Pemphigus Vulgaris Antibody Identifies Pemphaxin

Nguyen, Vu Thuong; Ndoye, Assane; Grando, Sergei A.

doi:10.1074/jbc.m003174200

Cited by 119 publications

(37 citation statements)

References 79 publications

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“…Our previous studies (45) demonstrated that although adsorption of a single type of pathogenic antibody eliminates the acantholytic activity of PVIgG, this autoantibody alone is not sufficient to induce acantholysis and skin blisters. However, adding it back to the preabsorbed PVIgG restores acantholytic activity of the latter (45). Thus, the pool of disease-causing PVIgG contains autoantibodies to a group of keratinocyte self-antigens, and it is the a synergistic action of these autoantibodies that breaks up the integrity of live epidermis and induces skin blistering.…”

Section: Discussionmentioning

confidence: 99%

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Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Marchenko

Chernyavsky

Arredondo

et al. 2010

Journal of Biological Chemistry

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115

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A loss of epidermal cohesion in pemphigus vulgaris (PV) results from autoantibody action on keratinocytes (KCs) activating the signaling kinases and executioner caspases that damage KCs, causing their shrinkage, detachment from neighboring cells, and rounding up (apoptolysis). In this study, we found that PV antibody binding leads to activation of epidermal growth factor receptor kinase, Src, p38 MAPK, and JNK in KCs with time pattern variations from patient to patient. Both extrinsic and intrinsic apoptotic pathways were also activated. Although Fas ligand neutralizing antibody could inhibit the former pathway, the mechanism of activation of the latter remained unknown. PV antibodies increased cytochrome c release, suggesting damage to mitochondria. The immunoblotting experiments revealed penetration of PVIgG into the subcellular mitochondrial fraction. The antimitochondrial antibodies from different PV patients recognized distinct combinations of antigens with apparent molecular sizes of 25, 30, 35, 57, 60, and 100 kDa. Antimitochondrial antibodies were pathogenic because their absorption abolished the ability of PVIgG to cause keratinocyte detachment both in vitro and in vivo. The downstream signaling of antimitochondrial antibodies involved JNK and late p38 MAPK activation, whereas the signaling of anti-desmoglein 3 (Dsg3) antibody involved JNK and biphasic p38 MAPK activation. Using KCs grown from Dsg3؊/؊ mice, we determined that Dsg3 did not serve as a surrogate antigen allowing antimitochondrial antibodies to enter KCs. The PVIgG-induced activation of epidermal growth factor receptor and Src was affected neither in Dsg3KCs nor due to absorption of antimitochondrial antibodies. These results demonstrated that apoptolysis in PV is a complex process initiated by at least three classes of autoantibodies directed against desmosomal, mitochondrial, and other keratinocyte self-antigens. These autoantibodies synergize with the proapoptotic serum and tissue factors to trigger both extrinsic and intrinsic pathways of cell death and break the epidermal cohesion, leading to blisters. Further elucidation of the primary signaling events downstream of PV autoantigens will be crucial for the development of a more successful therapy for PV patients.Pemphigus vulgaris (PV) 3 is an IgG autoantibody-mediated disease of skin and mucosa caused by a loss of epidermal cohesion and manifested by progressive blistering and non-healing erosions. The mechanism of detachment of keratinocytes (KCs) in PV, termed acantholysis, is a subject of intensive research. Elucidation of the pathophysiologic mechanism of acantholysis should facilitate development of novel pharmacologic approaches to prevent and treat blistering without systemic corticosteroids, a mainstay of treatment of PV patients. Acantholysis can be blocked both by inhibitors of signaling kinases, such as p38 MAPK (3), mammalian target of rapamycin (4), Src, and epidermal growth factor receptor (EGFR) kinase (2, 4 -7) and by other tyrosine kinases, phospholipase C, calmodulin...

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Section: Discussionmentioning

confidence: 99%

“…The mechanism of cell entry of antimitochondrial antibodies in PV may involve their binding to annexins at the keratinocyte plasma membrane (45,64). Annexins can relocate to the cytosol (65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Marchenko

Chernyavsky

Arredondo

et al. 2010

Journal of Biological Chemistry

Self Cite

115

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“…rPX-His specifically bound [ 3 H]ACh as well as nicotinic and muscarinic drugs, suggesting that PX is one of the KC AChR with dual, muscarinic and nicotinic, pharmacology known to be targeted by disease-causing Pab. Preabsorption of PV sera with rPX-His eliminated acantholytic activity, and eluted antibody immunoprecipitated native PX [31]. Although this antibody alone did not cause skin blisters in vivo, its addition to the preabsorbed PV IgG fraction restored acantholytic activity, indicating that acantholysis in PV results from synergistic action of autoantibodies to different self-antigens, including both AChR and desmosomal cadherins.…”

Section: Pab Identify Pemphaxin – a Novel Kc Annexin-like Molecule Bimentioning

confidence: 99%

“…The PV IgG eluted from a 75-kD KC protein band both stained epidermis in a pemphigus-like pattern and induced acantholysis in KC monolayers [31]. Screening of a keratinocyte λgt11 cDNA library with this antibody identified clones carrying cDNA inserts encoding a novel molecule that we named pemphaxin (PX) because it exhibits ∼40% similarity with annexin 2.…”

Section: Pab Identify Pemphaxin – a Novel Kc Annexin-like Molecule Bimentioning

confidence: 99%

Autoimmunity to Keratinocyte Acetylcholine Receptors in Pemphigus

Grando¹

2000

Dermatology

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120

106

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Pemphigus autoimmunity is not limited to antides- moglein antibodies. Nondesmoglein antibodies induce pemphigus-like lesions in neonatal mice. Acantholytic activity of pemphigus IgG harbors pharmacologic effects on keratinocyte shape and adhesion. Acantholytic antireceptor autoantibodies target: (1) a novel human α9 acetylcholine receptor regulating keratinocyte adhesion, and (2) pemphaxin, a novel keratinocyte annexin-like molecule binding acetylcholine. A ‘multiple-hit’ hypothesis reconciles recent findings of anti-acetylcholine-receptor autoimmunity in pemphigus and the fact that pemphigus patients also develop autoantibodies to adhesion molecules. The antiacantholytic activity of cholinergic agonists suggests a novel avenue for the development of a nonhormonal treatment of pemphigus.

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“…The cells were isolated from the epidermis and grown in 75-cm 2 flasks (Corning Glass) at 37°C in serumfree keratinocyte growth medium (KGM) containing 0.09 mM Ca 2ϩ in a humid 5% CO 2 incubator, as detailed elsewhere (59). On the day of the experiment, ϳ80% confluent second passage cultures derived from three different donors were washed and fed with fresh KGM containing either 1 mg/ml PV IgG, 1 mg/ml normal IgG, 0.25 mM MP, 1 mg/ml PV IgG after 2 h of pretreatment with 0.25 mM MP or no additions (control), and incubated for 8 h at 37°C in a humid 5% CO 2 incubator.…”

Section: Pemphigus and Control Igg Fractions-mentioning

confidence: 99%