The hallmark of pemphigus is the finding of IgG autoantibodies against the cell surface of keratinocytes. The pemphigus autoantibodies found in patients’ sera play a primary pathogenic role in inducing blisters. When IgG fraction from patients is passively transferred to neonatal mice, the mice develop blisters with typical histologic findings [3]. Even monovalent Fab’ fragments of IgG or single chain fragment variables (monoclonal antibodies isolated using phage display technique, consisting of the variable regions of light chain and heavy chain of immunoglobulin) from patients are sufficient to cause blisters in neonatal mice, indicating complement activation and surface cross-linking may not be relevant in keratinocyte detachment [8–10].

Immunoelectron microscopy localized both pemphigus vulgaris and pemphigus foliaceus antigens to the desmosomes, the most prominent cell–cell adhesion junctions in stratified squamous epithelia [11]. Immunochemical characterization of pemphigus antigens by immunoprecipitation or immunoblotting with extracts from cultured keratinocytes or epidermis demonstrated that the pemphigus vulgaris and foliaceus antigens were 130 kD and 160 kD transmembrane glycoproteins, respectively [4, 5, 12]. The 160 kD protein recognized by pemphigus foliaceus sera was subsequently shown to be identical with desmoglein 1 (Dsg1) by comparative immunochemical studies [13].

Molecular cloning of cDNA encoding Dsg1 and pemphigus vulgaris antigens indicated that both molecules were desmogleins, which are the members of the cadherin supergene family [6, 7] (Fig. 33.1). Thus, pemphigus was discovered to be an anti-desmoglein autoimmune disease. The pemphigus vulgaris antigen was termed desmoglein 3 (Dsg3).

Desmosomes are intercellular adhesive junctions in the epidermis and mucous membranes and contain two major transmembrane components, desmogleins and desmocollins, both of which are cadherin type cell adhesion molecules. Desmogleins have four isoforms (Dsg1 to Dsg4). Expression of Dsg1 and Dsg3 is basically restricted to stratified squamous epithelia, where blisters are formed in pemphigus, while Dsg2 is expressed in all desmosome-possessing tissues, including simple epithelia and myocardium [14]. Dsg4 plays an important adhesive role mainly in hair follicles because mutations in DSG4 gene cause abnormal hair development [15]. The molecular structure of desmogleins is unique and they have four cadherin repeats in their extracellular domain as do classic cadherins and have an extra carboxyl-terminal domain containing repeats of a 29 ± 1 residues (Fig. 33.1).

Compelling evidence has accumulated that IgG autoantibodies against Dsg1 and Dsg3 are pathogenic and play a primary role in inducing the blister formation in pemphigus. Essentially, all patients with pemphigus have IgG autoantibodies against Dsg1 and/or Dsg3, depending on the subtype of pemphigus [16, 17]. When anti-desmoglein IgG autoantibodies are removed from patients’ sera of pemphigus vulgaris, pemphigus foliaceus or paraneoplastic pemphigus by immunoadsorption with recombinant desmoglein proteins, the sera are no longer pathogenic in blister formation [18, 19]. Furthermore, anti-desmoglein IgG autoantibodies that were affinity-purified from pemphigus sera on the desmoglein recombinant proteins can cause blisters when injected in neonatal mice [19, 20]. Some pemphigus sera react with Dsg4 due to cross-reactivity of a subset of anti-Dsg1 IgG, although Dsg4/Dsg1-cross-reacting IgG has no demonstrable pathogenic effect [21]. IgG autoantibodies against acetylcholine receptors or annexin-like molecules are reported, but their pathogenic relevance in pemphigus remains to be determined [22–24].

Thus, the basic pathophysiology of pemphigus is that IgG autoantibodies raised against Dsg1 and/or Dsg3 inhibit their adhesive function and lead to the loss of the cell–cell adhesion of keratinocytes, resulting in blister formation. Recent studies, in which pathogenic and non-pathogenic monoclonal antibodies were isolated from pemphigus patients, suggest that patients would have polyclonal IgG with diverse pathogenic activities [10, 25, 26]. Although the mechanism of blister formation in pemphigus is not fully understood, it is considered that the loss of cell-cell adhesion is triggered by the combination of direct inhibition of Dsg interactions (steric hindrance), the activation of cellular signal pathways, and endocytosis of cell surface Dsg [27–29].

Although the disruption of desmoglein-dependent cell adhesion by autoantibodies is the basic pathophysiology underlying blister formation in pemphigus, the clinical spectrum is more complex. The complex clinical features of pemphigus are explained logically by the desmoglein compensation theory: Dsg1 and Dsg3 compensate for each other when they are coexpressed in the same cell [30–32] (Fig. 33.2).

The intraepithelial expression pattern of Dsg1 and Dsg3 is different between the skin and mucous membranes. In the skin, Dsg1 is expressed throughout the epidermis, but more intensely in the superficial layers, while Dsg3 is expressed in the lower portion of the epidermis, primarily in the basal and parabasal layers. In contrast, Dsg1 and Dsg3 are expressed throughout the squamous layer of mucosa, but Dsg1 is expressed at a much lower level than Dsg3.

Patients with pemphigus foliaceus have only anti-Dsg1 IgG autoantibodies (Table 33.2). Patients with the mucosal dominant type of pemphigus vulgaris have only anti-Dsg3 IgG autoantibodies, whereas those with the mucocutaneous type of pemphigus vulgaris have both anti-Dsg3 and anti-Dsg1 IgG autoantibodies [33, 34].

For example, when sera contain only anti-Dsg1 IgG, which interferes with the function of Dsg1, the presence of Dsg3 compensates for the loss of function of Dsg1 in the lower epidermis. In contrast, in upper epidermis, there is no compensation by Dsg3. Therefore, blisters only appear in the superficial epidermis of the skin because that is the only area in which Dsg1 is present without coexpression of Dsg3. Although the anti-Dsg1 IgG binds to mucosa, no blisters are formed because of the coexpression of Dsg 3. Thus, sera containing only anti-Dsg1 IgG cause superficial blisters in the skin without mucosal involvement, as is seen in patients with pemphigus foliaceus.

The desmoglein compensation theory also explains the clinical and histological phenotype of bullous impetigo and staphylococcal scalded skin syndrome (SSSS) [32]. The blisters of bullous impetigo and SSSS are caused by exfoliative toxin (ET), which is produced by Staphylococcus aureus. ET was recently discovered to bind specifically to Dsg1 and cleave only the site after glutamic acid residue 381 between extracellular domains 3 and 4 [35–37]. When ET reaches the skin and digests Dsg1 in the lower layers of the epidermis, Dsg3 compensates for the loss of function of Dsg1 and manages to maintain cell–cell adhesion, while no compensation by Dsg3 occurs in the superficial layers of the epidermis. Therefore, ET induces superficial blisters on the skin. In mucous membranes, the Dsg3 expressed throughout the squamous layers of the mucosa compensates for the impaired Dsg1 and maintains cell–cell adhesion with no mucosal involvement.

In addition to IgG autoantibodies against Dsg3 and/or Dsg1, patients with paraneoplastic pemphigus (PNP) develop characteristic IgG autoantibodies against multiple antigens with molecular weights of 500, 250, 230, 210, 190 and 170 kDa [19, 38] (Table 33.2). By immunochemical studies and cDNA cloning, most of these antigens were identified. The 500 kD antigen is plectin. The 250 kD and 210 kD antigens are desmoplakins I and II, respectively. The 230 kDa antigen is bullous pemphigoid antigen 1, the major plaque protein of the epidermal hemidesmosome and also a target antigen in bullous pemphigoid. The 210 kDa band also contains envoplakin. The 190 kDa antigen is periplakin, and 170 kDa antigen was recently identified as alpha-2-macroglobulin-like-1, a broad-range protease inhibitor [39, 40].

Anti-desmoglein antibodies play a role in inducing the loss of cellular adhesion of keratinocytes and initiate blister formation, while the pathophysiological relevance of the anti-plakin autoantibodies is unclear. The intracellular location of plakin proteins makes it unlikely that anti-plakin autoantibodies initiate pathology in paraneoplastic pemphigus because IgG cannot penetrate cell membranes. It is also important to bear in mind that not only humoral immunity but also cell-mediated cytotoxicity is involved in the pathogenesis of paraneoplastic pemphigus in a form of interface dermatitis. Patients with PNP show more severe and refractory oral erosions and stomatitis as well as more polymorphic skin eruptions when compared with classic forms of pemphigus. Recent studies using the pemphigus mouse model indicated that CD4⁺ T cells recognizing Dsg3 are able to directly infiltrate to dermal-epidermal junctions and induce interface dermatitis, suggesting the involvement of the cellular autoimmune reaction to epidermal antigens in PNP [41].

Pemphigus vulgaris has two clinical subtypes: mucosal dominant type and mucocutaneous type. Patients with mucosal dominant type show mucosal erosions mainly in the oral cavity with minimal or limited skin involvement. Patients with mucocutaneous type show extensive flaccid blisters and erosions on the skin in addition to the mucosal erosions. Any stratified squamous epithelia where Dsg1 and/or Dsg3 are expressed can be involved in pemphigus vulgaris.

Mucous membrane lesions are usually seen as painful erosions (Fig. 33.3). Intact blisters are rare, probably because they are fragile and break easily. Scattered and often extensive erosions may be seen on any part of the oral cavity. Extensive erosions and painful lesions in the mouth may result in decreased food and drink intake. Involvement of throat may produce hoarseness and difficulty in swallowing. The esophagus, conjunctiva, nasal mucosa, vagina, penis, anus and labia may also be involved. The diagnosis of pemphigus vulgaris tends to be delayed in patients presenting with only oral involvement, as compared to patients with skin lesions.

