Vasoactive intestinal peptide, whose receptor‐mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse

Summary Background Alopecia areata ( AA ) is an autoimmune disorder whose pathogenesis involves the collapse of the relative immune privilege ( IP ) of the hair follicle ( HF ). Given that vasoactive intestinal peptide ( VIP ) is an immunoinhibitory neuropeptide released by perifollicular sensory nerve fibres, which play a role in IP maintenance, it may modulate human HF ‐ IP and thus be therapeutically relevant for AA . Objectives To answer the following questions: Do human HF s express VIP receptors, and does their stimulation protect from or restore experimentally induced HF ‐ IP collapse? Is VIP signalling defective in AA HF s? Methods Firstly, VIP and VIP receptor ( VPAC 1, VPAC 2) expression in human scalp HF s and AA skin was assessed. In HF organ culture, we then explored whether VIP treatment can restore and/or protect from interferon‐γ‐induced HF ‐ IP collapse, assessing the expression of the key IP markers by quantitative (immuno‐)histomorphometry. Results Here we provide the first evidence that VIP receptors are expressed in the epithelium of healthy human HF s at the gene and protein level. Furthermore, VIP receptor protein expression, but not VIP + nerve fibres, is significantly downregulated in lesional hair bulbs of patients with AA , suggesting defects in VIP receptor‐mediated signalling. Moreover, we show that VIP protects the HF from experimentally induced IP collapse in vitro , but does not fully restore it once collapsed. Conclusions These pilot data suggest that insufficient VIP receptor‐mediated signalling may contribute to impairing HF ‐ IP in patients with AA , and that VIP is a promising candidate ‘ HF ‐ IP guardian’ that may be therapeutically exploited to inhibit the progression of AA lesions.