Blisters are fluid filled lesions in the skin. Some types of blister are caused by friction during physical exercise, while others are precipitated by allergic or drug reactions; the most severe symptoms are caused by the blisters formed due to genetic and autoimmune diseases.
Blisters (fluid-filled pockets between layers of the skin) develop under various conditions, the most common being physical exercise during which the skin is repeatedly rubbed when the frictional forces eventually separate the epidermal cells . Blisters due to friction occur most frequently in the palms of the hands and on the soles of the feet . Although common, blisters are not trivial; many conditions leading to blister formation may cause infection .
Much more severe are the blistering diseases caused by autoimmune or genetic bullous conditions . The autoimmune blistering diseases are a collection of conditions that can be divided into two groups. In pemphigus diseases, the separation of layers occurs within the epidermis, because antibodies against desmosomal proteins are present that weakens contacts between epidermal cells . In subepidermal (pemphigoid) diseases, the separation is between the epidermis and the dermis, caused by autoantibodies against hemidesmosomal proteins; this situation also occurs in epidermolysis bullosa acquisita .
Several diseases have been identified in both groups. In the pemphigus disease group, pemphigus vulgaris affects the mucous membranes and pemphigus foliaceus affects only the skin, whereas mucocutaneous diseases cause problems in both mucous membranes and skin. The different varieties have antibodies against different isotypes of a desmosomal adhesion protein . Paraneoplastic pemphigus is associated with neoplasia and is characterized by debilitating skin lesions, including stomatitis  .
Among the subepidermal diseases, bullous pemphigoid (BP) and pemphigoid gestationis are associated with severe itching . Linear IgA dermatosis is a disease of children. Epidermolysis bullosa acquisita, which is characterized by the presence of anti-collagen antibodies , has two variants: one is the inflammatory type that closely resembles BP and the other presents with blisters developing at mechanically exposed locations. Dermatitis herpetiformis is the cutaneous manifestation of celiac disease .
A large group of inherited subepidermal blistering diseases is called epidermolysis bullosa. Currently, mutations affecting ten genes have been identified that result in the blistering seen in the various forms of this disease .
Friction blisters are caused by a split in the stratum spinosum. The keratinocytes forming the top of the blister are normal and necrotic. The floor of the blister also has these types of keratinocytes, but in addition, it has edematous ones also. The blister is filled with clear serum unless infected.
For autoimmune blistering diseases, the best diagnostic tool is direct immunofluorescence microscopy. This can show the presence of bound autoantibodies on the skin or on mucous membranes of the patient in both pemphigus and pemphigoid (subepidermal) diseases.
Indirect immunofluorescence microscopy identifies circulating antibodies by testing for the binding of these proteins to monkey, guinea pig, or normal human skin substrates. The antibodies will bind to the target antigens in the test skin samples .
These assays are followed up by tests using western blot and enzyme-linked immunosorbent (ELISA) assays. There are commercially available ELISA kits for antibodies against several of the target antigens (transglutaminase, and components of desmosomes and hemidesmosomes). These tests can also be used to monitor the disease during immunosuppressant treatment .
Some of the blistering autoimmune diseases can be differentiated from each other based on indirect immunofluorescence. Others need the consideration of all available information for diagnosis, including clinical, histopathological, and immunofluorescence results .