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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

Summary  Pemphigus vulgaris (PV) is a severe autoimmune bullous disease involving both the skin and mucosal areas, and characterized by intraepithelial flaccid blisters and erosions. The pathogenesis of this disease is not yet completely understood, but novel insights into desmoglein biology and autoantibody pathogenesis have recently been published. Acantholysis in PV seems to result from a collective action of autoantibodies against various keratinocyte self antigens, of which desmogleins 1 and 3 are the most important. Additional antigens including desmocollins and nondesmosome components, such as the mitochondrion, might take part in disease activation. Recently, apoptosis was reported as a possible underlying mechanism of acantholysis. Furthermore, apoptolysis is believed to be the link between suprabasal acantholytic and cell-death pathways. We review the possible hypotheses of the pathogenesis of PV: the desmoglein compensation theory, the antibody-induced apoptosis theory, the basal-cell shrinkage hypothesis and the newly published apoptolysis theory.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

Pemphigus belongs to a group of potentially life-threatening organ-specific autoimmune blistering diseases. The two major varieties are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), which have morphologically characteristic acantholysis due to loss of cell–cell adhesion between the keratinocytes. Circulating autoantibodies are directed against desmoglein (Dsg)1 and/or Dsg3.1

It is known that these autoantibodies play an important role in the pathogenesis and development of PV.2 However, novel insights into Dsg biology and PV pathology have been proposed, and new questions are emerging as the conventional concepts of the pathogenesis of PV are being challenged. We review these proposed concepts with a view to advancing the understanding of the immunopathogenesis of PV.

Theories on the pathogenesis of pemphigus vulgaris

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

The desmoglein compensation theory

In 1999, Amagai and Stanley proposed the desmoglein compensation theory based on the distribution of Dsg1 and Dsg3 in the skin and mucosa.3–5 This landmark concept states that the existence of any one Dsg type is sufficient to maintain the integrity of the epidermis and mucosa. The clinical typing of pemphigus (PV and PF) and the main clinical symptoms of PV (mucosal-dominant and epidermal–mucosal types) are determined on the basis of both the differential antigenic distribution and generation of autoantibodies (Fig. 1).6

image

Figure 1.  The desmoglein compensation theory is based on the differential antigenic distribution and generation of autoantibodies. (a) The keratinocytes are closely connected to each other by desmosomes, in which the desmogleins are the transmembrane antigens. Desmoglein (Dsg)3 (blue) is distributed in the superficial epidermis and mucosa, and Dsg3 (red) in the deep epidermis and the entire mucosa. (b) An autoantibody against Dsg1 results in acantholysis of the superficial epidermis, causing superficial blisters; with the compensation of Dsg3, the mucous membrane remains intact. (c) By contrast, an autoantibody against Dsg3 merely results in acantholysis of mucosal epithelia because Dsg1 partially compensates for the function of Dsg3. (d) Acantholysis is widespread n the presence of autoantibodies against both Dsg1 and Dsg3.

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This theory has clarified the basic pathophysiology of pemphigus and the classification of the clinical features, and has been widely used in diagnosis and assessment of efficacy and prognosis. However, this theory cannot explain the epidermal-blister formation satisfactorily, and many important questions remain unanswered. Many challenges remain in re-examining the available evidence and elucidating the immunopathogenesis of this important disease.

‘Multiple hits’ hypothesis

Recent evidence has indicated that besides anti-Dsg1 and anti-Dsg3 antibodies, patients develop antibodies against additional desmosomal (i.e. desmocollins, plakins) and nondesmosomal proteins, such as cell-membrane receptors (nicotinic acetylcholine receptor, pemphaxin, thyroperoxidase and some other annexins).7–9 Volker et al. pointed out that desmocollin (Dsc)3 is expressed throughout the basal, spinous and lower granular layer. Blocking of Dsc3 function with a monoclonal antibody led to the formation of intraepidermal blisters.10,11 Non-desmosomal autoantigens such as pemphaxin, an α9-acetylcholine receptor, also provide relative contributions to PV.12,13 In addition, some patients were found to develop antimitochondrial antibodies, which could penetrate keratinocytes and react with mitochondrial proteins.14

