Alopecia Areata: An Autoimmune Disease of Multiple Players

Abstract

Alopecia areata (AA) is an autoimmune disease of the hair follicles. It is characterized by a well-defined non-scarring alopecic patch or patches that may extend to the entire scalp or lead to total body hair loss. Due to its unpredictable clinical course, AA causes substantial psychological harm. Despite the high prevalence of this disease and extensive research, its exact pathomechanism is unclear, and current treatments have a high relapse rate that has deemed AA incurable. Over the past few decades, researchers have investigated multiple potential factors that may help alleviate its pathogenesis and provide effective treatment. Given its complex immunopathogenesis, AA is considered an autoimmune disease with multiple factors. This review gathers current evidence that emphasizes molecular mechanisms, possible causative etiologies, and targeted immunotherapies for AA. Understanding its underlying mechanisms may shed light on new strategies to effectively manage AA in the future.

Keywords: alopecia totalis; alopecia universalis; autoimmunity; hair loss; inflammation.

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.