The primary skin lesions of pemphigus vulgaris are flaccid, thin-walled, easily ruptured blisters that appear anywhere on the skin surface (Fig. 33.4). The blisters arise on normal-appearing skin or erythematous bases. The blisters are fragile and soon rupture to form painful erosions that ooze and bleed easily. The erosions soon become partially covered with crusts that have little or no tendency to heal. Without appropriate treatment, pemphigus vulgaris can be fatal because large area of the skin lose epidermal barrier function, leading to loss of body fluids or secondary bacterial infection. Because of absence of cohesion in the epidermis, the upper layers are easily made to slip laterally by slight pressure or rubbing in active patients with pemphigus (Nikolsky sign).

Patients with pemphigus foliaceus develop scaly, crusted erosions, often on an erythematous base in the skin, but do not have apparent mucous membrane involvement even with widespread disease (Fig. 33.5). The absence of oral involvement may be a clue to clinically differentiate pemphigus foliaceus from pemphigus vulgaris.

The onset of disease is often subtle with a few scattered crusted lesions which come and go, and are frequently mistaken for impetigo. These lesions are usually well demarcated and scattered in a seborrheic distribution, including face, scalp, and upper trunk. Because the vesicle is so superficial and fragile, often only the crust and scale that result from a ruptured vesicle are seen. Disease may stay localized for years or may rapidly progress, in some cases, to generalized involvement resulting in an erythrodermic exfoliative dermatitis. Nikolsky sign is present. Generally patients with pemphigus foliaceus are not severely ill.

Paraneoplastic pemphigus is a recently described form of pemphigus that occurs in association with underlying neoplasms [38, 39]. PNP is unique and distinct from the classic forms of pemphigus vulgaris and foliaceus by clinical, histologic, and immunopathologic criteria. The associated neoplasms are non-Hodgkin’s lymphoma (42 %), chronic lymphocytic leukemia (29 %), Castleman’s tumor (10 %), malignant and benign thymoma (6 %), spindle cell neoplasms (reticulum cell sarcoma) (6 %), and Waldenstrom’s macroglobulinemia (6 %). The combination of non-Hodgkin’s lymphoma and chronic lymphocytic leukemia represents almost two thirds of cases. Castleman’s disease, which is a very rare lymphoproliferative lesion, is the third most commonly associated neoplasm. The absence of common tumors, such as adenocarcinoma of breast or bowel and squamous cell carcinomas, is notable.

The most constant clinical feature of paraneoplastic pemphigus is the presence of intractable stomatitis (Fig. 33.6). The severe stomatitis is usually the earliest presenting sign and after treatment it is the one that persists and is extremely resistant to therapy. This stomatitis consists of erosions and ulcerations that affect all surfaces of the oropharynx and characteristically extend onto the vermillion of the lip. Most patients also have a severe pseudomembranous conjunctivitis with scarring. Esophageal, nasopharyngeal, vaginal, labial, and penile mucosal lesions may also be affected.

The cutaneous lesions are quite polymorphic and may appear as erythematous macules, flaccid blisters and erosions resembling pemphigus vulgaris, tense blisters resembling bullous pemphigoid, erythema multiforme-like lesions, and lichenoid eruptions. Extensive cases show clinical resemblance with toxic epidermal necrolysis (TEN). The occurrence of blisters and erythema multiforme-like lesions on the palms and soles can be used to clinically differentiate paraneoplastic pemphigus from pemphigus vulgaris. Cutaneous lichenoid eruptions are very common together with severe stomatitis. In the chronic form of the disease lichenoid eruption may predominate over blistering lesions.

Paraneoplastic pemphigus is the only form of pemphigus that has involvement of non-stratified squamous epithelia. Approximately, 30–40 % of patients develop pulmonary symptoms [42, 43]. The earliest symptoms are progressive dyspnea, and pulmonary function studies show airflow obstruction, involving large and small airways, as seen in bronchiolitis obliterans, which can be fatal through respiratory failure. Recently, it has been demonstrated that the ectopic expression of Dsg3 or other epidermal antigens in the lung in the form of squamous metaplasia, which is often found in the lungs of PNP patients, is able to render the lung a target organ in PNP [44].

The characteristic histological finding of the classic form of pemphigus is intraepidermal blister formation due to loss of cell-to-cell adhesion (acantholysis) of keratinocytes without keratinocyte necrosis. In pemphigus vulgaris, acantholysis usually occurs just above the basal cell layer (suprabasilar acantholysis) (Fig. 33.7). A few rounded up (acantholytic) keratinocytes as well as clusters of epidermal cells are often seen in the blister cavity. Although the basal cells lose contact with their neighbors, they maintain their attachment to the basement membrane, thus giving the appearance of a “row of tombstones”. Eosinophilic spongiosis can be also seen in very early lesions of pemphigus.