**2. Blistering formation mechanisms**

There are different mechanisms underlying vesicle and bulla formations, these are spongiosis, achantholysis, ballooning degeneration, and cytolysis (epidermolysis) [1, 2].

### **2.1 Loss of intercellular cohesion**

*Acantholysis* is the loss of intercellular cohesion for various reasons. There may be many causes of primary acantholysis, the most known being pemphigus group diseases caused by autoantibodies against desmosome proteins. This condition can be caused by bacterial toxins, as in staphylococcal scalded skin syndrome, or by a genetic defect in the kertinocyte cell membrane, as in Hailey–Hailey disease [3–5].

*Spongiosis***,** which describes intercellular edema causes secondary loss of intercellular cohesion although the intercellular connections are structurally normal. Loss of cohesion appears as small cavities in the epidermis in histopathology. It is called spongiosis because of its sponge-like appearance. As the severity of inflammation increases, the small spaces formed coalesce to form vesicle-bulla formation. The best example of this situation is allergic contact dermatitis [6].

*Ballooning degeneration* is the appearance of affected spinous cells with pale cytoplasm swollen due to intracellular edema. Necrosis of these cells and loss of attachment to neighboring cells is the cause of secondary acantholysis. It is characteristically seen in infections caused by some viruses, such as herpes, smallpox, and Coxsakie [7].

*Cytolysis* of basal layer cells of the epidermis causes loss of epidermal cohesion. In the epidermolytic form epidermolysis bullosa, bullae form due to post-traumatic damage to genetically defective basal layer cells [8].

#### *2.1.1 Desmosomes, hemidesmosomes, and basal membrane*

Preservation of the integrity of the epidermis depends on secure adhesion between adjacent keratinocytes, and between basal keratinocytes and the underlying epidermal basement membrane (BM). The major adhesion units are hemidesmosomes and desmosomes. As a result of damage to these connections by genetic, immune, infectious, or physical reasons, intercellular connections are broken and extracellular fluid accumulates in the intercellular spaces. This fluid accumulation appears as vesicles, intact or opened bullae, and erosions [2].

Desmosomes are structures that connect the intracellular skeleton to the cell membrane and other cells. Proteins, such as desmogleins, desmocollins, plakoglobins, plakophilins, and desmoplakins form the structure of the desmosome. The genetic absence of these proteins or the autoantibodies developed against these proteins cause genetic and autoimmune bullous diseases [9–11].

Basal keratinocytes adhere to connective tissue via extracellular matrix proteins that constitute BM [12]. Epidermal BM between the epidermis and dermis contains four principal basement membrane components; laminins, type IV collagens, perlecan, and nidogens [13].

Laminin-332, the most abundant laminin, distribute both throughout the epidermal BM and condenses in hemidesmosomes. Laminin-511 supports keratinocyte adhesion too and both laminins are important in maintaining the structural integrity of the BM and interact with integrin a3b1 and a6b4. In addition to integrin receptors, laminin-332 interacts with multiple proteins such as collagen XVII, syndecan 1 and 4, perlecan, nidogen 1, fibulin 2, and collagen VII [13, 14].

Collagen IV is the second major component of BM and is vital for maintaining epidermal BM integrity. The laminin and collagen IV networks need to be connected for BM stability. This task in the epidermal BM is performed by nidogens. Perlecan is an additional possible linker. Another BM component, fibrillin 1, interacts with perlecan and forms microfibrils participating in the anchorage of the epidermal BM to the papillary matrix [13, 15].

Collagen VII (anchoring fibrils) expressed by both epidermal keratinocytes and dermal fibroblasts has evolved as a specialized non-redundant component of the DEJ ensuring the firm attachment of the epidermal BM to the papillary matrix [13, 16]. As opposed to anchoring filaments, anchoring fibrils are much larger and have a characteristic structure anti-parallel alignment of type VII collagen molecules [16].

Epidermal BM has evolved to contain additional supportive structures that ensure firm adhesion of the epidermis to the dermis. This zone known as the dermalepidermal junction (DEJ) is a functional unit composed of the plasma membrane of the basal keratinocyte with its hemidesmosomes, a lamina lucida, lamina densa, and a sublamina densa fibrous zone or reticular layer. DEJ plays a vital role in regulating communication between the epidermis and dermis and tissue reconstruction and repair [13–15].

Hemidesmosomes are cell-matrix junctions that connect epidermal keratinocytes to the BM. The core of each hemidesmosome consists of 180 kDa-bullous pemphigoid antigen (BP180, type XVII collagen, BPAG2), the two subunits of the α6β4 integrin, and a tetraspanin protein termed CD151. In BM, BP180 and α6β4 integrin interact with laminin–332. The cytoplasmic tail of the β4 integrin subunit binds both BP180 and two members of the plakin family, the 230 kDa bullous pemphigoid antigen (BP230 or BPAG1e) and plectin [12].

Subepidermal autoimmune bullous diseases (SABDs) are diseases characterized by subepidermal blisters that develop as a result of antibodies against DEJ components that are important structural proteins for the maintenance of dermo-epidermal integrity [17]. Bullous pemphigoid, mucous membrane pemphigoid, acquired epidermolysis bullosa, and linear IgA bullous dermatosis will be explained in these group disorders in this chapter.
