Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

Abstract

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg) 1 and Dsg 3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human ex vivo skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca2+ to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca2+) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level.

Tacrolimus reverses pemphigus vulgaris serum-enhanced expression of desmoglein in HaCaT cells via inhibition of heat shock protein-27 phosphorylation

“…The p38MAPK signaling pathway is an important signaling pathway that mediates Dsg3 internalization followed by depletion from endosomes [18]. A previous study reported that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPKdependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway [19].…”

Skin Blister Formation and Subepidermal Bullous Disorders

“…There may be many causes of primary acantholysis, the most known being pemphigus group diseases caused by autoantibodies against desmosome proteins. This condition can be caused by bacterial toxins, as in staphylococcal scalded skin syndrome, or by a genetic defect in the kertinocyte cell membrane, as in Hailey-Hailey disease [3][4][5].…”

“…Skin blistering diseases are clinically polymorphic large-group disorders and they sometimes may be devastating. These disorders may be classified according to [1] the level of the blister: subcorneal, mid epidermis, suprabasal, subepidermal; [2] the mechanism of blister formation (spongiosis, acantholysis, blistering degeneration, or epidermolysis); and [3] the type of inflammation (neutrophilic, lymphocytic, eosinophilic, mixed) [1]. In this section, pemphigoid group diseases such as bullous pemphigoid, mucous membrane pemphigoid, acquired epidermolysis bullosa, linear IgA bullous dermatosis, and anti p-200 pemphigoid will be explained with a brief introduction to blistering diseases of the skin.…”

Electron microscopy of desmosomal structures in the pemphigus human skin organ culture model

“…Mouse models of pemphigus, however, are hampered by the relatively complex experimental procedures ( 8 , 9 ) or by the differences in DSG expression patterns between mice and men ( 10 ). Organ skin models are being increasingly used to overcome these limitations and to implement the replace, reduce, and refine (3R) principles of animal research, including to replace animal experiments by appropriate alternatives ( 11 – 14 ). We recently developed a highly standardized human skin organ culture (HSOC) model of pemphigus using skin from donors of elective surgery ( 15 ).…”