Human Desmocollin 3‒Specific IgG Antibodies Are Pathogenic in a Humanized HLA Class II Transgenic Mouse Model of Pemphigus

Hudemann, Christoph; Maglie, Roberto; Prada, Maria Llamazares; Beckert, Benedikt; Didona, Dario; Tikkanen, Ritva; Schmitt, Thomas; Hashimoto, Takashi; Waschke, Jens; Hertl, Michael; Eming, Rüdiger

doi:10.1016/j.jid.2021.06.017

Cited by 16 publications

(15 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Schematic was created with BioRender.Com et al, 2014;. Dsc3 may also be involved in the activation of EGFR and p38MAPK (Hudemann et al, 2021;Spindler et al, 2009).…”

Section: De S Mosome S a S S I G Nalling H Ubsmentioning

confidence: 99%

“…On the other hand, Dsg2 was found not to regulate p38MAPK but rather to act as a compensation molecule for adhesion and thus is expressed in pemphigus lesions when Dsg3 adhesion is impaired (Hartlieb et al, 2013; Hartlieb et al, 2014; Sigmund et al, 2020). Dsc3 may also be involved in the activation of EGFR and p38MAPK (Hudemann et al, 2021; Spindler et al, 2009).…”

Section: Desmosomes As Signalling Hubsmentioning

confidence: 99%

See 1 more Smart Citation

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Yeruva

Waschke

2022

Journal of Anatomy

Self Cite

View full text Add to dashboard Cite

For electromechanical coupling of cardiomyocytes, intercalated discs (ICDs) are pivotal as highly specialized intercellular contact areas. ICD consists of adhesive contacts, such as desmosomes and adherens junctions (AJs) that are partially intermingled and thereby form an area composita to provide mechanical strength, as well as gap junctions (GJ) and sodium channels for excitation propagation. In contrast, in epithelia, mixed junctions with features of desmosomes and AJs are regarded as transitory primarily during the formation of desmosomes. The anatomy of desmosomes is defined by a typical ultrastructure with dense intracellular plaques anchoring the cadherin‐type adhesion molecules to the intermediate filament cytoskeleton. Desmosomal diseases characterized by impaired adhesive and signalling functions of desmosomal contacts lead to arrhythmogenic cardiomyopathy when affecting cardiomyocytes and cause pemphigus when manifesting in keratinocytes or present as cardiocutaneous syndromes when both cell types are targeted by the disease, which underscores the high biomedical relevance of these cell contacts. Therefore, comparative analyses regarding the structure and regulation of desmosomal contacts in cardiomyocytes and epithelial cells are helpful to better understand disease pathogenesis. In this brief review, we describe the structural properties of ICD compared to epithelial desmosomes and suggest that mechanisms regulating adhesion may at least in part be comparable. Also, we discuss whether phenomena such as hyperadhesion or the bidirectional regulation of desmosomes to serve as signalling hubs in epithelial cells may also be relevant for ICD.

show abstract

“…Schematic was created with BioRender.Com et al, 2014;. Dsc3 may also be involved in the activation of EGFR and p38MAPK (Hudemann et al, 2021;Spindler et al, 2009).…”

Section: De S Mosome S a S S I G Nalling H Ubsmentioning

confidence: 99%

Section: Desmosomes As Signalling Hubsmentioning

confidence: 99%

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Yeruva

Waschke

2022

Journal of Anatomy

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the IFN-γ- and TNF-α-stimulated group, the expression of 3278 genes (976 up-regulated and 1547 down-regulated) was changed; in the IFN-γ- and TNF-α-stimulated HaCaT cells of the PAB co-treatment group, the expression of 1298 genes (250 up-regulated and 293 down-regulated) was changed. Especially, the expression of inflammation-related genes such as TNFRSF9, CCL8, ICAM1, IL36G, APOL3, APOL2 [ 26 ], CXCL9 [ 27 ], and HLA-DRB1 [ 28 ] were down-regulated by PAB.…”

