Pemphigus autoimmunity: Hypotheses and realities

Abstract

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

“…In pemphigus foliaceus (PF), where fl accid skin blisters are present without mucosal erosions, the autoantibody profi le typically comprises Dsg1 as the only antigen from the desmosomal cadherin family. However, over 50 other antigens can react with sera from pemphigus patients of which the pathogenic signifi cance is largely unclear (Grando, 2012).…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…Although how these myriad signaling molecules are activated and involve in generation of pemphigus lesions is unclear, antibody activities against several different molecules, as such muscarinic and nicotinic receptors, of keratinocytes contained in PV-IgG (Grando, 2012) might play some important roles in generating various types of pemphigus. It would be speculated that these molecules may mediate to exert characteristic phenotypes of infl ammatory and necrolytic (apoptotic) pemphigus in addition to acantholysis, which is an inevitable hallmark for pemphigus ( Figure 5).…”

Prevalence of pemphigus incidence in the Bhuj, Kutch, Gujarat: a cross-sectional study

“…They are mucocutaneous blistering diseases that demonstrate a loss of cohesion of the epidermal cells (acantholysis) which result in the formation of clefts in the epidermis. [3][4][5] Autoantibodies directed against adhesion molecules cause epidermal keratinocytes to separate, resulting in intraepidermal bullae. Pemphigus is an uncommon disease with an incidence rate ranging from 0.5 to 3.2 per 100,000 per year.…”