These data indicate that pemphigus is a complex disease, initiated by at least three classes of autoantibodies directed against desmosomal, mitochondrial and other keratinocyte autoantigens. The recently published ‘multiple hits’ hypothesis explains the acantholysis in the disease.15 However, it is generally thought that the desmogleins are the most important factor in the disease. Clinically, the titre of anti-Dsg antibody correlates with disease activity. Experimentally, the disease can be modelled by passively transferring the autoantibody to neonatal mice, and removal of anti-Dsg3 IgG by immunoadsorption abolishes the blister-forming activity of PV sera. We recently investigated the subclasses of specific IgG and found that the IgG4 subclass was dominant in the acute stage, whereas IgG1 was in remission. In addition, antibodies targeting other autoantigens are nonpathogenic without the presence of anti-Dsg autoantibodies.10,11 Therefore, although the involvement of other autoantigens in the pathogenesis of PV has been explored, the relative contributions of these proteins remain a matter of debate.

The antibody-induced apoptosis theory

Current pemphigus research is elucidating new mechanisms of keratinocyte detachment in PV. Researchers have hypothesized that apoptosis may possibly be responsible for the underlying mechanisms of acantholysis.16–18 Under experimental conditions, the activation of apoptotic signalling can be induced by pemphigus IgG and anti-Fas receptor (anti-FasR) antibody. The pathway involves the secretion of soluble Fas ligand (FasL); an increase in the level of intracellular FasR, FasL, Bax and p53; a decrease in the level of Bcl-2; enrichment of caspase-8; and activation of caspases 1 and 3, and the death-inducing signalling complex (DISC), as a result of the aggregation of FasL, FasR and caspase-8. Inhibitors of caspases 1 or 3 were effective in suppressing IgG-mediated apoptosis and blocking acantholysis, supporting the idea that apoptosis contributes to cell dissociation (Fig. 2).19 The mechanisms of apoptosis in PV may be based on the PV IgG-triggered activation of signalling pathways, such as the epidermal growth factor receptor activation-dependent intracellular signalling (extracellular signal-regulated kinase) pathway, and the apoptosis (FasR) pathway (Fig. 2).20,21

image

Figure 2.  Activation of apoptotic signalling can be induced by pemphigus IgG and anti-FasR antibody. The apoptotic pathway involves the increase of intracellular Fas ligand and receptor (FasL FasR) Bax and p53, and the activation of several caspases, which results in cell swelling or cell apoptosis. Meanwhile, the binding of IgG to the epidermal growth factor receptor (EGFR) promotes the EGFR activation-dependent intracellular signalling (extracellular signal-regulated kinase; ERK) pathway and the apoptosis (FasR) pathway. However, the calpain inhibitor [Ac–Tyr–Val–Ala–Asp (YVAD)-CHO or N–Ac–Asp–Glu–Val–Asp (DEVD)-CHO] and the apoptosis inhibitor LKB1-interacting protein (FLIP)-1 can hinder the development of PV acantholysis by blocking apoptosis.

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Recently, some reports challenged the viewpoint that apoptosis occurs before acantholysis. They found that keratinocytes cultured in vitro with PV IgG could undergo acantholysis but no detectable apoptosis, such as nuclear fragmentation. Therefore, apoptosis may not be a prerequisite for the skin blistering in PV, but rather secondary to acantholysis.19,22 Taken together, the data indicate that PV is a disease caused by reduced cell adhesion and apoptosis, which occurs in association with cell detachment and which may be triggered by pathogenic IgG antibodies. As we know, these antibodies play important roles in PV, especially in the initial phase. However, understanding the mechanisms of apoptosis is pivotal for the development of more specific therapies.

The basal-cell shrinkage hypothesis and the apoptolysis theory

In recent years, some studies have reported that PV acantholysis mainly occurs in the superior basal layer, and is generally characterized by tombstone-like transformation of basal cells. Claude et al.23 proposed a new hypothesis of pemphigus pathogenesis in 2006, which suggests that after the pathogenic PV autoantibody binds to the keratinocyte receptor, a series of signal-transduction pathways trigger the rupture of the cytoskeleton, resulting in the collapse and shrinkage of the keratinocytes.24,25 This hypothesis explains why PV acantholysis mainly occurs at the basal layer, even though the keratinocytes in the superior basal layer remain connected. In 2009, a novel term, ‘apoptolysis’, was proposed by Grando et al.,26 which links the suprabasal acantholytic and cell death pathways to basal-cell shrinkage. The fundamental difference between apoptolysis and apoptosis in PV is that the basal cells shrink but do not die, rendering a ‘tombstone’ appearance to the PV lesions. It has been shown that PV IgG-induced caspase-8 activation and acantholysis can be prevented by anti-FasL antibody, which suggests that the structural damage (acantholysis) and death (apoptosis) of keratinocytes in PV are mediated by the same set of cell-death enzymes. This new concept distinguished the unique paradigm of cell damage and detachment in PV from other known forms of cell death.