Section: Discussionmentioning

confidence: 99%

Polyopes affinis Suppressed IFN-γ- and TNF-α-Induced Inflammation in Human Keratinocytes via Down-Regulation of the NF-κB and STAT1 Pathways

Lee

Kim

et al. 2022

Molecules

View full text Add to dashboard Cite

Polyopes affinis is a red algal species commonly found on the South coast and near Jeju Island, Korea. This study aimed to determine whether P. affinis extracts can inhibit the pathogenesis of T-helper-2 (Th2)-mediated inflammation in a human keratinocyte cell line of atopic dermatitis (AD). Cells were incubated with 10 ng/mL of interferon gamma (IFN-γ) and 10 ng/mL of tumor necrosis factor-alpha (TNF-α) at various concentrations of PAB (10, 30, and 60 µg/mL) and PAA (100, 500, and 1000 µg/mL) extracts. A gene-ontology (GO)-enrichment analysis revealed that PAB significantly enriched the genes associated with biological processes such as cell adhesion, immune response, inflammation, and chemokine-mediated pathways. PAB suppressed the expression of the secretory proteins and mRNAs that are associated with the thymus and the production of activation-regulated chemokines (TARC/CCL17) and macrophage-derived chemokines (MDC/CCL22). The effect of the extract on mitogen-activated protein kinases (MAPKs) was related to its inhibition of TARC/CCL17 and MDC/CCL22 production by blocking NF-κB and STAT1 activation. These results suggest that seaweed extract may improve AD by regulating pro-inflammatory chemokines. In conclusion, we first confirmed the existence of phloroglucinol, a polyphenol formed from a precursor called phlorotannin, which is present in PAB, and this result proved the possibility of PAB being used as a treatment for AD.

show abstract

“…Humanized mice were also generated using Pemphigus-related human class II HLAs, which led to the observation that if mice were humanized with an unrelated human HLA, they did not produce specific antibodies against DSG3 after immunization. Thus, it is possible to state that recognition of DSG3 protein epitopes by CD4+ cells is related to the HLA haplotype [35,36]. In vitro assays, such as the dispase-based dissociation assay, and the in vivo passive transfer model into neonatal mice were used jointly to verify the capacity of DSG1-and DSG3-specific adsorbers to remove circulating pathogenic autoantibodies from three PV patients [10].…”

Section: In Vivo Passive and Active Models For The Study Of Pemphigusmentioning

confidence: 99%

In Vitro, Ex Vivo, and In Vivo Models for the Study of Pemphigus

Lotti

Atene

Zanfi

et al. 2022

IJMS

View full text Add to dashboard Cite

Pemphigus is a life-threatening autoimmune disease. Several phenotypic variants are part of this family of bullous disorders. The disease is mainly mediated by pathogenic autoantibodies, but is also directed against two desmosomal adhesion proteins, desmoglein 1 (DSG1) and 3 (DSG3), which are expressed in the skin and mucosae. By binding to their antigens, autoantibodies induce the separation of keratinocytes, in a process known as acantholysis. The two main Pemphigus variants are Pemphigus vulgaris and foliaceus. Several models of Pemphigus have been described: in vitro, ex vivo and in vivo, passive or active mouse models. Although no model is ideal, different models display specific characteristics that are useful for testing different hypotheses regarding the initiation of Pemphigus, or to evaluate the efficacy of experimental therapies. Different disease models also allow us to evaluate the pathogenicity of specific Pemphigus autoantibodies, or to investigate the role of previously not described autoantigens. The aim of this review is to provide an overview of Pemphigus disease models, with the main focus being on active models and their potential to reproduce different disease subgroups, based on the involvement of different autoantigens.

show abstract

Human Desmocollin 3‒Specific IgG Antibodies Are Pathogenic in a Humanized HLA Class II Transgenic Mouse Model of Pemphigus

Cited by 16 publications

References 46 publications

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Polyopes affinis Suppressed IFN-γ- and TNF-α-Induced Inflammation in Human Keratinocytes via Down-Regulation of the NF-κB and STAT1 Pathways

In Vitro, Ex Vivo, and In Vivo Models for the Study of Pemphigus

Contact Info

Product

Resources

About