Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.

Amagai, Masayuki; Hashimoto, Takashi; Shimizu, Nobuyoshi; Nishikawa, Takeji

doi:10.1172/jci117349

Cited by 305 publications

(273 citation statements)

References 40 publications

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“…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.…”

Section: Pemphigus Vulgaris (Pv)mentioning

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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Section: Pemphigus Vulgaris (Pv)mentioning

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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“…Correctness of both constructs was verified by sequencing. pAcGHLT-A vectors were cotransfected with Baculo-DNA (SixPack; BD Clontech) into Sf21 insect cells, and recombinant baculoviruses were amplified using a previously described protocol (32). The recombinant proteins and the GST/6xHis control protein (generated by cotransfection of an empty pAcGHLT-A vector) were expressed in Sf21 cells as described previously (33).…”

Section: Expression and Purification Of Bp180 And Bp230 Recombinant Pmentioning

confidence: 99%

Autoreactive T and B Cells from Bullous Pemphigoid (BP) Patients Recognize Epitopes Clustered in Distinct Regions of BP180 and BP230

Thoma-Uszynski

Uter

Schwietzke

et al. 2006

The Journal of Immunology

111

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Bullous pemphigoid (BP) is a well-characterized model of autoantibody-mediated autoimmunity, which presumably depends on autoreactive Th cells that promote the activation of autoreactive B cells. The two major autoantigens of BP are BP180 and BP230, two components of dermoepidermal adhesion complexes. Both, autoreactive Th cell responses and autoantibody profiles were characterized in 35 patients with acute onset BP using BP180 and BP230 proteins. Our findings indicate the following: 1) autoreactive Th cells recognized epitopes within the NH2-terminal (77.1%), COOH-terminal (65.7%), and central portion (57.1%) of the BP180 ectodomain; 2) IgG autoantibodies were found to exhibit similar or identical reactivity against the NH2-terminal (82.8%), COOH-terminal (77.1%), and central portion (37.1%) of the BP180 ectodomain; 3) T and B cell reactivity with the NH2-terminal portion of the BP180 ectodomain was associated with extensive BP, whereas the central portion was more frequently recognized in limited BP; 4) only 7 of 16 (43.7%) and 6 of 16 (37.5%) BP patients showed a Th cellular response against the COOH- and NH2-terminal regions of BP230, respectively, whereas 5) IgG reactivity against the COOH- and NH2-termini of BP230 was detected in 5 of 16 (31.3%) and 6 of 16 (37.5%) patients, respectively. These results demonstrate that Th and B cell reactivities against BP180, are, in contrast to BP230 reactivity, almost constantly detectable in BP patients, and differential epitope recognition of BP180 seems to be associated with distinct clinical severity. These observations support the concept that BP180, but not BP230, is the primary autoantigen of BP critical for disease development.

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“…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)(5)(6)(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.…”

mentioning

confidence: 99%

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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Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.

Abstract: Pemphigus vulgaris (PV)

Cited by 305 publications

References 40 publications

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

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

Autoreactive T and B Cells from Bullous Pemphigoid (BP) Patients Recognize Epitopes Clustered in Distinct Regions of BP180 and BP230

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

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