THE DESMOSOME AND HEMIDESMOSOME IN CUTANEOUS AUTOIMMUNITY

Epidermal blister formation is the hallmark of three cutaneous autimmu ne diseases: pemphigus foliaceous (PF), pemphigus vulgaris (PV) and bu llous pemphigoid (BP). In PF and PV, blistering is due to acantholysis (cell-cell detachment) in the subcorneal and suprabasal epidermal lay ers, respectively, while BP is characterized by detachment of the basa l epidermal cells from the underlying dermis. For several years, we ha ve focused our research efforts on elucidating the pathogenic mechanis ms operating in these bullous diseases. Early studies performed by our research group and others revealed that in all three diseases, the pa tients produce autoantibodies that bind to target antigens located on the surface of cells that are undergoing detachment. Thus it was hypot hesized that these antiepidermal autoantibodies played a role in initi ating blister formation. We recognized that elucidating the normal mec hanisms of epidermal cell-cell and cell-dermis adhesion would help us understand the abnormal epidermal cell detachment seen in these patien ts. We hypothesized that under normal conditions these adhesive mechan isms in the epidermis are complex and dynamic and mediated by the inte raction of cell surface molecules unique to each layer of the epidermi s. Also, we postulated that PV, PF and BP autoantibodies may cause cel l detachment by impairing the function of their respective epidermal c ell surfaces. Support for this hypothesis has come from recent studies which showed that PV and PF autoantibodies recognize distinct, yet re lated, desmosomal glycoproteins in the cadherin family of calcium-depe ndent adhesion molecules. The epidermal antigen in PV is desmoglein-3 (dsg3), while in PF it is desmoglein-1 (dsg1). These anti-epidermal au toantibodies have been shown to be pathogenic in passive transfer expe riments. Neonatal mice injected with these antibodies develop intraepi dermal blisters chracteristic of the corresponding human disease. Auto antibodies in BP react with BP180 and BP230, two major components of t he hemidesmosome, a cell structure involved in dermal-epidermal adhesi on. Recent passive transfer mouse model studies performed in our labor atory have shown that antiBP180 antibodies can induce subepidermal bli stering in the experimental animals. Moreover, the pathogenic mechanis m was shown to be dependent on complement activation and recruitment o f neutrophils to the dermal-epidermal junction. In conclusion, desmoso mal glycoproteins are the targets of autoimmune injury in PV and PF. T he anti-epidermal autoantibodies may cause intraepidermal blisters by impairing the function of dsg1 and dsg3. In BP the hemidesmosome is th e target. It appears that antiBP180 antibodies cause subepidermal blis ter formation by triggering a complement- and neutrophil-mediated infl ammatory process.