**3. Pathogenesis**

The pathogenesis of pemphigus involves the targeting of inter-keratinocyte adhesion mole‐ cules by autoantibodies, leading to acantholysis and subsequent blister formation. There are

© 2013 Fernando et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

four subtypes of desmoglein, which are glycoproteins that belong to a superfamily of cadherin molecules and are essential components of desmosomal intracellular adhesive junctions [8]. The molecular target in PF is desmoglein-1, which is found predominantly in the upper layers of the epidermis of the skin [9] [10]. Two subtypes of PV are described. In mucosal-dominant PV, the molecular target is restricted to desmoglein-3, whereas in mucocutaneous PV, the target is desmoglein-3 and desmoglein-1.[8] Desmoglein-3 is found in mucous membranes and predominantly in the lower layers of the epidermis of the skin and hence explains the absence of mucous membrane involvement in PF. Current evidence suggests that autoantibodies to desmogleins cause the loss of this desmosome from the surface of the keratinocyte and rearrangement of the actin cytoskeleton. This results in an unidentified cascade of signalling events resulting in apoptotic cell death and acantholysis [11]. Autoantibodies to desmoglein-3 and desmoglein-1 are paramount in the pathogenesis of PV and PF. In PV, this is demonstrated by the fact that passive transfer of serum IgG to desmoglein-3 into newborn mice induces blister formation [12].

Genetic susceptibility by individuals that increases their risk for developing pemphigus is suggested by studies describing associations between certain HLA polymorphisms and subtypes of disease. For instance, HLA-DRB\*0102, 0404, 1402, and 1406 have been associated with endemic PF [5]. In 87 Italian patients, 61 with PV and 26 with PF, it was found that pemphigus vulgaris and pemphigus foliaceus share HLA-DRB1\*1401 and DQB1\*0503, are both associated with both PV and PF, whereas DRB1\*0402 is only prevalent in patients with PV [19]. In a group of 20 French patients [20] the HLA alleles DRB1\*0404 and DRB1\*0102 were found to be associated with PF. It remains to be determined, whether these HLA-polymor‐ phisms are true disease susceptibility genes given their role in antigen presentation. Alterna‐ tively, they may be markers of disease susceptibility through strong linkage disequilibrium with the causative gene. An environmental trigger may ultimately result in expression if disease in genetically susceptible individuals as is suspected to occur in endemic PF in Brazil[21]. Recently, it has been postulated that the inciting antigen in Brazil is a salivary

**Clinical Presentation Natural History/**

Commonest and most aggressive form of pemphigus: oral mucosal involvement common and often first site of presentation leading to extensive skin involvement.

Uncommon and less aggressive clinical variant of PV: presents with large verrucous confluent plaques and pustules localized to

Often begins and ends as typical PV. Needs more intense immune-suppression than seen with PV, with patients troubled by chronic relapses (and remissions).

Relatively benign, usually very well localised

superficial cutaneous blisters and erosions seen on histology as subcorneal

Very rare condition with the combined features of pemphigus foliaceus and SLE

flexural areas (axilla/groin).

disease.

acantholysis.

Pemphigus foliaceus (PF) Rare All forms of PF are characterised clinically by

**Prognosis/ Outcome**

Pemphigus Vulgaris and Pemphigus Foliaceus

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107

Fatal if untreated Good with treatment

Often progresses to pemphigus vulgaris

Frequent relapses (even with treatment)

Prolonged remission (with treatment)

More benign course than PV, with prolonged remission. **Target Antigens**

Desmoglein 3 (Dsg 3 is more common in oral epithelium) (& Desmoglein 1 (Dsg-1 & 3 are both found in skin))

Desmoglein 1

protein from a haematophagous black fly, *Simulium nigrimanum* [22].

Usually the first site involved

(in all 3 forms of pemphigus vegetans)

**Disease and Subtype(s)** *(alternate terms)*

Oral Cutaneous

Pemphigus vulgaris (PV) Common.

Pemphigus vegetans Rare

Pemphigus vegetans of Neumann

Pemphigus vegetans of Hallopeau

Pemphigus erythematosus ( "Senear-Usher syndrome")

Interaction between antigen specific T cells and B cells is postulated for the production of antibodies to desmoglein-3 and desmoglein-1. Autoantibody production has been shown, in vitro, to be dependent on mononuclear cells [13]. Further, aberrant T cell recognition of desmoglein-3 and desmoglein-1 is likely involved in the initiation and perpetuation of the B cell response.