The concept of apoptolysis is critical for the description of PV development, vividly linking the cell apoptosis and basic pathological features. However, it remains unclear whether apoptosis precedes acantholysis as an essential prerequisite, or whether apoptosis is merely a middle step in the pathogenesis of PV. Further research is needed to explore this novel mechanism.

Perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

With so many interesting questions unanswered, the pathogenesis of PV is still in controversial. Various disease models have been proposed to describe the complex pathogenesis of PV. Autoantibodies produced by patients with PV play a major role in the disease, as shown by passive-transfer models. Desmogleins are the main target antigen, although other autoantigens are also being explored. It is noteworthy that these newly found autoantigens cannot trigger PV alone without the presence of anti-Dsg antibodies; however, they may exacerbate the disease. Apoptosis has be found in the lesional skin of some patients with pemphigus. Pathogenic autoantibodies may induce apoptosis without keratinocyte death both in vitro and in vivo. Apoptotic signalling may precede acantholysis, and acantholysis may lead to apoptosis, which in turn might further enhance cell dissociation. Collectively, our understanding of the pathogenesis of PV continues to be enhanced by newly found molecules and antigenic targets, which it is hoped will facilitate the identification of specific therapies for PV.

Learning points

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions
  •  PV is a complex autoimmune disease explained by several hypotheses. It is widely accepted that autoantibodies play a major role in the pathogenesis of PV.
  •  In addition to Dsg1 and DSg2, other autoantigens have recently been investigated, such as other desmosomal antigens and nondesmosomal antigens. However, anti-Dsg1 and anti-Dsg3 antibodies are the most important in the pathogenesis of PV.
  •  In PV, apoptosis is induced by pemphigus autoantibodies both in vivo and in vitro.
  •  Acantholysis may result from the collapse of the keratinocyte cytoskeleton, with subsequent shrinkage of the basal cells.
  •  Apoptolysis is a novel mechanism in the pathogenesis of PV, which is similar to the apoptotic pathway, with basal-cell shrinkage and suprabasal acantholysis.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

This work was supported by National Natural Science Foundation of China (No.30771932) and Shanghai Rising-Star Program (08QH14019).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

CPD questions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

Question 1

The following hypotheses are possible in pemphigus except:

a) The basal-cell shrinkage hypothesis

b) The non-desmoglein targets theory

c) The antibody-induced apoptosis theory

d) The desmoglein compensation theory

e) The complement compensation theory

Question 2

Which are the most important self antigens in pemphigus?

a) Desmocollins, plakins

b) Pemphaxin, thyroperoxidase

c) Desmocollin (Dsc)1, Dsc3

d) Desmoglein (Dsg)1, Dsg3

e) The 9-acetylcholine receptor, mitochondria

Question 3

Which molecule was down-regulated in the pathway of apoptosis in pemphigus?

a) Soluble Fas ligand

b) Intracellular Fas receptor

c) Intracellular Fas ligand

d) Bcl-2

e) p53

Question 4

If a patient shows positive anti-desmoglein (Dsg)1 and negative anti-Dsg3, which disease is likely?

a) Pemphigus vulgaris

b) Pemphigus foliaceus

c) Benign mucous membrane pemphigoid

d) Pemphigus vegetans

e) Bullous pemphigoid

Question 5

The reason why acantholysis mainly occurs at the basal layer, whereas the keratinocytes in the superior basal layer remain connected, is mostly the result of which one of the following?

a) Distance between the cells

b) Dysfunction of desmocollin 3

c) Cytoskeleton components and cell surface receptors are significantly different between basal cells and suprabasal cells

d) Complement activation

e) Spatial conformation

Instructions for answering questions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Theories on the pathogenesis of pemphigus vulgaris
  5. Perspectives
  6. Learning points
  7. Acknowledgement
  8. References
  9. CPD questions
  10. Instructions for answering questions

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