The final destiny of acantholytic cells in pemphigus is Fas mediated

Pacheco-Tovar, MG; Avalos‐Díaz, Esperanza; Vega‐Memije, Elisa; Bollain-y-Goytia, Juan José; Lopez-Robles, Erendira; Hojyo‐Tomoka, M. T.; Domínguez‐Soto, Luciano; Herrera‐Esparza, Rafael

doi:10.1111/j.1468-3083.2009.03162.x

Cited by 22 publications

(33 citation statements)

References 23 publications

(45 reference statements)

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“…The inability of FasL neutralizing antibodies to reverse the pathogenic antibody-induced increase in stiffness is somewhat surprising, as an activation of the Fas-FasL apoptotic pathway has repeatedly been implicated in PV pathomechanisms [37], [38]. However, previous studies relied on observations from biopsy materials or in vitro studies with patient sera or purified IgG.…”

Section: Discussionmentioning

confidence: 99%

Nanorobotic Investigation Identifies Novel Visual, Structural and Functional Correlates of Autoimmune Pathology in a Blistering Skin Disease Model

Seiffert-Sinha¹,

Yang

Fung

et al. 2014

PLoS ONE

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There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3. We demonstrate that pathogenic (blister-forming) anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming) anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps - an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a “2-Hit” model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.

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Section: Discussionmentioning

confidence: 99%

Nanorobotic Investigation Identifies Novel Visual, Structural and Functional Correlates of Autoimmune Pathology in a Blistering Skin Disease Model

Seiffert-Sinha¹,

Yang

Fung

et al. 2014

PLoS ONE

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“…It has been documented by different research groups that in the skin of PV patients, keratinocytes exhibit signs of apoptosis that precede their detachment and blister formation, and that PV IgG and sera induce biomolecular markers of apoptosis and oncosis in keratinocyte monolayers and skin organ cultures [225,230-235]. Two groups of PV patients, each producing autoantibodies activating predominantly either apoptotic or oncotic cell death pathway, have been identified [225].…”

Section: Molecular Mechanisms Of Keratinocyte Detachment In Pemphigusmentioning

confidence: 99%

Pemphigus autoimmunity: Hypotheses and realities

2011

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The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.

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“…Subsequent studies demonstrated that PVIgG binding to KCs causes secretion of soluble FasL, increased production and cellular amounts of FasR and FasL (soluble and membranal), co-aggregation of FasL and FasR with caspase 8 in a membranal deathinducing signaling complex, and down-regulation of the apoptosis inhibitor FLIP-l (5,10,11,14,27,28). The keratinocyte FasR can be also triggered by FasL expressed by the cytotoxic T cells (29) found in the skin of PV patients (30). Dr. Pincelli and co-workers (31) have recently reported that FasL neutralizing antibody can prevent PVIgG-induced apoptolysis both in vitro and in vivo .…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Marchenko

Chernyavsky

Arredondo

et al. 2010

Journal of Biological Chemistry

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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The final destiny of acantholytic cells in pemphigus is Fas mediated

Abstract: This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.

Cited by 22 publications

References 23 publications

Nanorobotic Investigation Identifies Novel Visual, Structural and Functional Correlates of Autoimmune Pathology in a Blistering Skin Disease Model

Nanorobotic Investigation Identifies Novel Visual, Structural and Functional Correlates of Autoimmune Pathology in a Blistering Skin Disease Model

Pemphigus autoimmunity: Hypotheses and realities

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

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