title: Expression of neuropeptide-degrading enzymes in alopecia areata: an immunohistochemical study.
abstract: BACKGROUND
  Much clinical evidence suggests that the nervous system, including psychological factors, can influence the course of alopecia areata (AA). However, there has been little substantial evidence of specific participation of cutaneous neurogenic factors in the disease process.
  
  
  OBJECTIVE
  As previous studies have demonstrated that stress elicits the release of the neuropeptide substance P (SP) from peripheral nerves and that some patients with AA show prominent SP expression in nerves surrounding their hair follicles, we aimed to evaluate the role of SP in AA.
  
  
  METHODS
  We used immunohistochemistry to examine the expression of SP and SP-degrading enzymes in scalp biopsies from patients with AA and from healthy controls.
  
  
  RESULTS
  Affected hair follicles in the centre of the areas of hair loss of patients with AA were richly innervated by SP-staining nerve fibres. Strong expression of the SP-degrading enzyme, neutral endopeptidase (NEP), was observed in hair follicles not only in the acute progressive phase of AA but also in the chronic stable phase. Expression of NEP in hair follicles from the margins of areas of hair loss was stronger than in normal controls, but was weaker than in the centre of the areas of hair loss. In addition, endothelial immunoreactivity for angiotensin-converting enzyme (also capable of degrading SP) was not observed in the centre of the areas of hair loss, which was in significant contrast to normal controls as well as to the margins of areas of hair loss where it was expressed. Further, intense expression of endothelial leucocyte adhesion molecule-1 on vessels and many degranulating mast cells was observed adjacent to affected hair follicles in AA, in admixture with dense lymphocytic inflammation.
  
  
  CONCLUSIONS
  These findings suggest that SP is endogenously released by dermal nerve fibres around hair follicles and that it may play an important part in epithelial-mesenchymal-neuroectodermal interactions in AA. This study reveals that SP and its degrading enzymes are involved in the pathogenesis of AA, which in turn might explain the pathological significance of neurogenic and psychogenic aspects in the disease process.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. toyoam@toyama-mpu.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Toyoda
authors.forename: T
authors.initials: T
authors.lastname: Makino
authors.forename: M
authors.initials: M
authors.lastname: Kagoura
authors.forename: M
authors.initials: M
authors.lastname: Morohashi
mesh_terms: D000328:Adult; D000506:Alopecia Areata / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D018859:Hair Follicle / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008407:Mast Cells / Q000648:ultrastructure; D015260:Neprilysin / Q000378:metabolism*; D009412:Nerve Fibers / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012535:Scalp / Q000201:enzymology* / Q000294:innervation / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D019040:E-Selectin; D009479:Neuropeptides; D013373:Substance P; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin