Hair follicle immune privilege and its collapse in alopecia areata

Abstract

Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular antigen presentation via MHC class I and II molecules, along with prominent expression of “no danger” signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro‐inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T‐cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T‐cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re‐establishment of a functional HF IP, which will also provide superior protection from disease relapse.

Autoimmunity in Segmental Vitiligo

“…programmed death ligand-1 (PD-L1), indoleamine 2,3-dioxygenase (IDO)] have been found to regulate the immune privilege of the hair follicle. Inhibition of these factors by immunotherapy for melanoma results often in the development of vitiligo-like lesions very similar to NSV (30,31). It is therefore plausible to speculate that SV is less dependent on changes in factors regulating immune privilege compared to NSV (32).…”

Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases

“…1 tofacitinib free base, 2 anionic squalenyl derivative, 3 phosphate buffer, 4 tofacitinib citrate, 5 ethanol, 6 dimethyl sulfoxide.…”

“…Alopecia areata (AA) is one of the major non-scarring hair loss disorders with a lifetime incidence of 2% [1][2][3]. AA is a complex disorder that involves breakdown of the immune privilege of anagen hair follicles (HFs), leads to an attack of the immune system, and causes reversible hair loss with a 2 of 17 preserved HF [1,4]. Although AA is a non-life-threatening disease, it still has a significant effect on the patients' quality of life [1,5].…”

Compartmentalised metabolic programmes in human anagen hair follicles: New targets to modulate epithelial stem cell behaviour, keratinocyte proliferation and hair follicle immune status?

“…Moreover, lactate can exert immunomodulatory effects, such as through the polarisation of macrophages towards anti‐inflammatory phenotypes or by impeding immunosurveillance by T and NK cells, thereby regulating inflammation and immunity in the tissue microenvironment 3–6,13,14 . As ex vivo experiments have shown that the human anagen HF can metabolise 90% of glucose to lactate, 1 this raises the question whether lactate production and shuttling plays a supportive role in HF growth or in immunomodulation, supporting the HF’s physiological immune privilege (HF IP) 15,16 …”