc17 cellular mucosal and cutaneous infiltrate. Moreover, long-term treatment of one patient with recalcitrant oral LP with ustekinumab led to healing of the ulcerative oral lesions and a reduction of peripheral blood and lesional IL-17 T cells. Finally, treatment with guselkumab led to a marked clinical improvement in a patient with recalcitrant erosive oral LP. These findings show for the first time that therapeutic targeting of Th17/Tc17 cells leads to a pronounced clinical amelioration of mucosal and cutaneous LP and strongly suggests that IL-17-producing T cells are central to disease pathogenesis. Thus, therapeutic targeting of Th17/Tc17 cells opens new therapeutic avenues in the treatment of recalcitrant LP.
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http://dx.doi.org/10.3389/fimmu.2019.01808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685396PMC
September 2020

Pemphigus: Current and Future Therapeutic Strategies.

Front Immunol 2019 25;10:1418. Epub 2019 Jun 25.

Department of Dermatology and Allergology, Philipps University, Marburg, Germany.

Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.
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http://dx.doi.org/10.3389/fimmu.2019.01418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603181PMC
October 2020

Thymoma-Associated Paraneoplastic Autoimmune Multiorgan Syndrome-From Pemphigus to Lichenoid Dermatitis.

Front Immunol 2019 21;10:1413. Epub 2019 Jun 21.

Department of Dermatology and Allergology, Philipps-University, Marburg, Germany.

Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens. We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders. Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma. In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.
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http://dx.doi.org/10.3389/fimmu.2019.01413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598597PMC
October 2020

Identification of Autoreactive B Cell Subpopulations in Peripheral Blood of Autoimmune Patients With Pemphigus Vulgaris.

Front Immunol 2019 14;10:1375. Epub 2019 Jun 14.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Pemphigus vulgaris (PV) is a rare blistering disease caused by IgG autoantibodies against the epidermal adhesion molecules desmoglein (Dsg)3 and Dsg1 providing a well-characterized paradigm of an antibody-mediated organ-specific autoimmune disease. In PV patients who have achieved clinical remission after B cell-depleting therapy, relapses often coincide with a reoccurrence of B cells and Dsg-specific autoantibodies. Here, we analyzed Dsg3-specific B cell subpopulations (i.e., total CD19 B cells, CD19CD27B cells, CD19CD27 memory B cells, and CD19CD27CD38 plasmablasts) in peripheral blood of both PV patients ( = 14) at different stages of disease and healthy individuals ( = 14) by flow cytometry using fluorescently labeled recombinant human Dsg3 protein. Applying this approach, Dsg3-specific B cells could be detected at low frequencies (0.11-0.53% of CD19 B cells) and numbers of Dsg3-specific memory B cells were significantly increased in PV patients in clinical remission receiving minimal immunosuppressive therapy. Finally, we confirmed that Dsg3-reactive memory B cells were able to produce anti-Dsg3 IgG autoantibodies upon activation. Thus, monitoring of Dsg3-specific B cells in PV is of particular interest to further characterize the immunopathogenesis of PV.
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http://dx.doi.org/10.3389/fimmu.2019.01375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587433PMC
November 2020

Immortalized Human hTert/KER-CT Keratinocytes a Model System for Research on Desmosomal Adhesion and Pathogenesis of Pemphigus Vulgaris.

Int J Mol Sci 2019 Jun 26;20(13). Epub 2019 Jun 26.

Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.

Pemphigus Vulgaris is an autoimmune disease that results in blister formation in the epidermis and in mucosal tissues due to antibodies recognizing desmosomal cadherins, mainly desmoglein-3 and -1. Studies on the molecular mechanisms of Pemphigus have mainly been carried out using the spontaneously immortalized human keratinocyte cell line HaCaT or in primary keratinocytes. However, both cell systems have suboptimal features, with HaCaT cells exhibiting a large number of chromosomal aberrations and mutated p53 tumor suppressor, whereas primary keratinocytes are short-lived, heterogeneous and not susceptible to genetic modifications due to their restricted life-span. We have here tested the suitability of the commercially available human keratinocyte cell line hTert/KER-CT as a model system for research on epidermal cell adhesion and Pemphigus pathomechanisms. We here show that hTert cells exhibit a calcium dependent expression of desmosomal cadherins and are well suitable for typical assays used for studies on Pemphigus, such as sequential detergent extraction and Dispase-based dissociation assay. Treatment with Pemphigus auto-antibodies results in loss of monolayer integrity and altered localization of desmoglein-3, as well as loss of colocalization with flotillin-2. Our findings demonstrate that hTert cells are well suitable for studies on epidermal cell adhesion and Pemphigus pathomechanisms.
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http://dx.doi.org/10.3390/ijms20133113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651391PMC
June 2019

Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion.

Front Immunol 2019 24;10:1128. Epub 2019 May 24.

Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.

