Pemphigus vulgaris (PV) is a life-long, potentially fatal
IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-
desmoglein (Dsg) 3 ± 1 and antimitochondrial
antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with
neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and
ATP production and induced
cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects of AMA on KCs are reversible, they become irreversible, leading to epidermal blistering (
acantholysis), when AMA synergize with anti-Dsg
antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg
antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering
acantholysis irreversible. In conclusion, FcRn is a common acceptor
protein for internalization of AMA and, perhaps, for PV
autoantibodies to other intracellular
antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this
autoimmune disease and possibly other
autoimmune diseases.