Alopecia Areata: A Review of Disease Pathogenesis

F. Rajabi; L.A. Drake; M.M. Senna; N. Rezaei


The British Journal of Dermatology. 2018;179(5):1033-1048. 

In This Article

The Neuroendocrine-immune Axis

Another explanation for the involvement of stress in the pathogenesis of AA is by means of the neuroendocrine-immune axis (Figure 3). This axis is composed of a miniature equivalent of the hypothalamic-pituitary-adrenal axis (HPA) in the skin, and the nerve plexus present around HFs.[151–160] The key mediators between the neuroendocrine and immune systems are mast cells.[161] Stress protagonists such as corticotropin-releasing hormone (CRH), substance P (SP) and nerve growth factor provoke mast-cell degranulation, which leads to inflammation via release of histamine, tumour necrosis factor–α, IL–6 and IL–1.[162–166] SP directly promotes ectopic expression of MHC-I (indicative of IP collapse) on anagen HFs.[164] SP and nerve growth factor are also able to induce catagen directly.[167–169]

Figure 3.

Neuroendocrine-immune system and mast cells. Hair follicle cells (keratinocytes, melanocytes and fibroblasts) express CRH, adrenocorticotropic hormone, urocortin and their receptors, creating a local equivalent of the HPA axis with fully functional feedback loops. Mast-cell-derived proteases activate PAR2 on their cell surfaces creating positive feedback. PAR2 is also expressed by sensory neurons, boosting the release of SP. Some of the neurotransmitter and hormone receptors also appear on lymphocytes, macrophages and keratinocytes, indicating their direct role in neurogenic inflammation, catagen and perhaps immune privilege collapse. CRH, corticotropin-releasing hormone; CRHR, CRH receptor; CRP, C-reactive protein; HPA, hypothalamic-pituitary-adrenal; IL, interleukin; NGF, nerve growth factor; NGFR, NGF receptor; NK–1R, neurokinin 1 receptor; NT, neurotensin; PACAP, pituitary adenylate cyclase-activating polypeptide; PAR, protease-activated receptor; SP, substance P; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.

Experimental models have demonstrated stress-induced catagen and provocation of inflammation, but apparent hair loss was never evident.[170–173] AA lesions show altered HPA responses and insufficient adaptation to repeated stress along with increased expression of SP nerve fibres, CRH and adrenocorticotropic hormone. The physical contact between CD8+ T cells and mast cells is also higher in AA.[174–177]