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

From Immune Privilege Collapse to Actual Immune Response

As mentioned above, IFN–γ and tumour necrosis factor–α are the first cytokines produced and released around HFs by either NK cells or activated T cells. IFN–γ induces expression of MHC-I, NKG2D and chemokines such as CXCLs, all of which could perpetuate a vicious cycle of inflammation.[24,25,45,49,77,120,121] IFN–γ is so important in the disease process that IFN–γ gene knockout C3H/HeJ mice have shown resistance to AA induction, and antibodies against IFN–γ have resulted in prevention of hair loss in this mouse model.[76,77]

Three of the IFN–γ–induced chemokines in AA are CXCL9, CXCL10 and CXCL11.[77,120,121] They play a critical role in immune response development and maintenance by attracting immune cells. Ito et al. have demonstrated increased expression of CXCL10, CCL3 and CCL5 around HFs in AA, and CXCR3 positivity in T-cell infiltrations, with activated T cells having higher chemotactic velocities.[72]

IL–2, IL–15 and their receptors on CD8+ T cells also show increased expression around HFs, and blocking these ILs prevents AA in mice.[76,77,122] Their source could be either the activated immune cells or stressed keratinocytes.[123–125] IL–15 limits the suppressive effect of regulatory T cells[125,126] and transforms resting NK cells into effector cells by promoting NKG2D expression.[127,128] It can also directly trigger multiple steps of the NKG2D signalling pathway leading to Janus kinase activation and shifting CD8+ T cells towards cytotoxic functions independently of T-cell receptors. These cells are known as lymphokine-activated killer cells.[129,130]

Involvement of T helper (Th)17 has also been suggested by genetic studies and investigations demonstrating an increase in tissue and serum levels of its related cytokines.[131–135] As Th17 is the dominant response in psoriasis, normal hair growth at the sites of psoriatic plaques (Renbök phenomena) may challenge its importance in AA.[136,137] Secondary to cell-mediated immunity, expression of MHC-II and its interaction with CD4+ T cells lead to humoral immunity and antibody formation. However, these antibodies are incapable of disease induction.[138] A few studies have also demonstrated higher IgE levels in the sera and presence of eosinophils in the histology of such lesions, but their importance remains unclear.[139,140]

There are few reports on the association of low vitamin D levels with AA development and severity,[141–144] but vitamin D analogues as therapeutic modalities have failed to demonstrate a solid positive outcome.[145–148] Furthermore, vitamin D receptor gene polymorphisms have shown no association with AA.[149]

A mathematical model for AA revealed that cytokines such as IFN–γ and IP modulators have stronger effects on disease development and recovery than cellular dynamics.[150]