Additionally, in PV, HLA Class 2 alleles including HLA DRβ1\*0402, β1\*1401, β1\*0503 may be involved in the presentation of desmoglein-3 peptides to autoreactive T cells. However, similar associations are not observed in PF [14]. Further it has been observed that autoantibodies of the Th2-dependent IgG4 subtype are present in active disease but are not detectable in inactive disease or healthy individuals [15]. In active disease, IgG1 and IgG4 recognises epitopes in EC1 (amino acids 50-79, Bos 1) and EC2 (amino acids 200-29, Bos 2) of desmoglein-3. In inactive disease, only autoantibodies of the Th1-dependent IgG1 subtype to EC1 are detectable [15]. These observations suggest that IgG4 against EC2 is the main antibody responsible for acantholysis, but that this process may be facilitated or enhanced by IgG4 against EC1 [14].

A Th2 response predominates in PV. This suggests that Th2 cells are needed to activate B cells to initiate antibody production [16]. Further, in PV and PF, imbalance between Th2 and Th1 cytokines in terms of the elevation of the former against the suppression of the latter is postulated to contribute to pathogenesis [16],[17]. It is possible that Th17 and Treg pathways may also be integral. However, the association between Th cell subsets and disease activity is not well understood.

PV autoantibodies also bind large portions of keratinocytes outside desmosomal structures. Autoantibodies against other keratinocyte surface antigens such as desmoglein-4, desmocol‐ lins, acetylcholine receptors, pemphaxin and α-9 acetylcholine receptors, of which some or maybe all, may be involved in the pathogenesis of PV [8]. It is not clear whether blister formation is a direct result of these antibodies or occurs indirectly through immune mediated pathways which involve inflammatory cells and cytokines [14]. For instance, TNF-α is observed to be raised in PV compared to healthy controls, and may also increase with disease activity [16],[18].

Genetic susceptibility by individuals that increases their risk for developing pemphigus is suggested by studies describing associations between certain HLA polymorphisms and subtypes of disease. For instance, HLA-DRB\*0102, 0404, 1402, and 1406 have been associated with endemic PF [5]. In 87 Italian patients, 61 with PV and 26 with PF, it was found that pemphigus vulgaris and pemphigus foliaceus share HLA-DRB1\*1401 and DQB1\*0503, are both associated with both PV and PF, whereas DRB1\*0402 is only prevalent in patients with PV [19]. In a group of 20 French patients [20] the HLA alleles DRB1\*0404 and DRB1\*0102 were found to be associated with PF. It remains to be determined, whether these HLA-polymor‐ phisms are true disease susceptibility genes given their role in antigen presentation. Alterna‐ tively, they may be markers of disease susceptibility through strong linkage disequilibrium with the causative gene. An environmental trigger may ultimately result in expression if disease in genetically susceptible individuals as is suspected to occur in endemic PF in Brazil[21]. Recently, it has been postulated that the inciting antigen in Brazil is a salivary protein from a haematophagous black fly, *Simulium nigrimanum* [22].

four subtypes of desmoglein, which are glycoproteins that belong to a superfamily of cadherin molecules and are essential components of desmosomal intracellular adhesive junctions [8]. The molecular target in PF is desmoglein-1, which is found predominantly in the upper layers of the epidermis of the skin [9] [10]. Two subtypes of PV are described. In mucosal-dominant PV, the molecular target is restricted to desmoglein-3, whereas in mucocutaneous PV, the target is desmoglein-3 and desmoglein-1.[8] Desmoglein-3 is found in mucous membranes and predominantly in the lower layers of the epidermis of the skin and hence explains the absence of mucous membrane involvement in PF. Current evidence suggests that autoantibodies to desmogleins cause the loss of this desmosome from the surface of the keratinocyte and rearrangement of the actin cytoskeleton. This results in an unidentified cascade of signalling events resulting in apoptotic cell death and acantholysis [11]. Autoantibodies to desmoglein-3 and desmoglein-1 are paramount in the pathogenesis of PV and PF. In PV, this is demonstrated by the fact that passive transfer of serum IgG to desmoglein-3 into newborn mice induces

Interaction between antigen specific T cells and B cells is postulated for the production of antibodies to desmoglein-3 and desmoglein-1. Autoantibody production has been shown, in vitro, to be dependent on mononuclear cells [13]. Further, aberrant T cell recognition of desmoglein-3 and desmoglein-1 is likely involved in the initiation and perpetuation of the B

