Binding of pemphigus vulgaris IgG to antigens in desmosome core domains excludes immune complexes rather than directly splitting desmosomes

Aoyama, Yumi; Nagai, Miki; Kitajima, Yasuo

doi:10.1111/j.1365-2133.2010.09672.x

Cited by 30 publications

(32 citation statements)

References 25 publications

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“…However, this direct access of IgG to Dsg3 within desmosomes does not always appear to be operative. Our studies have revealed that even if halfdesmosome-like structures are bound with PV-IgG-gold particles in low Ca 2þ medium, these half-desmosomes covered with PV-IgG-gold particles do not inhibit the formation of desmosomes; instead, the gold-decorated half-desmosomes are coupled to form complete desmosomes during Ca 2þ switch, with gold particles being sandwiched in the core of resultant desmosomes [53] (Fig. 7).…”

Section: Two Principal Hypotheses For the Pathomechanisms Of Pemphigumentioning

confidence: 91%

“…These sandwiched antibodies are also supposed to include anti-Dsg3 antibodies against Ca 2þ -dependent epitopes at N-terminal domain, because at least 30 minutes are required for the formation of desmosomes after Ca 2þ switch and few minutes are enough for antibodies to bind to antigens. On the other hand, time-lapsed immunofluorescence studies demonstrate that the PV-IgG, which penetrates into the core domain of desmosomes and binds to Dsg3 during the first 2-minute incubation with PV-IgG (anti-Dsg3), is mostly excluded from the desmosomes within 5 hours following washing and incubation with a PVIgG-free medium [53] (Fig. 8).…”

Section: Two Principal Hypotheses For the Pathomechanisms Of Pemphigumentioning

confidence: 96%

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New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

Kitajima

2012

The Kaohsiung J of Med Scie

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Desmosomes in keratinocytes are the most important intercellular adhering junctions that provide structural strength for the epidermis. These junctions are connected directly with desmosomal cadherin proteins. Desmosomal cadherins are divided into four desmogleins (Dsgs), Dsg1-4, and three desmocollins (Dscs), Dsc1-3, all of which are involved in desmosomal adhesion by homo- and/or heterophilic binding between Dsgs and Dscs in a Ca(2+)-dependent manner. Cadherins are present on the cell surface and anchor keratin intermediate filaments (KIFs) to their inner cytoplasmic surface to generate an intracellular KIF-skeletal scaffold through several associate proteins, including plakoglobin, plakophillin, and desmoplakins. As such, the desmosomal contacts between adjacent cells generate an intercellular KIF scaffold throughout the whole epidermal sheet. However, despite these critical roles in maintaining epidermal adhesion and integrity, desmosomes are not static structures. Rather, they are dynamic units that undergo regular remodeling, i.e., assembly and disassembly, to allow for cell migration within the epidermis in response to outside-in signaling during epidermal differentiation. Recently, two cell-cell adhesion states controlled by desmosomes have been recognized, including "stable hyperadhesion (Ca(2+)-independent)" and "dynamic weak-adhesion (Ca(2+)-dependent)" conditions. These conditions are mutually reversible through cell signaling events involving protein kinase C (PKC) and epidermal growth factor receptor. Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by anti-Dsg3 antibodies. Binding of these antibodies to Dsg3 causes endocytosis of Dsg3 from the cell surface and results in the specific depletion of Dsg3 from desmosomes, an event linked to acantholysis in the epidermis. This binding of anti-Dsg3 antibody to Dsg3 in epidermal keratinocytes activates PKC, to generate the "weak-adhesion (Ca(2+)-dependent)" state of desmosomes. The weak-adhesion desmosomes appear to be the susceptible desmosomal state and a prerequisite for Dsg3 depletion from desmosomes, pivotal and specific events leading to PV blistering. These observations allow us to propose a concept for pemphigus blistering disorders as a "desmosome-remodeling impairment disease" involving a mechanism of Dsg3 nonassembly and depletion from desmosomes through PV immunoglobulin G-activated intracellular signaling events.

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Section: Two Principal Hypotheses For the Pathomechanisms Of Pemphigumentioning

confidence: 91%

Section: Two Principal Hypotheses For the Pathomechanisms Of Pemphigumentioning

confidence: 96%

New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

Kitajima

2012

The Kaohsiung J of Med Scie

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“…Using cultured keratinocytes, PVIgG and AK23 treatments induced internalization and depletion of Dsg 3 from cell membrane (Triton-X-100 soluble) fractions within 30 -60 min and depletion of Dsg3 from cytoskeleton (Triton-X-100 insoluble) fractions including desmosomes within later 24 -48 h Aoyama et al, 2010;Calkins et al, 2006: Sato et al, 2000Williamson et al, 2006;Yamamoto et al, 2007). These results suggest that the fi rst depletion of Dsg3 from non-desmosomal pool is linked to the secondary depletion of Dsg3 from desmosomes, causing a decrease in cell adhesion strength.…”