Pemphigus is an autoimmune dermatosis in which mucocutaneous blisters are induced primarily by autoantibodies against Desmoglein (Dsg) 1 and 3. Pemphigus vulgaris (PV) usually is associated with autoantibodies against Dsg3 whereas pemphigus foliaceus (PF) patients present autoantibodies against Dsg1. Several signaling pathways were proposed to cause loss of keratinocyte adhesion. However, relevance of different signaling pathways and role of Dsg1 and 3 to trigger signaling are not fully understood. Here, we show that Ca chelation reduced PV-IgG- and PF-IgG-mediated loss of HaCaT keratinocyte cohesion whereas EGFR inhibition did not inhibit effects of PF-IgG. PV-IgG activated EGFR in a Src-dependent manner whereas both PV-IgG and PF-IgG caused Ca influx independent of EGFR. ERK activation was Src-dependent in response to PV-IgG but not PF-IgG. To delineate the roles of Dsg isoforms to trigger signaling pathways, Dsg3- and Dsg2-deficient HaCaT keratinocyte cell lines were generated using CRISPR/Cas9. Dsg3- but not Dsg2-deficient cells were protected against PV-IgG-induced loss of cell adhesion. Ca influx and ERK activation in response to PF-IgG were preserved in both cell lines.
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http://dx.doi.org/10.3389/fimmu.2019.01128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543754PMC
September 2020

Role of Src and Cortactin in Pemphigus Skin Blistering.

Front Immunol 2019 4;10:626. Epub 2019 Apr 4.

Chair of Vegetative Anatomy, Institute of Anatomy, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.

Autoantibodies against desmoglein (Dsg) 1 and Dsg3 primarily cause blister formation in the autoimmune disease pemphigus vulgaris (PV). Src was proposed to contribute to loss of keratinocyte cohesion. However, the role and underlying mechanisms are unclear and were studied here. In keratinocytes, cell cohesion in response to autoantibodies was reduced in Src-dependent manner by two patient-derived PV-IgG fractions as well as by AK23 but not by a third PV-IgG fraction, although Src was activated by all autoantibodies. Loss of cell cohesion was progredient in a timeframe of 24 h and AK23, similar to PV-IgG, interfered with reconstitution of cell cohesion after Ca-switch, indicating that the autoantibodies also interfered with desmosome assembly. Dsg3 co-localized along cell contacts and interacted with the Src substrate cortactin. In keratinocytes isolated from cortactin-deficient mice, cell adhesion was impaired and Src-mediated inhibition of AK23-induced loss of cell cohesion for 24 h was significantly reduced compared to wild-type (wt) cells. Similarly, AK23 impaired reconstitution of cell adhesion was Src-dependent only in the presence of cortactin. Likewise, Src inhibition significantly reduced AK23-induced skin blistering in wt but not cortactin-deficient mice. These data suggest that the Src-mediated long-term effects of AK23 on loss of cell cohesion and skin blistering are dependent on cortactin-mediated desmosome assembly. However, in human epidermis PV-IgG-induced skin blistering and ultrastructural alterations of desmosomes were not affected by Src inhibition, indicating that Src may not be critical for skin blistering in intact human skin, at least when high levels of autoantibodies targeting Dsg1 are present.
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http://dx.doi.org/10.3389/fimmu.2019.00626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461052PMC
September 2020

[Autoimmune bullous dermatoses : Update on treatments and rare forms].

Hautarzt 2019 Apr;70(4):234-235

Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Fachbereich Medizin, Philipps-Universität Marburg, Baldingerstr., 35043, Marburg, Deutschland.

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http://dx.doi.org/10.1007/s00105-019-4391-yDOI Listing
April 2019

Perspective From the 5th International Pemphigus and Pemphigoid Foundation Scientific Conference.

Front Med (Lausanne) 2018 8;5:306. Epub 2018 Nov 8.

Department of Dermatology, University of Pennsylvania, Philadelphia, PA, United States.

The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), "Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science" was held in Orlando, Florida, on May 15-16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials.
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http://dx.doi.org/10.3389/fmed.2018.00306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236000PMC
November 2018

Bullöse Autoimmundermatosen.

J Dtsch Dermatol Ges 2018 Nov;16(11):1339-1360

Klinik für Dermatologie und Allergologie, Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg.

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http://dx.doi.org/10.1111/ddg.13688_gDOI Listing
November 2018

Bullous autoimmune dermatoses.

J Dtsch Dermatol Ges 2018 Nov;16(11):1339-1358

Department of Dermatology and Allergology, Marburg University Medical Center, Marburg, Germany.

