Pemphigus vulgaris (PV) is a mucocutaneous blistering disease characterized by
IgG autoantibodies against the stratified squamous epithelium. Current understanding of PV pathophysiology does not explain the mechanism of
acantholysis in patients lacking
desmoglein antibodies, which justifies a search for novel targets of
pemphigus autoimmunity. We tested 264
pemphigus and 138 normal control sera on the multiplexed
protein array platform containing 701 human genes encompassing many known keratinocyte cell-surface molecules and members of
protein families targeted by organ-non-specific PV
antibodies. The top 10
antigens recognized by the majority of test patients' sera were
proteins encoded by the DSC1, DSC3, ATP2C1, PKP3, CHRM3, COL21A1, ANXA8L1, CD88 and CHRNE genes. The most common combinations of target
antigens included at least one of the adhesion molecules DSC1, DSC3 or PKP3 and/or the
acetylcholine receptor CHRM3 or CHRNE with or without the
MHC class II antigen DRA. To identify the PV
antibodies most specific to the disease process, we sorted the data based on the ratio of patient to control frequencies of
antigen recognition. The frequency of
antigen recognition by patients that exceeded that of control by 10 and more times were the molecules encoded by the CD33, GP1BA, CHRND, SLC36A4, CD1B, CD32, CDH8, CDH9, PMP22 and HLA-E genes as well as
mitochondrial proteins encoded by the NDUFS1, CYB5B, SOD2, PDHA1 and FH genes. The highest specificity to PV showed combinations of
autoantibodies to the
calcium pump encoded by ATP2C1 with
C5a receptor plus DSC1 or DSC3 or
HLA-DRA. The results identified new targets of
pemphigus autoimmunity. Novel
autoantibody signatures may help explain individual variations in disease severity and treatment response, and serve as sensitive and specific
biomarkers for new diagnostic assays in PV patients.