Induction of Pemphigus Phenotype by a Mouse Monoclonal Antibody Against the Amino-Terminal Adhesive Interface of Desmoglein 3

Tsunoda, Kazuyuki; Ota, Takayuki; Aoki, Miyo; Yamada, Taketo; Nagai, Tetsuo; Nakagawa, Taneaki; Koyasu, Shigeo; Nishikawa, Takeji; Amagai, Masayuki

doi:10.4049/jimmunol.170.4.2170

Cited by 278 publications

(398 citation statements)

References 45 publications

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“…The hypothesis of autoantibody-mediated direct interference with Dsg binding was possible to believe because Dsg3 was discovered to be a cadherin-type cell adhesion molecule (8,9). Studies using mouse monoclonal Dsg3 antibodies targeting well characterized parts of the Dsg3 extracellular subdomain supported this concept (3,20). On the other hand, direct inhibitory effects of PV-IgG and PF-IgG on Dsg1 transinteraction were not detectable (3,4), which led us to propose that direct interference with Dsg binding is specific for PV and may at least in part explain the more severe clinical phenotype of PV when compared with PF (1).…”

Section: Discussionmentioning

confidence: 69%

“…The control tandem peptide CP-2 (20 M), however, did not prevent PV-IgG-mediated reduction in Dsg3 transinteraction (53% Ϯ 3% Dsg3 binding activity), demonstrating specificity of Dsg3 transinteraction for TP. We performed similar experiments with mouse PV antibody AK 23, which targets the Dsg3 adhesive interface and blocked Dsg3 transinteraction (3,20). AK 23-induced inhibition of Dsg3 transinteraction (21% Ϯ 9%) was also prevented by TP (112% Ϯ 2%).…”

Section: Sp Blocked Homophilic Dsg3 and Dsg1 Transinteraction Whereamentioning

confidence: 99%

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Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus

Heupel

Müller

Efthymiadis

et al. 2009

Journal of Biological Chemistry

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Pemphigus vulgaris (PV) autoantibodies directly inhibit desmoglein (Dsg) 3-mediated transinteraction. Because cellular signaling also seems to be required for PV pathogenesis, it is important to characterize the role of direct inhibition in pemphigus acantholysis to allow establishment of new therapeutic approaches. Therefore, we modeled the Dsg1 and Dsg3 sequences into resolved cadherin structures and predicted peptides targeting the adhesive interface of both Dsg3 and Dsg1. In atomic force microscopy single molecule experiments, the selfdesigned cyclic single peptide specifically blocked homophilic Dsg3 and Dsg1 transinteraction, whereas a tandem peptide (TP) consisting of two combined single peptides did not. TP did not directly block binding of pemphigus IgG to their target Dsg antigens but prevented PV-IgG-induced inhibition of Dsg3 transinteraction in cell-free (atomic force microscopy) and cell-based (laser tweezer) experiments, indicating stabilization of Dsg3 bonds. Similarly, PV-IgG-mediated acantholysis and disruption of Dsg3 localization in HaCaT keratinocytes was partially blocked by TP. This is the first evidence that direct inhibition of Dsg3 binding is important for PV pathogenesis and that peptidomimetics stabilizing Dsg transinteraction may provide a novel approach for PV treatment. Autoantibodies in pemphigus vulgaris (PV)4 are mainly directed against the adhesion molecules desmoglein (Dsg) 3 and Dsg1 (1, 2). Recently, we provided direct evidence that PV autoantibodies directly block Dsg3 transinteraction (3). In contrast, Dsg1 autoantibodies in pemphigus foliaceus (PF) were found to disrupt Dsg1 transinteraction most likely via cellular signaling events rather than by direct inhibition (3, 4). However, it still remained unanswered whether direct inhibition of Dsg3 transinteraction is the sole pathogenic mechanism in mucosaldominant PV where autoantibodies against Dsg3 but not against Dsg1 are present (1). Alternatively, direct inhibition could act in concert with autoantibody-induced cellular signaling or may just be an epiphenomenon secondary to skin blistering (1, 5-7).The idea of direct interference with Dsg transinteraction by pemphigus autoantibodies has been proposed when Dsg3 was discovered to be a cadherin-type cell adhesion molecule (8, 9). From structural and mutational analyses, it was concluded that classical cadherins are able to form adhesive dimers through their N-terminal cadherin extracellular domain (EC1) via different interaction schemes (10 -13). Investigations of desmosomes using electron tomography from tissue sections also indicated various interaction models for desmosomal cadherins (14). Some of these interaction models resembled the interaction schemes found in the high resolution crystal structure analyses of N-and E-cadherin.This study was designed to modulate Dsg3 and Dsg1 transinteraction by using peptides fitting the most likely Dsg adhesive interface revealed by three-dimensional modeling. In an earlier study, it was reported that peptides targeting the putativ...

