Alopecia Areata: An Autoimmune Disease of Multiple Players

Figures & data

Figure 1 Immune system activation in AA. After the NKG2D receptor is recognized by the NKG2D associated ligands (MICA, ULBP3, and ULBP6), it promotes aggregation of CD8⁺NKG2D⁺ T cells. Activated CD8⁺NKG2D⁺ T cells mainly produce IFN-γ to upregulate MHC class I and II expression via the JAK-STAT pathway and generate GZMB to induce apoptotic cell death. Concurrently, CD8⁺NKG2D⁺ T cells increase an upregulation of γ-chain cytokines (IL-2 and IL-15), which create a positive feedback loop by promoting the activation of IFN-γ–producing CD8⁺NKG2D⁺ T cells. NK cells and CD4⁺ T cell subtypes (Th17 and T reg cells) also produce IFN-γ. NK cells attack hair follicles upon the binding of NKG2D ligand to NKG2D receptor and through CXCR3 ligands expression (CXCL9, CXCL10, and CXCL11). While CD4⁺ T cell subtypes, initiated by upregulation of MHC class II, trigger several pro-inflammatory cytokines and chemokines. PDCs play a role in the pathogenesis by producing a large amount of type I IFN to enhance the activation of CD8⁺, CD4⁺, and NK cells. However, TNF-α, created by CD4⁺ and CD8⁺ T cells, also have negative effects by suppressing PDCs activity and interfering with the keratinocytes differentiation.

Abbreviations: AA, alopecia areata; CXCL, chemokine (C-X-C motif) ligand; CXCR3, C-X-C Motif Chemokine Receptor 3; GZMB, granzyme B; IFN, interferon, IL, interleukin; JAK, Janus kinase; MHC, major histocompatibility complex; MICA, major histocompatibility complex class I chain-related gene A; NK, natural killer; PDCs, plasmacytoid dendritic cells; Treg cells, regulatory T cells; STAT, signal transducer and activator of transcription; Th cells, T-helper cells; TNF, tumor necrosis factor; ULBP, UL16-binding protein.

Table 1 Pathogenetic Factors and Targeted Immunotherapies of Alopecia Areata

Pathogenetic Factors	Roles	Immunotherapies	Mechanism of Treatment
Autoantigens	● Stimulating autoreactive cytotoxic T lymphocytes	● Not available	-
Immune cells
- CD8^+NKG2D^+ T cells	● Increasing the production of IFN-γ and γ-chain cytokines via JAK/STAT pathway ● Inducing apoptotic cell death by producing GZMB	● Anti-CD2	● Binding with CD2, causing deactivation of T cells ● Inducing apoptosis in both CD4^+ and CD8^+ memory T cells
		● Anti-CD11a	● Inhibiting T cell activation and migration
- Th17 cells	● Secreting proinflammatory cytokines (IL-17, IL-22, and IL-23)	● Contact immunotherapy	● Decreasing the level of IFN-γ, IL-12, and Th17 cytokines ● Reducing the inflammatory cells ● Disturbing APCs migration
		● Anti-IL-12/IL-23	● Inhibiting Th1 differentiation, proinflammatory cytokines, and Th17 cell proliferation
- Treg cells	● Suppressing excessive lymphocyte activity	● Statins	● Downregulating Th1 cytokines and upregulating Th2 cytokines via modulation of the JAK/STAT pathway ● Increasing activated Treg cells ● Inhibiting of leukocyte adhesion and extravasation into HF
		● Low-dose IL-2	● Recruiting Treg cells (CD4+CD25+FoxP3+)
- PDCs	● Producing type 1 IFN (IFN-α and β) through TLR7 and TLR9 stimulation	● Not available	-
Cytokines
- IFN-γ	● Inducing MHC expression that stimulates NKG2D receptors ● Signaling through JAK/STAT pathway which helps promoting adaptive immune response	● JAKis	● Terminating T cell-mediated immune response ● Blocking IFN-γ signaling and γ-chain cytokines ● Restoring anagen phase of the hair follicle
		● PDE4 inhibitors	● Reducing IFN-γ by upregulation of cAMP ● Downregulating MHC class II expression
		● Anti-IFN-γ	● Blocking IFN-γ which leads to the downregulation of MHC expression and immune-cell recruitment
- TNF-α	● Providing anti-proliferative effect on epithelial cells and keratinocytes ● Abrogating hair growth and inducing catagen phase of HF ● Suppressing the development of PDCs	● Anti-TNF-α	● Activating Treg cells ● Inhibiting proinflammatory cytokines such as IFN-γ, IL-6, and IL-1
- CXCR3	● Promoting Th1-mediated immune responses by the accumulation of immune cells	● Not available	-
Th2 immune response	● Under investigation	● Not available	-

Abbreviations: APCs, antigen presenting cells; cAMP, cyclic adenosine monophosphate; CXCR3, C-X-C Motif Chemokine Receptor 3; GZMB, granzyme B; HF, hair follicle; IFN, interferon; IL, interleukin; JAK, Janus kinase; JAKi, Janus kinase inhibitors; MHC, major histocompatibility complex; NK, natural killer; PDCs, plasmacytoid dendritic cells; PDE, phosphodiesterase; Treg cells, regulatory T cells; STAT, signal transducer and activator of transcription; Th cells, T-helper cells; TNF, tumor necrosis factor; TLR, Toll-like receptor.