Additionally, in PV, HLA Class 2 alleles including HLA DRβ1\*0402, β1\*1401, β1\*0503 may be involved in the presentation of desmoglein-3 peptides to autoreactive T cells. However, similar associations are not observed in PF [14]. Further it has been observed that autoantibodies of the Th2-dependent IgG4 subtype are present in active disease but are not detectable in inactive disease or healthy individuals [15]. In active disease, IgG1 and IgG4 recognises epitopes in EC1 (amino acids 50-79, Bos 1) and EC2 (amino acids 200-29, Bos 2) of desmoglein-3. In inactive disease, only autoantibodies of the Th1-dependent IgG1 subtype to EC1 are detectable [15]. These observations suggest that IgG4 against EC2 is the main antibody responsible for acantholysis, but that this process may be facilitated or enhanced by IgG4 against EC1 [14]. A Th2 response predominates in PV. This suggests that Th2 cells are needed to activate B cells to initiate antibody production [16]. Further, in PV and PF, imbalance between Th2 and Th1 cytokines in terms of the elevation of the former against the suppression of the latter is postulated to contribute to pathogenesis [16],[17]. It is possible that Th17 and Treg pathways may also be integral. However, the association between Th cell subsets and disease activity is

PV autoantibodies also bind large portions of keratinocytes outside desmosomal structures. Autoantibodies against other keratinocyte surface antigens such as desmoglein-4, desmocol‐ lins, acetylcholine receptors, pemphaxin and α-9 acetylcholine receptors, of which some or maybe all, may be involved in the pathogenesis of PV [8]. It is not clear whether blister formation is a direct result of these antibodies or occurs indirectly through immune mediated pathways which involve inflammatory cells and cytokines [14]. For instance, TNF-α is observed to be raised in PV compared to healthy controls, and may also increase with disease

blister formation [12].

106 Skin Biopsy - Diagnosis and Treatment

cell response.

not well understood.

activity [16],[18].



**Disease and Subtype(s)** *(alternate terms)*

direct immune-fluorescence,

**4. Clinical features**

**4.1. Pemphigus vulgaris**

**4.2. Pemphigus foliaceus**

42%)[24].

**Clinical Presentation Natural History/**

Pathogenesis: heterozygous mutations of the ATP2C1 gene leads to a malfunction of the encoded protein hPMR1 - hPMR1 being a high-affinity calcium transport ATPase pump of the Golgi complex. A low level of intracellular Ca2+ induces premature keratinocyte proliferation, which leads to dysfunctional desmosomal proteins and thus abnormal keratinocyte adhesion. PV = pemphigus vulgaris; PF = pemphigus foliaceous, SLE = systemic lupus erythematosus, FS = Fogo Sevagem, DIF =

cf = in contrast, BP = bullous pemphigoid, AD = autosomal dominant inheritance, Ca2+ = calcium ion

Patients with PV usually present, in the initial stage, with highly painful erosions of the oral mucosa (Figures 1, 2) [23], but other mucous membranes such as the nasal, laryngo-esophageal, genital, anal and conjunctival mucosae can be involved. Some patients have mucosal dominant disease whereas in others cutaneous lesions develop and manifest as flaccid blisters followed by denuding and ulceration (Figure 3). A direct Nikolksy's sign can be elicited where tangential pressure on the on perilesional skin causes the epidermis to separate from the dermis. Skin lesions have a predilection for the trunk, groins, axillae, scalp, face, and pressure points. Secondary infection and dehydration are frequent cause of morbidity and mortality. Studies that differentiate PV according to clinical phenotype have shown a lower mortality in patients with predominantly mucosal PV (1–17%) compared with those with mucocutaneous PV (34–

Non-endemic PF usually presents in middle age or older adults whereas endemic PF is more common in children and young adults. FS in Tunisian affect women 4 times as often as men [7]. In both non-endemic and endemic PF, patients usually report the eruption of blisters on the scalp, face and upper trunk but they are fragile and some patients present instead with multiple painful crusted erosions (Figure 4). There is no history of mucosal involvement.

\*hypopyon= sterile leukocytic exudate, seen in the anterior chamber of the eye

**Table 1.** Clinical and Immunohistochemical Variants of Pemphigus

**Prognosis/ Outcome**

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**Target Antigens** 109


PV = pemphigus vulgaris; PF = pemphigus foliaceous, SLE = systemic lupus erythematosus, FS = Fogo Sevagem, DIF = direct immune-fluorescence,

cf = in contrast, BP = bullous pemphigoid, AD = autosomal dominant inheritance, Ca2+ = calcium ion

\*hypopyon= sterile leukocytic exudate, seen in the anterior chamber of the eye

**Table 1.** Clinical and Immunohistochemical Variants of Pemphigus
