Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus

Spindler, Volker; Heupel, Wolfgang-Moritz; Efthymiadis, Athina; Schmidt, Enno; Eming, Rüdiger; Rankl, Christian; Hinterdorfer, Peter; Müller, Thomas; Drenckhahn, Detlev; Waschke, Jens

doi:10.1074/jbc.m109.024810

Cited by 104 publications

(111 citation statements)

References 38 publications

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“…Fifteen protein antigens with potential relevance to PV (5,20,(27)(28)(29)(30)(31)(32)(33)(34)(35) were printed on glass slides in triplicate (details provided in Materials and Methods). To establish and validate our methodology, individual arrays were probed with commercially available antibodies generated against specific printed antigens to demonstrate the specificity of Abs to the plated proteins and to ensure that the proteins were antigenically intact (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Antigens were selected based on a comprehensive survey of literature aimed at identifying potentially disease relevant targets of autoAbs in PV (5,9,(26)(27)(28)(29)(30)(31)(32)(33)(34). Fifteen PV-associated autoantigens were identified and printed on the array: Dsg1-4, muscarinic acetylcholine receptor subtypes M1 and M3-M5 (mAChR1 and -3-5), desmocollins 2 and 3 (Dsc2 and -3), E-cadherin (E-cad), Fc receptor-e 1 (FceR1), pemphaxin (ANXA9), plakoglobin (PKG), and thyroid peroxidase (TPO).…”

Section: Methodsmentioning

confidence: 99%

“…identified by a thorough review of the literature (5,9,(26)(27)(28)(29)(30)(31)(32)(33)(34). The selected proteins were printed onto glass slides and used to probe the serum of patients with pemphigus, healthy first-or second-degree relatives of patients with PV, and unrelated control subjects.…”

Section: Significancementioning

confidence: 99%

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Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first-and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.pemphigus | autoantibody | protein microarray P emphigus vulgaris (PV) is a blistering autoimmune skin disease characterized by the presence of autoantibodies (autoAbs) directed against keratinocyte surface antigens (1, 2). Although early immunofluorescence studies demonstrated the presence of autoAbs in patient sera that bound to the surface of keratinocytes, a direct role of autoAbs in disease pathogenesis was not established until purified patient IgG (PVIgG) was shown to elicit blister formation upon passive transfer in mice (3). The main targets of these autoAbs were identified as Desmoglein (Dsg) 3 and 1, cadherin proteins that constitute key components of desmosomes, protein complexes responsible for maintaining cell-cell adhesion (4-7). Later experiments in which patient sera depleted of anti-Dsg3 Abs failed to produce blisters when passively transferred to mice (8) seemingly cemented the notion that these autoAbs alone were responsible for blister formation. As a result, subsequent research in the field has focused primarily on autoAbs directed against Dsgs.The assertion that anti-Dsg autoAbs alone are pathogenic was first challenged when PVIgG, lacking any anti-Dsg1 autoAbs, produced blisters when passively transferred into Dsg3-null mice (9). Additionally, several studies have shown that anti-Dsg Ab titers do not necessarily correlate with disease activity, and a subset of patients with PV do not harbor any detectable anti-Dsg Abs (10-14). The presence of pathogenic autoAbs directed against non-Dsg targets could account for th...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, the data obtained via AFM experiments demonstrate that under cell-free conditions, IgG fractions of PV patients interfere with Dsg3 trans-interaction (Heupel et al, 2008;Spindler et al, 2009). More directly, the probability of steric hindrance was substantiated by data provided by using pathogenic monoclonal antibodies, AK 23, which was directed against the amino-terminal sequence of EC 1 (Tsunoda et al, 2003).…”

Section: Steric Hindrance Conceptmentioning

confidence: 99%

“…A heterophilic binding at the extracellular portion of Dsg2 and Dsc1a in a Ca 2 ϩ -dependent manner has been shown via coimmunoprecipitation experiments using lysates from cells stably expressing Dsc1a, with anti-Dsc or anti-Dsg antibodies (Chitaev & Troyanovsky, 1997). Single molecule atomic force microscopy (AFM) revealed homophilic trans-interactions of Dsc3 as well as Dsc3 heterophilic interactions with Dsg1 (but not with Dsg3; Spindler et al, 2009). …”

Section: Putative Molecular Integrity Of Desmosomesmentioning

confidence: 99%

150^thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

Kitajima

2014

Cell Communication & Adhesion

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Desmosomes are the most important intercellular adhering junctions that adhere two adjacent keratinocytes directly with desmosomal cadherins, that is, desmogleins (Dsgs) and desmocollins, forming an epidermal sheet. Recently, two cell -cell adhesion states of desmosomes, that is, " stable hyper-adhesion " and " dynamic weak-adhesion " conditions have been recognized. They are mutually reversible through cell signaling events involving protein kinase C (PKC), Src and epidermal growth factor receptor (EGFR) during Ca 2 ϩ -switching and wound healing. This remodeling is impaired in pemphigus vulgaris (PV, an autoimmune blistering disease), caused by anti-Dsg3 antibodies. The antibody binding to Dsg3 activates PKC, Src and EGFR, linked to generation of dynamic weak-adhesion desmosomes, followed by p38MAPK-mediated endocytosis of Dsg3, resulting in the specifi c depletion of Dsg3 from desmosomes and acantholysis. A variety of pemphigus outside-in signaling may explain different clinical (non-infl ammatory, infl ammatory, and necrolytic) types of pemphigus. Pemphigus could be referred to a " desmosome-remodeling disease involving pemphigus IgG-activated outside-in signaling events " .

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Paraneoplastic Pemphigus Herpetiformis With IgG Antibodies to Desmoglein 3 and Without Mucosal Lesions

Prado

Brice²,

Fukuda³

et al. 2011

Arch Dermatol

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Background: Pemphigus herpetiformis (PH) is a rare clinical entity that combines the clinical features of dermatitis herpetiformis and the immunopathologic features of pemphigus. The target antigen is usually desmoglein 1, with exceptional cases manifesting autoantibodies against desmoglein 3. More recently, it has been found that many patients with PH also demonstrate autoantibodies against desmocollin. The association of PH with a malignant neoplasm is rare. Observations: We describe a patient with PH and a lung neoplasm. Immunologic studies demonstrated IgG an-tibodies to desmoglein 3 and to an unknown 178-kDa protein but no antibodies to desmocollin. Conclusions: The association of PH with a thoracic malignant neoplasm has been reported in only 4 previous cases, and the neoplasm could be responsible for the unusual immunologic profile in the patient described herein. To our knowledge, this is the first report of PH with an associated neoplasm in which only anti-desmoglein 3 antibody was detected.

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Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus

Cited by 104 publications

References 38 publications

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

150^thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

Paraneoplastic Pemphigus Herpetiformis With IgG Antibodies to Desmoglein 3 and Without Mucosal Lesions

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Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus

Cited by 104 publications

References 38 publications

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

Paraneoplastic Pemphigus Herpetiformis With IgG Antibodies to Desmoglein 3 and Without Mucosal Lesions

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150^thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus