Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies.

Stanley, John R.; Koulu, Leena; Thivolet, Charles

doi:10.1172/jci111426

Cited by 229 publications

(110 citation statements)

References 31 publications

(37 reference statements)

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…Each serum immunoprecipitated the characteristic PVA complex (containing the 130-kD antigen) from extracts of normal epidermis or cultured keratinocytes (9,33). This immunoprecipitation has been shown to be specific for PV patient sera (9,33).…”

Section: Patient Sera Antibodies and Rabbit Antiseramentioning

confidence: 89%

Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes

Kárpáti

Amagai

Prussick

et al. 1993

The Journal of Cell Biology

110

View full text Add to dashboard Cite

Abstract. Pemphigus vulgaris antigen (PVA) is a member of the desmoglein subfamily of cadherin cell adhesion molecules. Because autoantibodies in this disease cause blisters due to loss of epidermal cell adhesion, and because desmoglein is found in the desmosome cell adhesion junction, we wanted to determine if PVA is also found in desmosomes. By immunofluorescence, PV IgG bound, in a dotted pattern, to the cell surface of cultured human keratinocytes induced to differentiate with calcium, suggesting junctional staining. However, by preembedding, immunogold electron microscopic studies only slight labeling could be detected in desmosomes, presumably because of difficulty in gold penetration of intact desmosomes. We therefore treated the keratinocytes with 0.01% trypsin in 1 mM calcium, conditions known to preserve cadherin antigenicity but that caused slight separation of desmosomes, before immunogold staining. In this case there was extensive labeling of the extracellular part of desmosomes but not of the interdesmosomal cell membrane which was stained with anti-/32-microglobulin antibodies. To confirm the specificity of this binding we showed that antibodies raised in rabbits against the extracellular portions of PVA also bound desmosomes in these cultures. In intact mouse epidermis we could also show slight, but specific, immunogold desmosomal labeling with PV IgG. Furthermore, neonatal mice injected with PV IgG affinity purified on PVA showed desmosomal separation with the IgG localized to desmosomal cores. These results indicate that PVA is organized and concentrated within the desmosome where it presumably functions to maintain the integrity of stratifying epithelia. p EMPHIGUS vulgaris (PV) ~ is an autoimmune diseasein which blisters of skin and mucous membranes result from loss of epithelial cell-to-cell adhesion, a pathologic process called acantholysis (31). Immunofluorescence studies demonstrate that PV patients have IgG bound on their epidermal cell surfaces in vivo and also have circulating IgG that binds to the cell surface of normal stratified squamous epithelia (5, 6). These PV autoantibodies have been shown to be pathogenic by both clinical and experimental observations (for review see reference 29).The antigen (PVA) recognized by PV autoantibodies has been characterized by immunochemical methods. Immunoprecipitation of cultured keratinocyte and normal human epidermal extracts demonstrates that PV sera bind a 130-kD glycoprotein which forms a stoichiometric complex with plakoglobin (22), a plaque protein of intercellular adhering junctions (i.e., desmosomes and adherens junctions) (8).Recent eDNA cloning has demonstrated that the PVA is a member of the cadherin supergene family (3). The origi-

show abstract

Section: Patient Sera Antibodies and Rabbit Antiseramentioning

confidence: 89%

Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes

Kárpáti

Amagai

Prussick

et al. 1993

The Journal of Cell Biology

110

View full text Add to dashboard Cite

show abstract

“…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)(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.…”

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.

View full text Add to dashboard Cite

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...

show abstract

“…Desmozomal bütünlü-¤ün bozulmas› bir adezyon molekülü olan desmogleinin ekstrasellüler k›sm›na karfl› geliflen otoantikorlar taraf›ndan oluflturulur. Bunlar›n aras›nda desmoglein 1 (dsg 1) ve desmoglein 3 (dsg 3) en iyi tan›mlanm›fl olanlar›d›r [4][5][6][7][8] . Pemfigus hastalar›n›n takibinde klinik düzelmenin yan›nda hastal›k aktivitesini izlemek için adjuvan, objektif verilere gereksinim duyulmufltur.…”

Section: Giriflunclassified

“…Pemfigusta epidermal antijenlere karfl› oluflmufl otoantikorlar bül oluflumundan sorumlu tutulmaktad›r [2][3][4][5][6][7] . Klinik ve histopatolojik tan›y› bu otoantikorlar›n çeflitli yöntemler ile saptanmas› desteklemektedir.…”

Section: Tart›flmaunclassified

Pemfigusta Desmoglein Antikor Serum Düzeyleri ile Direkt İmmünofloresan Bulgularının Hastalığın Klinik Aktivitesi ile İlişkisi

Yilmaz¹,

Başkan²,

Budak³

et al. 2011

Turkderm

View full text Add to dashboard Cite

ÖzetAmaç: Pemfigus deri ve mukozalarda bül oluflumuyla seyreden, otoimmün bir hastal›kt›r. Bu çal›flmada bül oluflumunda rolü olan desmoglein-1 (dsg-1) ve desmoglein-3 (dsg-3)'e karfl› oluflmufl antikorlar›n saptanmas›nda kullan›lan iki yöntem olan direkt immün-floresan (IF) inceleme ve ELISA yönteminin hastal›k aktivitesi ve remisyonla iliflkisi araflt›r›lmaktad›r. Gereç ve Yöntem: Çal›flmaya 23'ü pemfigus vulgaris, 2'si pemfigus foliaseus tan›s› alm›fl toplam 25 hasta al›nd›. Hastalar›n tedavi öncesi ve klinik remisyonun 3., 6. ve 12. aylar›ndaki anti-dsg-1 ve anti-dsg-3 serum antikor düzeyleri ELISA ile araflt›r›ld›. Efl zamanl› olarak aktif hastal›kta lezyon kenar›ndan, remisyonda ise sa¤lam kalça derisi/alt dudak mukozas›ndan direkt IF inceleme yap›ld›. Nüks halinde tetkikler tekrarland›. Bulgular: Pemfigus vulgaris hastalar›n›n tedavi öncesi 17'sinde (%73,9) anti-dsg-1 antikoru, hepsinde (%100) anti-dsg-3 antikoru pozitif saptand›. ‹ki pemfigus foliaseus olgusunda tedavi öncesi anti-dsg-1 pozitif de¤erlerde iken anti-dsg-3 negatif saptand›. Antidsg-1 antikor serum düzeyleri deri fliddet skoru ile (r: 0,577; p: 0,003), anti-dsg-3 antikor serum düzeyleri ise oral mukoza fliddet skoru ile korele idi (r: 0,539; p: 0,008). Tam remisyona giren hastalar›n 16's›nda (%84,2) tedavi öncesi direkt IF'da saptanan birikim remisyonla birlikte negatifleflti. Nüks gözlenen 9 hastan›n hepsinde nüks s›ras›nda anti-dsg-1 ve/veya anti-dsg-3 serum düzeylerinde art›fl saptand›. Dokuz olgunun 3'ünde ise klinik remisyon halinde iken nüksten 1-4 ay öncesinde serum antikor düzeylerinde yük-selme tespit edildi. Sonuç: Bu çal›flmada serum desmoglein otoantikor de¤erlerinin hastal›k fliddeti ve aktivitesi ile iliflkili olabilece¤ini saptad›k. Klinik remisyon esnas›nda desmoglein antikorlar›n›n seri ölçümleri takip ve tedavi modifikasyonunda yol gösterici olabilir. (Türkderm 2011; 45: 77-82) Anahtar Kelimeler: Pemfigus vulgaris, pemfigus foliaseus, direkt immünfloresan, desmoglein antikorlar›, hastal›k aktivitesi Summary Background and Design: Pemphigus is an autoimmune disease that results in blistering of the skin and mucous membranes. In this study, we investigated the relationship between disease activity and remission with ELISA scores and direct immunofluorescence (IF) -two methods used for the detection of antibodies against desmoglein-1 (dsg-1) and desmoglein-3 (dsg-3) that are responsible for blister formation. Material and Method: Twenty-three pemphigus vulgaris patients and two pemphigus foliaceus patients were enrolled in the study. The serum levels of anti-dsg-1 and anti-dsg-3 antibodies were measured with ELISA before therapy and at 3, 6, and 12 month of clinical remission. Concurrently, direct IF was performed on perilesional skin during active disease and on normal buttock skin/lower lip mucosa in remission. The tests were repeated if relapse has occured. Results: Anti-dsg-1 was detected in 17 (73.9%) pemphigus vulgaris patients and anti-dsg-3 in 23 (100%) pemphigus vulgaris patients. In two pemphigus foliaceus patient...

show abstract

Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies.

Cited by 229 publications

References 31 publications

Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes

Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes

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

Pemfigusta Desmoglein Antikor Serum Düzeyleri ile Direkt İmmünofloresan Bulgularının Hastalığın Klinik Aktivitesi ile İlişkisi

Contact Info

Product

Resources

About