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Section: Discussionmentioning

confidence: 69%

Section: Sp Blocked Homophilic Dsg3 and Dsg1 Transinteraction Whereamentioning

confidence: 99%

Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus

Heupel

Müller

Efthymiadis

et al. 2009

Journal of Biological Chemistry

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“…The finding that most of the T cell peptides of Dsg3 are located in the first three ECD of Dsg3 is of interest since this region of the Dsg3 ectodomain harbors the major Ab epitopes (31). Two recent studies identified the NH 2 terminus of Dsg3 (aa 1-161) as the major binding site for pathogenic autoAb (31,32); within this region a stretch consisting of aa 25-88 was found to represent an immunodominant epitope for circulating autoAb (31). To map conformational epitopes of Dsg3, Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg1-specific residues were generated by baculovirus expression.…”

Section: Discussionmentioning

confidence: 99%

T Cell Recognition of Desmoglein 3 Peptides in Patients with Pemphigus Vulgaris and Healthy Individuals

Veldman¹,

Gebhard²,

Uter

et al. 2004

The Journal of Immunology

105

104

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Pemphigus vulgaris is a severe autoimmune disease caused by autoantibodies against the cutaneous adhesion molecule, desmoglein 3 (Dsg3). The aim of this study was to characterize the specificity of autoreactive Th cells, which presumably regulate Dsg3-specific autoantibody production. Ninety-seven Th1 and Th2 clones isolated from 16 pemphigus patients and 12 HLA-matched healthy donors recognized the Dsg3 peptides, DG3(78-94), DG3(96-112), DG3(189-205), DG3(205-221), and DG3(250-266). Peptide DG3(96-112), and to a lesser extent DG3(250-266), was recognized by the majority of T cells from patients and healthy donors in association with HLA-DRB1*0402 and DQB1*0503 which were prevalent in the pemphigus patients and Dsg3-responsive healthy donors. Analyzing the Vβ-chain of the TCR of the DG3(96-112)-specific T cells showed no restricted TCR usage. Peptides DG3(342-358) and DG3(376-392) were exclusively recognized by T cell clones (n = 13) from patients while DG3(483-499) was only recognized by T cell clones (n = 3) from a healthy donor. All Dsg3 peptides contained conserved amino acids at relative positions 1, 4, and 6; amino acids with a positive charge at position 4 presumably represent anchor motifs for DRB1*0402. These findings demonstrate that T cell recognition of distinct Dsg3 peptides is restricted by distinct HLA class II molecules and is independent from the development of pemphigus vulgaris.

