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.

Figure 1

Characterization of anti-keratinocyte antibody profiles of PV and PF sera by immunoprecipitation with proteins from cultures of human epidermal keratinocytes resolved by 7.5% SDS-PAGE. Modified from Ref. [18].

Figure 2

The imaginary appearances of epidermis in the skin of PV patients that produce both Dsg 1 and 3 antibodies based on the postulates of Dsg compensation hypothesis vs. real appearance of lesional epidermis in PV patients.

Figure 3

Profiles of PV IgGs absorbed by recombinant Dsg 1 and Dsg 3 baculoproteins in the Western blots of keratinocyte proteins resolved by 7.5% SDS-PAGE. Lane 1, reaction of PV IgG purified on the rDsg3-His construct with human keratinocytes. Lane 2, no primary antibody control for lane 1. Lane 3, no primary antibody control for lanes 4 and 5. Lane 4, reaction of PV IgG purified on the rDsgl-Ig-His construct with Dsg3^null keratinocytes. Lane 5, reaction of PV IgG purified on the rDsg3-Ig-His construct with Dsg3^null” keratinocytes. The positions of relative molecular mass (M_r) markers run in parallel lanes of each blot are shown to the left of the respective blot. The apparent relative M_r of keratinocyte protein bands visualized due to PV antibody binding is shown to the right of lanes 2 and 5 in the columns designated M_r. Modified from Ref. [18].

Figure 4

Hypothetical scheme of the time course of pathobiologic events leading to acantholysis in pemphigus. In stage I, antibodies to PERP and/or cellular AChRblock the physiologic control of polygonal cell shape and intercellular adhesion. This increases phosphorylation of adhesion molecules with their subsequent dissociation from the adhesion units on CM, and also initiates programed cell death. In stage II, the tonofilament (TF). cytoskeleton collapses and keratinocytes shrink with associated sloughing of desmosomes which elicits autoimmune response to the desmosomal antigens. In stage III, anti-Dsg antibodies bind to their targets on the CM of keratinocytes thus precluding formation of new intercellular junctions. Modified from Ref. [55].

Figure 5

Hypothetical scheme of immune dysregulation in PV. Abbreviations: APC, antigen-presenting cells; IL, interleukin. Modified from Ref. [339].

Figure 6

Hypothetical scheme of early signaling steps during first 6h after PV IgG binding to keratinocytes and their correlation with the major intracellular pathobiologic events. Abbreviations: EGFR, epidermal growth factor receptor; Dsg, desmoglein; NDAgs, non-Dsg antigens. From Ref. [47].

Figure 7

Hypothetical scheme of signaling events mediating keratinocyte damage in PV. Abbreviations: AMPVAb, anti-mitochondrial PV antibody; Cs, caspase; FasL, Fas ligand; FasR, Fas receptor; MRPVAg, mitochondria-related PV antigen; NO, nitric oxide; OPVAb, PV antibodies of other specificities, including anti-AChR and anti-PERP antibodies; OPVAg, other types of putative PV antigens; PVAb, PV antibody; TNFa, tumor necrosis factor a. Modified from Ref. [37].

Figure 8

Hypothetical scheme of keratinocyte apoptolysis in PV. Step 1: apoptolysis is triggered by binding of autoantibodies to the PV antigens capable of transducing apopotolytic signals from the keratinocyte plasma membrane, such as PERP and AChRs. Step 2: outside-in signaling from ligated antigens launches the cell death cascades. Step 3: collapse and retraction of the TFs cleaved by executioner caspases and dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules result in basal cell shrinkage, most of desmosomes remain intact. Step 4: massive cleavage of cellularproteins by activated cell death enzymes leads to collapse of the cytoskeleton and tearing off desmosomes from the CM with subsequent production of scavenging (i.e. secondary) autoantibodies mainly to sloughed adhesion molecules. Step 5: suprabasal acantholytic cells die rendering a tombstone appearance to surviving basal cells. Modified from Ref. [1].