The pathogenic role of autoantibodies in pemphigus vulgaris. M. Pan, X. Liu and J. Zheng.. Clinical and

Experimental Dermatology.2011:703–707

INTRODUCTION• Potentially life threatening organ-specific autoimmune

blistering diseases.• Higher rates are reported in specific regions of the

world, such as Brazil(Christopher A. D’Angelis.The Pathology of Pemphigus: A Mini-Review. N A J Med Sci. 2013;6(1):37-40)

• The two major varieties are pemphigus vulgaris (PV) and pemphigus foliaceus (PF).

• Their difference lies in the level of acantholysis, with the former in the suprabasilar level and the latter in the subcorneal level(Dr. P. T. Chan. Review on Pathogenesis of Pemphigus.

Hong Kong Dermatology & Venereology Bulletin62 2002;10(2):62-68)

THE STRUCTURE OF DESMOSOME

• Organelles responsible for cell-to-cell adhesion in keratinocytes.

• The extra cellular part, desmoglea, is composed of transmembrane adhesion glycoproteins belonging to the cadherin superfamily, which includes desmogleins and desmocollins.

Dr. P. T. Chan. Review on Pathogenesis of Pemphigus. Hong Kong Dermatology & Venereology Bulletin62 2002;10(2):62-68

• The intracellular part, desmosomal plaques, has two groups of proteins.

The first group, plakin family (desmoplakins, envoplakin, periplakin, plectin), binds to cytokeratin filaments.

The second group of proteins, namely plakoglobin and plakophilin, bind to the intracellular domain of cadherins

Theories on the pathogenesis of pemphigus vulgaris

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.

• landmark concept states that the existence of any one Dsg type is sufficient to maintain the integrity of the epidermis and mucosa.

(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.

• Patient with active disease have circulating and tissue bound autoantibodies of both the immunoglobulins G1 and G4 subclasses.

• Immunofluorescence reveals the presence of IgG antibody in a fishnet pattern.

Rajendran R, Sivapathasundharam B. Disease of the skin(chapter19).Shafer’s Text book of Oral Pathology. 5th edn, Elesevier pp.1125.

Philip J, Lewis R,George P.Immune mediated disorders(chapter8).contemporary oral and maxillofacial pathology .2nd edn,Mosby pp.265

Antigens in various pemphigus diseases

‘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).

• Blocking of desmocollin Dsc3 function with a monoclonal antibody led to the formation of intraepidermal blisters.

• some patients were found to develop antimitochondrial antibodies, which could penetrate keratinocytes and react with mitochondrial proteins.

• 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 antibody-induced apoptosis theory

• Apoptosis may possibly be responsible for the underlying mechanisms of acantholysis.

• The activation of apoptotic signalling can be induced by pemphigus IgG and anti-Fas receptor (anti-FasR) antibody.

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.

• 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.

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.

• 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.

• In 2009, a novel term, ‘apoptolysis’, was proposed by Grando et al., 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.

Short comings • There is a mistake in figure 1(Desmoglein

(Dsg)3 (blue) is distributed in the superficial epidermis and mucosa ,no blue colour is there in diagram.Dsg 1-green Dsg3-red).

• No explanation of structure of desmoglein.• No conclusion of other theories except The

desmoglein compensation theory.

Conclusion

• Autoantibodies produced by patients with PV play a major role in the disease.

• Desmogleins are the main target antigen.• 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.

References• Christopher A. D’Angelis.The Pathology of Pemphigus: A

Mini-Review. N A J Med Sci. 2013;6(1):37-40.• Dr. P. T. Chan. Review on Pathogenesis of Pemphigus. Hong

Kong Dermatology & Venereology Bulletin62 2002;10(2):62-68.

• Rajendran R, Sivapathasundharam B. Disease of the skin(chapter19).Shafer’s Text book of Oral Pathology. 5th edn, Elesevier pp.1125.

• Philip J, Lewis R,George P.Immune mediated disorders(chapter8).contemporary oral and maxillofacial pathology .2nd edn,Mosby pp.265.