Exploring Alopecia Areata Complexity: Current Research and Treatments

The skin, the body’s largest organ, covers the outer surface and forms a boundary with the environment. Its primary role is to act as a physical and chemical barrier, shielding the body from external aggressions. However, it also serves as an immune organ, harboring innate and adaptive immune cells that work together to eliminate pathogens after tissue damage.

Inappropriate immune responses in the skin can result in autoimmune skin diseases (AISDs), such as pemphigus, dermatitis herpetiformis, vitiligo, and alopecia areata (AA).

In this article, we will focus on alopecia areata: what this skin condition is, how it clinically manifests, and what we know about its pathogenesis.

How Does Alopecia Areata Manifest Clinically?

Alopecia areata is a complex autoimmune condition that clinically manifests by a transient, non-scarring hair loss (on the scalp or any hair-bearing body site) with preservation of the hair follicle.

Alopecia areata presents a lifetime incidence of about 2% worldwide, affects both sexes equally and shows no significant racial predominance. While this condition might occur at any age, most cases arise before the age of 40 years, with an average age of onset between 25 and 36 years.

Several subtypes of alopecia areata with distinct presentations have been described. The most common subtype is a small round or patchy bald lesion (patchy alopecia areata), typically on the scalp, that can progress to total loss of scalp hair only (alopecia totalis) and total hair loss of the entire body (alopecia universalis).

Molecular Mechanisms Underlying Alopecia Areata Pathogenesis

The exact etiopathogenesis of alopecia areata is not yet fully understood and several factors, such as genetic predisposition, autoimmunity, and environmental triggers (including emotional or physical stress) contribute to the disease.

Anagen-stage hair follicles are considered an ”immune privileged” site from the level of the bulge downwards to the bulb, relatively preventing autoimmune responses against autoantigens expressed during this stage.

A breakdown of anagen hair bulb immune privilege is a major precondition for the development of AA. Increasing exposure of anagen hair follicle-associated autoantigens and loss of the immune privilege site may result from local increased secretion of INF-γ, cytokines and chemokines (e.g., IL-15, IL-2, CXCL2), upregulation of NKG2D ligands, and MHC I and MHC II molecules, besides the decrease of the local immunosuppressant molecules (”immune privilege guardians”) such as TGF-β1, IL-10 and α-MSH.

In AA, stimulatory factors may activate CD8+ NKG2D+ T-cells, which were shown to be necessary and sufficient for the induction of the disease in mouse models, and produce IFN-γ through JAK1 and JAK3 pathways.

Stimulated CD8+ NKG2D+T-cells secrete IFN-γ that binds to its receptor IFN-γR on follicular epithelial cells, inducing IL-15 production by these cells via JAK1 and JAK2. Then, IL-15 binds to its receptor IL-15Rα on CD8+ T-cells, further stimulating IFN-γ production through JAK1 and JAK3 pathways, which amplify the positive feedback loop.

IFN-γ promotes the breakdown of hair follicle immune privilege, which results in the exposure of autoantigens to CD8+NKG2D+ T-cells and facilitates the autoimmune attack on hair follicles.

Simultaneously, other immune cells, including DCs, CD4+ T-cells, NK T-cells, mast cells, and eosinophils, accumulate around hair bulbs and attack them in a characteristic “swarm of bees” pattern.

Current Therapeutics and Research

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