Vitiligo: An Autoimmune Skin Disease and its Immunomodulatory Therapeutic Intervention

Abstract

Vitiligo is a chronic autoimmune depigmenting skin disorder characterized by patches of the skin losing functional melanocytes. Multiple combinatorial factors are involved in disease development, among which immune T cells play a prominent role. The immune cells implicated in melanocyte destruction through adaptive immunity include CD8⁺ cytotoxic T cells and regulatory T cells, and aberrantly activated skin-resident memory T cells also play a role in melanocyte destruction. Over the past several years, major progress in understanding vitiligo pathogenesis has led to the development of targeted therapies. Janus kinase (JAK) inhibitors, which share the similar mechanism that autoactivates CD8⁺ T cells in chronic inflammatory diseases, have been reported to have therapeutic significance in vitiligo. Recently, immunomodulatory therapeutic interventions in vitiligo have been emerging. Mesenchymal stem cells (MSCs) regulate cytokine secretion and the balance of T-cell subsets, which makes them a promising cell-based treatment option for autoimmune diseases. The induction of MSC-mediated immunomodulation is complicated and occurs by contact-dependent mechanisms and soluble extracellular vesicle (EV) mediators. EVs released from MSCs contain various growth factors and cytokines with anti-inflammatory effects in the skin immune response. Here, we summarize and discuss the progress to date in targeted therapies that immunomodulate the niche environment of vitiligo, from the clinical trial of JAK inhibitors to the potential of MSCs and MSC-EVs. The available information was collected to highlight the need for further research into the treatment of vitiligo.

Keywords: autoimmune skin disorder; janus kinase; skin-resident memory T (TRM) cell; stem cell therapy; vitiligo.

FIGURE 1

Vitiligo pathogenesis and currently available treatments for vitiligo. (A) Pathologies of vitiligo. In vitiligo, melanocytes are more susceptible to oxidative stress, which in turn targets antigens to nearby dendritic cells and induces their maturation into efficient antigen-presenting cells. Upon endogenous or exogenous stress, NK cells produce IFN-γ that induces the production of chemokines. Binding of IFN-γ to its receptor activates the JAK/STAT pathway and leads to T-cell recruitment and function, which induces melanocyte apoptosis. Established vitiligo is maintained by T_RM cells, which remain long-lived in the skin through IL-15–dependent signaling. (B) Immunomodulated therapeutic intervention in vitiligo. Immunomodulatory therapies are currently available treatments for vitiligo, including the increase of T_reg cells to neutralize effector CD8⁺ T-cell function, small molecule–targeted drugs of JAK inhibitors to block IFN-γ–CXCR3–CXCL9/10 signaling axis, and anti-CD122 antibody (IL-15 receptor subunit) to decrease IFN-γ production and deplete autoreactive CD8⁺ T_RM cells. DC, dendritic cells; NK, natural killer cells; T_RM, skin-resident memory T cells; JAK, Janus kinase; IFN-γ, interferon-gamma; CXCL, chemokine (C-X-C motif) ligand; CXCR, chemokine (C-X-C motif) receptor; STAT, signal transducer and activator of transcription; T_reg, regulatory T cells; IL-2, interleukin 2; IL-15, interleukin 15; TNFR2, tumor necrosis factor receptor 2.

FIGURE 2

The immunomodulatory effects of mesenchymal stem cells in vitiligo. The induction of MSC-mediated immunomodulation is complicated through (A) cell–cell contact–dependent mechanisms and (B) several soluble mediators that are secreted from MSCs. Treg, regulatory T cells; Th1, T helper 1 cell; Th2, T helper 2 cell; Th17, T helper 17 cell; DCs, dendritic cells; NK, natural killer cells; MSC, mesenchymal stem cell; IL, interleukin; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta.