Pemphigus is a group of rare and potentially life-threatening autoimmune disorders characterized by the formation of blisters and erosions on the skin and mucous membranes. Central to the pathogenesis of pemphigus are autoantibodies targeted against desmogleins, which are specific proteins essential for the adhesion between epidermal cells (keratinocytes). The primary types of pemphigus are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), distinguished by the specific desmogleins they target and their clinical manifestations.
Testing for pemphigus autoantibodies is done by immunofluorescence and is the first laboratory step in diagnosing pemphigus.
Molecular Basis of Pemphigus and Its Autoantibodies
Pemphigus is primarily mediated by autoantibodies (mainly IgG) against desmoglein-1 (Dsg1) and desmoglein-3 (Dsg3). Desmogleins are a subtype of cadherins, which are calcium-dependent adhesion molecules that form the core of desmosomes—intercellular junctions that tightly bind cells together in the epidermis. Desmoglein-1 is found predominantly in the upper layers of the epidermis, whereas desmoglein-3 is located mainly in the basal and immediate suprabasal layers.
In pemphigus vulgaris, autoantibodies are typically against desmoglein-3, and lesions can occur on mucous membranes and the skin. In pemphigus foliaceus, the immune response primarily targets desmoglein-1, leading to superficial blisters on the skin without mucosal involvement.
Pathophysiology of Autoantibodies in Pemphigus
The binding of autoantibodies to desmogleins disrupts the adhesive function of these proteins, a process known as acantholysis, which leads to the loss of cell-cell adhesion and the formation of intraepidermal blisters. The autoantibodies interfere with desmoglein function by directly blocking the adhesive interface or triggering a signaling cascade that modifies the desmosomal architecture, weakening cell-cell adhesion.
Moreover, recent studies suggest that the pathogenicity of these autoantibodies involves more than just steric hindrance. The binding of autoantibodies may initiate a change in the intracellular signaling pathways, leading to a reorganization or disassembly of desmosomes. This active process of acantholysis contributes to the clinical severity seen in pemphigus patients.
Diagnostic Significance of Autoantibodies in Pemphigus
The detection of autoantibodies against desmogleins is crucial for the diagnosis of pemphigus. Indirect immunofluorescence (IIF) on monkey esophagus or human skin is used. ELISA for autoantibodies against Dsg1 and Dsg3 provides a highly specific and quantitative measure of autoantibody levels, which is helpful for initial diagnosis and monitoring disease activity and response to therapy.
Clinical Implications and Management
Identifying the specific autoantibodies in pemphigus is essential for appropriate management and treatment. Treatment strategies typically aim to reduce the production of autoantibodies and suppress the overall immune response. This includes the use of systemic corticosteroids, immunosuppressants such as azathioprine, mycophenolate mofetil, and cyclophosphamide, and more recently, biological therapies like rituximab, which targets CD20 on B-cells to reduce autoantibody production.
See also
- Pemphigoid Antibodies (Antibodies against Epidermal Basement Membrane)
- Collagen VII, Antibodies
- BP180, IgG antibodies
- BP180, IgA Antibodies
- BP230, Antibodies
- Desmoglein-1, Antibodies
- Desmoglein-3, Antibodies
- Dapsone