Pathophysiologically, bullous autoimmune dermatoses are caused by autoantibodies directed against adhesion molecules or structural proteins of the skin and mucous membranes, clinically resulting in blister formation. Depending on the respective target proteins of the autoimmune response and their location in the skin, a distinction is made between intraepidermal (pemphigus disorders), junctional (pemphigoid disorders), and subepidermal (epidermolysis bullosa acquisita, dermatitis herpetiformis) autoimmune blistering diseases. The most common bullous autoimmune dermatosis, bullous pemphigoid is characterized by marked clinical variability and intense pruritus. Predominantly affecting elderly individuals, there has been a significant increase in its incidence in recent years. While mucosal lesions occur in less than 30 % of bullous pemphigoid patients, the second most common bullous autoimmune dermatosis, pemphigus vulgaris, typically presents with oral erosions as the predominant and - frequently - initial symptom. Its onset is usually in the 4 to 6 decade of life. Scarring is typically found in subepidermal blistering disorders such as epidermolysis bullosa acquisita or mucous membrane pemphigoid. Diagnosis is based on clinical and histological findings as well as direct and indirect immunofluorescence and detection of circulating autoantibodies. Although a number of controlled clinical trials have been conducted in recent years, treatment of bullous autoimmune disorders is still primarily based on clinical experience. Therapeutic options include topical and systemic corticosteroids as well as adjuvant immunosuppressants. Recalcitrant cases may require treatment with immunoadsorption, intravenous immunoglobulins, or the monoclonal anti-CD20 antibody rituximab.
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http://dx.doi.org/10.1111/ddg.13688DOI Listing
November 2018

Adjuvant high-dose intravenous immunoglobulins for recalcitrant erosive oral lichen planus: mixed clinical responses.

Eur J Dermatol 2018 Aug;28(4):496-501

Department of Dermatology and Allergology, Philipps University Marburg, Germany.

Background: Erosive oral lichen planus (OLP) is, at times, extremely difficult to treat and has a major impact on patients' quality of life. There are only limited therapeutic options, such as topical and systemic glucocorticoids, retinoids, and immunosuppressants with considerable side effects and limited efficacy upon chronic use.

Objectives: In the present individualised clinical trial, we assessed the efficacy of adjuvant intravenous immunoglobulins (IVIG; 2 g/kg/monthly cycle) in addition to the oral retinoid, acitretin, in three patients with refractory OLP over a period of two to six months.

Materials & Methods: The efficacy of adjuvant IVIG treatment was evaluated using the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) which measures both extent of mucosal lesions and functional sequelae.

Results: The three OLP patients showed mixed responses to adjuvant IVIG treatment, ranging from therapeutic efficacy to a lack of response to IVIG.

Conclusions: In light of the observed therapeutic responses and a lack of good therapeutic options, adjuvant IVIG, although costly, warrants further investigation as a treatment option for OLP.
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http://dx.doi.org/10.1684/ejd.2018.3370DOI Listing
August 2018

Targeted Therapies for Autoimmune Bullous Diseases: Current Status.

Drugs 2018 Oct;78(15):1527-1548

Department of Dermatology, Philipps University, Baldingerstr., 35043, Marburg, Germany.

Autoimmune bullous skin disorders are rare but meaningful chronic inflammatory diseases, many of which had a poor or devastating prognosis prior to the advent of immunosuppressive drugs such as systemic corticosteroids, which down-regulate the immune pathogenesis in these disorders. Glucocorticoids and adjuvant immunosuppressive drugs have been of major benefit for the fast control of most of these disorders, but their long-term use is limited by major side effects such as blood cytopenia, osteoporosis, diabetes mellitus, hypertension, and gastrointestinal ulcers. In recent years, major efforts were made to identify key elements in the pathogenesis of autoimmune bullous disorders, leading to the identification of their autoantigens, which are mainly located in desmosomes (pemphigus) and the basement membrane zone (pemphigoids). In the majority of cases, immunoglobulin G, and to a lesser extent, immunoglobulin A autoantibodies directed against distinct cutaneous adhesion molecules are directly responsible for the loss of cell-cell and cell-basement membrane adhesion, which is clinically related to the formation of blisters and/or erosions of the skin and mucous membranes. We describe and discuss novel therapeutic strategies that directly interfere with the production and regulation of pathogenic autoantibodies (rituximab), their catabolism (intravenous immunoglobulins), and their presence in the circulation and extravascular tissues such as the skin (immunoadsorption), leading to a significant amelioration of disease. Moreover, we show that these novel therapies have pleiotropic effects on various proinflammatory cells and cytokines. Recent studies in bullous pemphigoid suggest that targeting of immunoglobulin E autoantibodies (omalizumab) may be also beneficial. In summary, the introduction of targeted therapies in pemphigus and pemphigoid holds major promise because of the high efficacy and fewer side effects compared with conventional global immunosuppressive therapy.
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http://dx.doi.org/10.1007/s40265-018-0976-5DOI Listing
October 2018

The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts.

Front Immunol 2018 2;9:1788. Epub 2018 Aug 2.

Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany.

IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.
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http://dx.doi.org/10.3389/fimmu.2018.01788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082936PMC
October 2019

45th meeting of the Arbeitsgemeinschaft Dermatologische Forschung.

Exp Dermatol 2018 07;27(7):798-802

Department of Dermatology, Laboratory of Experimental Dermatology, University of Magdeburg, Magdeburg, Germany.

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http://dx.doi.org/10.1111/exd.13695DOI Listing
July 2018