Deciphering the Complex Immunopathogenesis of Alopecia Areata

Abstract

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.

Keywords: NK cells; T lymphocytes; aetiology; alopecia areata; dendritic cells; immunopathogenesis; keratinocytes; macrophages; mast cells.

Figure 1

Immune privilege collapse of the anagen hair follicle in a patient with AA. Healthy HFs’ immune-privileged status is ensured by the lower expression of MHC I/II and APC and upregulation of immunosuppressive molecules, known as “IP guardians”, such as α-MSH, TGF-β1, and IL-10. The breakdown of HF-IP is essential for the onset of AA, and it occurs when the balance of signaling pathways upholding this IP is overwhelmed by those leading to collapse. In AA patients, IP compromises the upregulation of MHC I/II, adhesion molecules, and NKG2D ligands; migration of T lymphocytes in the lower part of the hair bulb; increased secretion of cytokines, such as IFN-γ, TNF-α, IL-2, and IL-15; and decreased IP guardians. Adapted from [90].

Figure 2

Immune cells responsible for AA development. Cytotoxic CD8+ T cells (CD8⁺NKG2D⁺ T cells) are the first immune cells that infiltrate the HF surrounding and are considered to be the main drivers of disease pathogenesis. CD8⁺NKG2D⁺ T cells produce IL-2, IL-15, GZMB, and IFN-γ. IL-2 and IL-15 maintain CD8+NKG2D+ T cells via a positive feedback loop. GZMB promotes cell lysis, while IFN-γ triggers collapse of HF-IP by inducing JAK/STAT signaling. NK cells also express the NKG2D and may attack the HF cells upon binding the NKG2D ligand in similar manner as the CD8+ cells. Effector CD4+ and NK cells both produce IFN-γ, which then further induces the production of chemokines (CXCR3, CXCL-9, CXCL-10, and CXCL-11) and maintains inflammation by attracting other immune cells into the peribulbar space. Plasmacytoid dendritic cells (pDCs) produce large quantities of type I interferons (IFN-α and β), which induce CD4+, CD8+, and NK responses toward the HFs in AA patients. Adapted from [9,13].