Mechanisms of blister induction by autoantibodies

Abstract

Autoimmune diseases are characterized by defined self-antigens, organ specificity, autoreactive T cells and/or autoantibodies that can transfer disease. Autoimmune blistering diseases are organspecific autoimmune diseases associated with an immune response directed to structural proteins mediating cell-cell and cell-matrix adhesion in the skin. While both autoreactive T and B cells have been detected and characterized in patients with autoimmune blistering diseases, current evidence generally supports a pathogenic role of autoantibodies for blister formation. The immunopathology associated with blisters induced by autoantibodies relies on several mechanisms of action. Autoantibodies from patients with pemphigus diseases can exert a direct effect just by binding to their target mediated by steric hindrance and/or by triggering the transduction of a signal to the cell. In most subepidermal autoimmune blistering conditions, in addition to the binding to their target antigen, autoantibodies need to interact with factors of the innate immune system, including the complement system and inflammatory cells, in order to induce blisters. Generally, decisive progress has been made in the characterization of the mechanisms of blister formation in autoimmune skin diseases. However, various aspects, including the exact contribution of steric hindrance and signal transduction for pemphigus IgG-induced acantholysis or the fine tuning of the inflammatory cascade triggered by autoantibodies in some subepidermal blistering diseases, still need to be addressed. Understanding the mechanisms by which autoantibodies induce blisters should facilitate the development of more specific therapeutic strategies of autoimmune blistering diseases.

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

“…A likely scenario is that, after binding to their target at the dermal-epidermal junction, Abs against type VII collagen trigger a cascade of events that includes the activation of the complement network and/or engagement of FcRs on leukocytes recruited into the skin. Potent inflammatory mediators, including cytokines, reactive oxygen species, and proteases released by granulocytes, most probably amplify local inflammation and are instrumental for tissue destruction (1).…”

Induction of Complement-Fixing Autoantibodies against Type VII Collagen Results in Subepidermal Blistering in Mice

“…Interestingly, these mechanisms differ markedly. Although autoantibodies from patients with pemphigus and mucous membrane pemphigoid cause blisters just by binding to their targets, lesion induction by autoantibodies from patients with bullous pemphigoid and epidermolysis bullosa acquisita (EBA) 3 appears to require subsequent activation of inflammation pathways (11)(12)(13).…”

“…EBA, a severe autoimmune subepidermal blistering disease of skin and mucous membranes, is characterized by tissue-bound and circulating IgG Abs to the dermal-epidermal junction (DEJ) (12). Patients' serum autoantibodies bind to the 290-kDa type VII collagen, the major component of anchoring fibrils (18).…”

Autoimmune bullous disorders

“…Bullous autoimmune dermatoses have a common pathogenic mechanism involving binding of autoantibodies to specific adhesion molecules in epidermal desmosomes, and in some cases in the area of the dermo-epidermal basement membrane zone. The binding of circulating autoantibodies and the induction of an inflammatory reaction in the area of target structures lead to loss of adhesion with subsequent intra-or subepidermal blister formation (1). The clinical appearance is heterogeneous and secondary eruptions such as erosions, encrustation, impetiginisation, and scarred secondary erosions can dominate the clinical picture.…”