050 Anti-thyroid peroxidase antibodies demonstrate functional effects on keratinocyte signaling and cell-adhesion in Pemphigus vulgaris

Abstract

It is increasingly recognized that Pemphigus vulgaris (PV) patients develop autoantibodies (autoAbs) directed at targets additional to desmoglein (Dsg) 3 and 1. We have previously identified a subset of patients that harbor autoAbs against thyroid peroxidase (TPO). We have also shown that commercially available anti-TPO Abs are capable of disrupting cell-cell adhesion in keratinocyte monolayers and can modulate signaling pathways known to be relevant to blister formation. To further investigate the extent to which anti-TPO autoAbs play a role in disease pathogenesis we evaluated the affect of anti-TPO Abs in several in vitro assays. 1) We show that commercially available anti-TPO Abs increase p38MAPK activation within 4 h after treatment. 2) We demonstrate that depletion of either anti-TPO or anti-Dsg3 autoAbs from IgG purified from patient sera (PVIgG) dampens the ability of PVIgG to increase intracellular calcium levels in keratinocytes. 3) We demonstrate that the adsorption of anti-TPO autoAbs from patient sera reduces the ability of PVIgG to cause fragmentation of a keratinocyte monolayer. This effect is less dramatic compared to the depletion of anti-Dsg3 autoAbs and is most pronounced when using PVIgG from patients shown by ELISA to possess anti-TPO but not anti-Dsg3 or -1 autoAbs. We also show that PVIgG from patients who do not possess autoAbs against Dsg3, Dsg1, or TPO is still pathogenic, suggesting other autoAb specificities may also be relevant to disease in some patients. Collectively, our data suggests that anti-TPO autoAbs may contribute to disease pathogenesis in PV and that, in some cases, autoAbs directed against targets beyond TPO, Dsg3, or Dsg1 may be relevant in disease. Further studies are needed to characterize the broader scope, specificity, and pathogenicity of the autoAb response in PV in vivo.