Vitamin D and alopecia areata: possible roles in pathogenesis and potential implications for therapy

Abstract

Alopecia areata is characterized by the loss of hair on the scalp and elsewhere on the body. It affects approximately 2% of the general population. It is believed to be an autoimmune disease. However, its pathogenesis remains incompletely understood. Recent studies have revealed a substantial link between vitamin D and alopecia areata. But the underlying mechanism still yet to be deciphered. This article reviews the current literature and discusses the possible roles of vitamin D in the pathogenesis of alopecia areata in the context of (1) loss of immune privilege in hair follicle, (2) autoreactive effector T cells and mast cells, (3) nature killer group 2 member d-positive cytotoxic T cells, (4) Janus kinase/signal transducers and activators of transcriptional signaling pathway, (5) regulatory T cells, (6) immune checkpoints, and (7) oxidative stress, which are believed to play important roles in autoimmunity in AA. This paper provides new insights into research directions to elucidate the exact mechanisms of vitamin D in the pathogenesis. Calcipotriol, a vitamin D analog, has been reported to be topically used in treating alopecia areata with promising results. Combination therapy of vitamin D analogs with corticosteroids might also be used in treating alopecia areata.

Keywords: Alopecia areata; autoimmune; calcipotriol; vitamin D.

Figure 1

Possible effects of vitamin D on immune cells in AA. HF IP collapse is a key element in AA immunopathogenesis. IFN-γ contributes to IP collapse by increasing HF MHC class I and II molecules. Vitamin D may contribute to maintain the IP of HF by decreasing the production of IFN-γ. HF IP collapse with exposure of autoantigens leads to an accumulation of autoreactive effector T cells (“swarm of bees”) in which CD8⁺ T cells attack the anagen stage HF with help of CD4⁺ T cell (Th1 and Th17). Vitamin D can inhibit proliferation and cytokine production of CD8⁺ T cell and CD4⁺ T cell (Th1 and Th17). Besides, vitamin D may inactivate T cells by down-regulating abnormally up-regulated intracellular TLRs in AA. Vitamin D may also contribute to prevent HF IP collapse and decrease CD8⁺ T cell activation in AA by inhibiting MCs and interfering cross-talk between MCs and CD8⁺ T cells. Cytokines involved in the pathogenesis of AA are dependent on JAK-STAT pathway. Inhibition of JAK/STAT pathway by vitamin D may in turn block the effects of key cytokines involved in the immunopathogenesis of AA. Treg cells maintain peripheral tolerance to prevent IP collapse and inhibit auto-reactive effector T cells. Vitamin D may contribute to control the overactive self-effector T cells in AA by enhancing the inhibitory function of Treg cells.

Figure 2

Possible effects of vitamin D on CD8⁺NKG2D⁺ T cells in AA. CD8⁺NKG2D⁺ T cells are the dominant immune effectors in AA. These cells express CXCR3 that plays a key role in skin CD8⁺NKG2D⁺ T cell trafficking in AA. NKG2D activating ligand MICA and CXCR3 ligand CXCL-10 are upregulated in AA. Vitamin D can downregulate MICA and CXCL-10, contributing to prevent the skin NKG2D⁺CD8⁺ T cell activation and trafficking in AA.

Figure 3

Possible effects of vitamin D on CTLA-4 and PD-1 in AA. A. Effect of CTLA-4 and PD-1 inhibitors. CTLA-4 is induced in effector T cells upon activation and is constitutively expressed by Treg cells. CTLA-4 preferentially binds to B7 co-stimulatory molecules on APCs, depriving effector T cells of the CD28 co-stimulatory signal to impair the activation of effector T cells. PD-1 expresses in T cells and various immune cells. PD-L1, a ligand of PD-1, can be found on several kinds of immune cells. Binding of PD-1 to PD-L1 generates a strong inhibitory signal, down-regulating T cell activity. CTLA-4 and PD-1 are critical in maintenance of tolerance to self-antigens to prevent autoimmunity. CTLA-4 inhibitor blocks the binding of CTLA-4 to B7 and PD-1 inhibitor blocks the binding of PD-1 to PDL-1 respectively, enhancing T cell activation. Activation of effector T cells leads to self-tolerance breakdown and autoimmune response as immune-related adverse events including AA. B. Effect of vitamin D. Vitamin D enhances CTLA-4, depriving effector T cells of the CD28 co-stimulatory signal to impair the activation of effector T cells. Vitamin D enhances PD-1/PDL-1 to impair the activation of effector T cells. Inactivation of effector T cells maintains self-tolerance, preventing autoimmune response in AA.