Figure 2.

Proposed role of the immunogenic cell death in pemphigus foliaceus. 1: Keratinocytes exposed to exogenous PF risk factors, such as mosquito saliva (71, 72), ultraviolet irradiation (79), and thiol molecules (80), present several stress-derived peptides through HLA class I molecules. These peptides are recognized by cytotoxic T CD8+ cells and natural killer (NK) cells, which launch the immunogenic pathway. 2: This pathway induces damage-associated molecular patterns, including membrane exposure of CALR (81). CALR is transported from the endoplasmic reticulum to the outer cell membrane (81), a process mediated by EIF2AK3 (24). Calreticulin then interacts with SIRPA on the surface of dendritic cells, giving it a signal known as “eat me,” responsible for stimulating phagocytosis (81). Relaying the opposite signal is CD47, an outer surface membrane protein that also interacts with SIRPA and antagonizes the activity of CALR, inhibiting phagocytosis (81). We hypothesize that in PF the “eat me” signals prevail over the “don't eat me” signals, increasing the phagocytosis of keratinocyte debris by dendritic cells. 3: Dendritic cells then present keratinocyte peptides, as those derived from desmoglein 1, to T helper cells. 4: T lymphocytes stimulate auto-antibody production by B lymphocytes. 5: The immunogenic cell death process initiated by exogenous stimuli also activates an adaptive immune response, which includes recruitment, and activation of both cytotoxic T lymphocytes and natural killer cells.