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“…Therefore, pathogenic mAbs that recognize both Dsg3 and Dsg1 cause cell dissociation of cultured keratinocytes, suprabasal blisters in human skin, and Dsg3 endocytosis, whereas pathogenic mAbs that recognize only Dsg3 will cause Dsg3 endocytosis but will not cause cultured cell dissociation or blisters in human skin unless compensatory adhesion by Dsg1 is also inactivated, by either pathogenic antiDsg1 autoantibodies or staphylococcal exfoliative toxin, which cleaves Dsg1 (38 -40). Supplemental Table S1 summarizes the antigen specificity of the mAbs used in our study, including AK23, a pathogenic anti-Dsg3 mAb isolated from an active immune mouse model of PV (41).…”

Section: Pathogenic Pv Mabs That Cause Internalization Of Dsg3 and Thmentioning

confidence: 99%

p38 MAPK Activation Is Downstream of the Loss of Intercellular Adhesion in Pemphigus Vulgaris

Mao

Sano

Park

et al. 2011

Journal of Biological Chemistry

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Pemphigus vulgaris (PV) is a potentially fatal blistering disease characterized by autoantibodies against the desmosomal adhesion protein desmoglein (Dsg) 3. Whether autoantibody steric hindrance or signaling through pathways such as p38 MAPK is primary in disease pathogenesis is controversial. PV mAbs that cause endocytosis of Dsg3 but do not dissociate keratinocytes because of compensatory adhesion by Dsg1 do not activate p38. The same mAbs plus exfoliative toxin to inactivate Dsg1 but not exfoliative toxin alone activate p38, suggesting that p38 activation is secondary to loss of adhesion. Mice with epidermal p38␣ deficiency blister after passive transfer of PV mAbs; however, acantholytic cells retain cell surface Dsg3 compared with wild-type mice. In cultured keratinocytes, p38 knockdown prevents loss of desmosomal Dsg3 by PV mAbs, and exogenous p38 activation causes internalization of Dsg3, desmocollin 3, and desmoplakin. p38␣ MAPK is therefore not required for the loss of intercellular adhesion in PV, but may function downstream to augment blistering via Dsg3 endocytosis. Treatments aimed at increasing keratinocyte adhesion could be used in conjunction with immunosuppressive agents, potentially leading to safer and more effective combination therapy regimens. Pemphigus vulgaris (PV)2 is a potentially fatal autoimmune blistering disorder caused by autoantibodies to keratinocyte cell adhesion proteins known as desmogleins (1). The pathognomonic histologic finding in PV is suprabasal acantholysis, or the detachment of intact keratinocytes from each other because of loss of intercellular adhesion. A characteristic clinical finding in PV is Nikolsky's sign, in which blisters can be induced in otherwise normal-appearing skin by applying pressure or mechanical shear force, reflecting the loss of intercellular adhesion even in skin without overt blisters (2).PV autoantibodies primarily target desmoglein (Dsg) 3, a transmembrane adhesion molecule of desmosomes (3). Passive transfer experiments using neonatal mice have established the pathogenicity of the anti-Dsg3 autoantibodies in PV (4, 5). The anatomic site of blister formation is thought to be due to the tissue-specific expression patterns of different Dsg isoforms, also known as the desmoglein compensation theory. Dsg3 is expressed by basal keratinocytes of mucosa and skin, whereas Dsg1 is expressed by basal keratinocytes in skin but not mucosa (6, 7). Therefore, patients with Dsg3 autoantibodies demonstrate blistering in the mucosa, where compensatory adhesion by Dsg1 is not present (mucosal-dominant PV). In some patients who progress to develop Dsg1 in addition to Dsg3 autoantibodies, suprabasal blisters appear in both the mucosa and skin (mucocutaneous PV) (8 -10).Epitope mapping studies have shown that pathogenic PV autoantibodies preferentially bind the amino-terminal domain of Dsg3 that is predicted to form the transadhesive interface between cells, based on analogy to ultrastructural models for the classical cadherins (11-13). PV IgG has also been shown...

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Induction of Pemphigus Phenotype by a Mouse Monoclonal Antibody Against the Amino-Terminal Adhesive Interface of Desmoglein 3

Cited by 278 publications

References 45 publications

Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus

Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus

T Cell Recognition of Desmoglein 3 Peptides in Patients with Pemphigus Vulgaris and Healthy Individuals

p38 MAPK Activation Is Downstream of the Loss of Intercellular Adhesion in Pemphigus Vulgaris

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