The Pemphigus Vulgaris pathophysiology overview
Pemphigus vulgaris is a rare yet severe autoimmune blistering disorder that primarily affects the skin and mucous membranes. Its pathophysiology involves a complex interplay between genetic predisposition, immune system dysregulation, and targeted autoantibody production. Understanding this process provides insight into why the disease manifests as fragile blisters and erosions and aids in developing effective treatments.
At the core of pemphigus vulgaris is an autoimmune response where the body’s immune system mistakenly targets specific proteins vital for cell-to-cell adhesion within the skin and mucous membranes. These proteins are desmosomal cadherins, mainly desmoglein 3 and, in some cases, desmoglein 1. Desmogleins are essential for maintaining the structural integrity of keratinocytes— the predominant cells in the epidermis. When these proteins are compromised, the cohesion between keratinocytes weakens, leading to the formation of intraepidermal blisters.
The immune system’s role involves the production of pathogenic autoantibodies—primarily IgG subclasses—that target desmogleins. The generation of these autoantibodies results from a breakdown in immune tolerance, often influenced by genetic factors such as certain HLA alleles, which predispose individuals to abnormal immune responses. Environmental triggers, including infections or certain drugs, may further stimulate autoantibody production, although the precise triggers are still under investigation.
Once these autoantibodies bind to desmogleins on keratinocyte surfaces, they interfere with the proteins’ adhesive functions. This disruption leads to acantholysis, a process characterized by the loss of cohesion between keratinocytes. The weakening of cell adhesion causes the epidermis to become fragile, and blister formation ensues within the superficial layers of the epidermis. These intraepidermal blisters are typically flaccid and easily rupture, resulting in painful erosions on the skin and mucous membranes.
The immune-mediated damage can also trigger secondary inflammatory responses. Complement activation and recruitment of inflammatory cells, such as eosinophils and neutrophils, exacerbate tissue destruction and contribute to the clinical severity. Histopathologically, a hallmark of pemphigus vulgaris is the presence of acantholytic cells—keratinocytes that have lost adhesion—within the blister cavity, observed as “tombstone” basal cells attached to the basement membrane.
In summary, the pathophysiology of pemphigus vulgaris centers on autoimmune targeting of desmosomal proteins, leading to loss of keratinocyte cohesion, blister formation, and tissue destruction. This understanding has paved the way for targeted therapies, such as immunosuppressants and monoclonal antibodies like rituximab, aimed at reducing autoantibody production and restoring immune tolerance.