Section: Desmoglein Internalization/disassembly Conceptmentioning

confidence: 99%

“…The other mechanism by which pemphigus autoantibodies destroy the functions of their specifi c target antigens is depletion of Dsgs from desmosomes at protein levels, leading to the generation of fragile desmosomes Aoyama et al, 2010;Kitajima, 2013). Using cultured keratinocytes, PVIgG and AK23 treatments induced internalization and depletion of Dsg 3 from cell membrane (Triton-X-100 soluble) fractions within 30 -60 min and depletion of Dsg3 from cytoskeleton (Triton-X-100 insoluble) fractions including desmosomes within later 24 -48 h Aoyama et al, 2010;Calkins et al, 2006: Sato et al, 2000Williamson et al, 2006;Yamamoto et al, 2007).…”

Section: Desmoglein Internalization/disassembly Conceptmentioning

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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“…23,24 Polyclonal anti-Dsg3 IgG antibodies in sera from pemphigus patients and pemphigus model mice are now widely accepted to comprise mixtures of both pathogenic and nonpathogenic IgGs, based on the results of studies using monoclonal antibodies from patients and mice. 5,6 A growing number of studies suggest that inhibition of signaling pathways such as MAPK and c-Myc, [25][26][27] as well as endocytic processing of Dsg3, 28,29 can prevent loss of keratinocyte adhesion in PV IgG-treated cells. Overall, these studies suggest that PV IgG may modulate the assembly and disassembly kinetics of desmosomes, and that modifying keratinocyte signaling pathways can blunt keratinocyte sensitivity to PV IgG.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

Tsunoda

Ota

Saito

et al. 2011

The American Journal of Pathology

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Pemphigus vulgaris is an autoimmune disease caused by IgG antibodies against desmoglein 3 (Dsg3). Previously, we isolated a pathogenic mAb against Dsg3, AK23 IgG, which induces a pemphigus vulgaris-like phenotype characterized by blister formation. In the present study, we generated a transgenic mouse expressing AK23 IgM to examine B-cell tolerance and the pathogenic role of IgM. Autoreactive transgenic B cells were found in the spleen and lymph nodes, whereas antiDsg3 AK23 IgM was detected in the cardiovascular circulation. The transgenic mice did not develop an obvious pemphigus vulgaris phenotype, however, even though an excess of AK23 IgM was passively transferred to neonatal mice. Similarly, when hybridoma cells producing AK23 IgM were inoculated into adult mice, no blistering was observed. Immunoelectron microscopy revealed IgM binding at the edges of desmosomes or interdesmosomal cell membranes, but not in the desmosome core, where AK23 IgG binding has been frequently detected. Furthermore, in an in vitro dissociation assay using cultured keratinocytes, AK23 IgG and AK23 IgM F(ab=) 2 fragments, but not AK23 IgM, induced fragmentation of epidermal sheets. Together, these observations indicate that antibodies must gain access to Dsg3 integrated within desmosomes to induce the loss of keratinocyte cell-cell adhesion. These findings provide an important framework for improved understanding of B-cell tolerance and the pathophysiology of blister formation in pemphigus. Pemphigus vulgaris (PV) is a life-threatening, organ-specific autoimmune blistering disease of the skin and mucous membranes. It is characterized clinically by painful oral erosions and flaccid skin blisters, histologically by suprabasal acantholysis (ie, loss of cell-cell adhesion between suprabasal keratinocytes), and immunopathologically by IgG autoantibodies against desmoglein 3 (Dsg3), a cadherin-type cell-cell adhesion molecule found in desmosomes.1,2 Compelling evidence indicates that IgG autoantibodies against Dsg3 are pathogenic and play a primary role in inducing blister formation in pemphigus. IgGs affinity-purified from the sera of PV patients using the extracellular domain of Dsg3 cause suprabasal acantholysis when injected into neonatal mice.3 When anti-Dsg3 IgG is immunoadsorbed from the sera of PV patients using the same Dsg3 domain, those sera lose their ability to cause blister formation in neonatal mice. 4 Furthermore, monoclonal antibodies (mAbs) against Dsg3 from a model mouse and from PV patients induce the formation in mice of blisters with typical PV histology. 5,6 The pathogenic roles of autoantibodies against nondesmoglein molecules remain to be clarified. 7,8 We previously developed a PV model mouse by the adoptive transfer of lymphocytes from Dsg3 Ϫ/Ϫ mice immunized with rDsg3 to Rag2 Ϫ/Ϫ mice that express Dsg3. 9Recipient mice showed stable anti-Dsg3 IgG production and developed a PV phenotype characterized by mucosal erosions and acantholytic blisters, similar to those seen in PV patients. We subsequently isolated AK...

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Binding of pemphigus vulgaris IgG to antigens in desmosome core domains excludes immune complexes rather than directly splitting desmosomes

Abstract: These results suggest that the PV IgG/Dsg3 immune complexes are excluded from the desmosomal core domain rather than directly splitting the desmosome.

Cited by 30 publications

References 25 publications

New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

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

Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

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Binding of pemphigus vulgaris IgG to antigens in desmosome core domains excludes immune complexes rather than directly splitting desmosomes

Abstract: These results suggest that the PV IgG/Dsg3 immune complexes are excluded from the desmosomal core domain rather than directly splitting the desmosome.

Cited by 30 publications

References 25 publications

New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

New insights into desmosome regulation and pemphigus blistering as a desmosome‐remodeling disease

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

Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

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