autoimmune disease

1. The pathogenic role of
autoantibodies in pemphigus
vulgaris. M. Pan, X. Liu and J. Zheng..
Clinical and Experimental
Dermatology.2011:703–707

2. 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)

3. 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

4. • 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

5. Theories on the pathogenesis
of pemphigus vulgaris

6. 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.

7. (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.

8. (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.

9. • 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

10. Antigens in various pemphigus
diseases

12. ‘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).

13. • 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.

14. 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.

15. 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.

16. • 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.

17. 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.

18. • 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.

19. • 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.

20. 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.

21. 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.

22. 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.