Production Of Epidermal Acantholysis In Normal Human Skin In Vitro By The Igg Fraction From Pemphigus Serum

Abstract

Normal human skin was maintained in organ cultures for several days in Ham's F-10 medium with good preservation of the epidermal cells. When the partially purified IgG fraction from the pooled sera of patients with pemphigus vulgaris or pemphigus foliaceous was added to this culture system, after 24 hr some evidence of epidermal acantholysis was seen. By 72 hr, extensive suprabasilar epidermal acantholysis had occurred in which the acantholytic cells were indistinguishable histologically from the acantholytic cells in biopsies from skin lesions of patients with pemphigus vulgaris. In the control cultures (i.e., F-10 medium or F-10 medium + normal human serum IgG), none of these changes was seen. Direct immunofluorescent staining of these explants using fluorescein-labeled goat antihuman IgG showed that by 6 hr binding of the pemphigus IgG had occurred in the intercellular cement substance of the epidermis. The staining intensity was maximal by 18 to 20 hr. When the pemphigus serum was fractionated by DEAE-cellulose column chromatography, three major IgG-containing peaks (presumably IgG) were eluted which bound to the epidermoid intercellular substance and caused acantholysis in culture. The complement system did not play a role in the antibody-induced acantholysis since complement was not included in this system and heating the reconstituted F-10 + pemphigus IgG for 1 hr at 58 degrees C did not destroy the acantholytic activity. Autoradiographic experiments showed that after about 2 days in culture the rates of incorporation of RNA and protein precursors in the suprabasilar cells in the presence of pemphigus IgG were reduced to less than 10% of the normal IgG controls, whereas these synthetic activities of the basal cells were only slightly affected. These observations lead to the proposal that it is the interaction of the pemphigus autoantibody(s) with the suprabasilar epidermal cell which initiates and possibly substains the process(es) of acantholysis.

Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction

“…emphigus is a severe autoimmune blistering skin disease (1,2) caused by autoantibodies against keratinocyte surface Ags (3)(4)(5). It has been demonstrated that pathogenic pemphigus autoantibodies are directed to the cadherin-type adhesion molecules desmoglein (Dsg) 3 1 and 3 (6 -9).…”

Anti-epidermal-cell-surface pemphigus antibody detaches viable epidermal cells from culture plates by activation of proteinase.

“…Skin biopsies from pemphigus patients reveal deposition of immunoglobulin between epidermal cells and rounding up and loss of adhesion between cells (3); this latter change is referred to as acantholysis (3). Michel and coworkers (4,5) and others (6,7) have shown that explants of whole human skin grown in the presence of immunoglobulin from pemphigus patients develop acantholysis of the basal epidermal cells. The mechanism by which binding of pemphigus immunoglobulin to epidermal cells induces loss of adhesion between cells is unknown.…”

Is Endoplasmic Reticulum Stresslinked to the Pathogenesis of Pemphigus Vulgaris?

“…In 1964, Beutner and Jordon discovered that patients suffering from pemphigus had IgG autoantibodies directed against the surface of keratinocytes (Beutner and Jordon 1964). In the late 1970s to early 1980s, studies showing that pemphigus autoantibodies related to blister formation in skin organ culture systems as well as by passively transferring IgG fractions of patients with pemphigus vulgaris into neonatal mice contributed to our understanding of disease pathogenesis (Schiltz and Michel 1976;Anhalt et al 1986). In the midto late 1980s, target antigens underwent immunochemical characterization (Stanley et al 1982;Hashimoto et al 1990) while in 1991, studies revealed that target antigens were the cadherin-type adhesion molecules of desmosomes desmoglein 1 (DSG1) and DSG3, (Koch et al 1990, Amagai et al 1991).…”