Pemphigus autoimmunity: Hypotheses and realities

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

Splenic regulation of the murine pulmonary lymph node response.

Exposure to intratracheal immunization and aerosolization with soluble antigen plus murmayl-dipeptide (MDP) induces the development of plaque-forming cells in the pulmonary draining lymph nodes of two of three inbred mouse strains. Splenectomy before immunization led to a heightened plaque-forming cell response in the two responder mouse strains. Adoptive transfer of spleen cells from one strain exposed to sperm whale myoglobin via the respiratory tract revealed the presence of antigen-specific suppressor cells. These observations suggest that the spleen may play a role in the down-regulation of an immune response elicited in the pulmonary draining lymph nodes by exposure of the respiratory tract to soluble antigens plus MDP

Hemolytic Plaque Inhibition by Synthetic Antigenic Peptides of Sperm Whale Myoglobin

We have investigated the systemic antibody response to sperm whale myoglobin (SWMb) antigenic sites in three strains of inbred mice using an inhibition of plaque assay. Sperm whale myoglobin was attached to sheep red blood cells (SRBC) via rabbit anti-SRBC Fab\u27 fragments. Inhibition of lysis was obtained with synthetic peptides representing the purported five antigenic sites but not with a peptide whose sequence was unrelated to SWMb and synthetic peptides of SWMb from outside the antigenic sites gave minimal or no inhibition. The results of our studies show that the pattern of response to the five antigenic sites differs in each strain, but that almost total inhibition is obtained in all strains with these five sites. The antigenic dominance of these sites supports the concept of discrete antigenic sites on soluble proteins. They also suggest a reason for contrary reports in the literature based on hybridoma technology