The pathophysiology of bullous pemphigoid involves the functional changes that produce this autoimmune blistering disease. The process begins when the immune system incorrectly identifies structural components of the skin as threats, initiating a cascade of events. This starts with the production of autoantibodies that target these skin proteins. The binding of these autoantibodies sets off an inflammatory response that separates skin layers, forming the condition’s characteristic blisters.
The Autoimmune Trigger and Target Antigens
The skin’s outermost layer, the epidermis, is securely fastened to the underlying dermal layer at the dermo-epidermal junction. Within this junction, structures called hemidesmosomes act like anchors to ensure skin integrity. In bullous pemphigoid, the autoimmune response is directed at two protein components of these hemidesmosomes.
One of the primary targets is bullous pemphigoid antigen 230 (BP230), a protein located inside the skin cells of the epidermis. BP230 helps link the internal structure of the cell to the hemidesmosome anchor. Its main function is to provide stability to the cell and fortify the connection between the epidermis and the dermis.
The other major autoantigen is bullous pemphigoid antigen 180 (BP180), also known as type XVII collagen. BP180 is a transmembrane protein that passes through the cell membrane of basal keratinocytes. Part of the BP180 protein extends outside the cell, where it directly fastens the epidermis to the dermis, contributing to dermo-epidermal adhesion.
Antibody Production and Immune Response Activation
The development of bullous pemphigoid begins when the immune system loses tolerance for BP180 and BP230, identifying them as foreign substances. This loss of tolerance triggers B cells to mature and produce autoantibodies. These proteins are designed to find and bind to the BP180 and BP230 antigens.
The predominant type of autoantibody produced is Immunoglobulin G (IgG), which are the main drivers of the disease process. After being produced, IgG antibodies circulate through the bloodstream to the skin. They accumulate at the dermo-epidermal junction and bind to the BP180 and BP230 antigens, marking them for destruction.
Another class of autoantibodies, Immunoglobulin E (IgE), also has a role in the disease’s manifestation. Elevated levels of IgE that target BP antigens are frequently observed in patients. The binding of IgE to receptors on immune cells like mast cells and eosinophils contributes to the intense itching, or pruritus, that often accompanies the skin lesions.
Inflammatory Cascade and Cell Recruitment
Once IgG autoantibodies bind to BP antigens at the basement membrane zone, they initiate an inflammatory response by activating the complement system. This system is a network of blood proteins that creates a domino effect of biochemical reactions when activated. The binding of IgG triggers the classical complement pathway, generating several inflammatory molecules.
Among the molecules produced are C3a and C5a, which are classified as anaphylatoxins. These protein fragments have pro-inflammatory effects, increasing vascular permeability and allowing fluid to leak from blood vessels. They also function as chemoattractants, which are chemical signals that recruit inflammatory cells to the site of antibody binding.
The complement component C5a is particularly effective at recruiting leukocytes to the dermo-epidermal junction. The primary cells drawn in by this signal are neutrophils, a type of white blood cell that are first responders to inflammation. Eosinophils, another type of white blood cell, are also heavily recruited to the site and are a characteristic feature in the skin lesions.
Tissue Damage and Blister Formation
The arrival of neutrophils and eosinophils at the dermo-epidermal junction marks the beginning of the destructive phase. These recruited cells are packed with granules containing various enzymes. In a process called degranulation, the neutrophils and eosinophils release these enzymes directly onto the basement membrane to break down tissue components.
This enzymatic assault degrades the structural integrity of the hemidesmosome and surrounding basement membrane. Neutrophils release proteases, such as neutrophil elastase, which break down proteins. Both cell types also release matrix metalloproteinases (MMPs), which degrade extracellular matrix components like collagen and the BP180 antigen.
This enzymatic destruction weakens the connection between the epidermis and the underlying dermis, causing the layers to separate. As the hemidesmosomal anchors are dismantled, a space forms between the layers. Fluid from leaky blood vessels seeps into this space, and its accumulation creates the tense, fluid-filled blisters (bullae) that define the condition.