Frontiers in Lichen Planopilaris and Frontal Fibrosing Alopecia Research: Pathobiology Progress and Translational Horizons

Abstract

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary, lymphocytic cicatricial hair loss disorders. These model epithelial stem cell (SC) diseases are thought to result from a CD8⁺ T-cell‒dominated immune attack on the hair follicle (HF) SC niche (bulge) after the latter has lost its immune privilege (IP) for as yet unknown reasons. This induces both apoptosis and pathological epithelial‒mesenchymal transition in epithelial SCs, thus depletes the bulge, causes fibrosis, and ultimately abrogates the HFs' capacity to regenerate. In this paper, we synthesize recent progress in LPP and FFA pathobiology research, integrate our limited current understanding of the roles that genetic, hormonal, environmental, and other factors may play, and define major open questions. We propose that LPP and FFA share a common initial pathobiology, which then bifurcates into two distinct clinical phenotypes, with macrophages possibly playing a key role in phenotype determination. As particularly promising translational research avenues toward direly needed progress in the management of these disfiguring, deeply distressful cicatricial alopecia variants, we advocate to focus on the development of bulge IP and epithelial SC protectants such as, for example, topically effective, HF‒penetrating and immunoinhibitory preparations that contain tacrolimus, peroxisome proliferator-activated receptor-γ, and/or CB1 agonists.

Keywords: 5ARI, 5α-reductase inhibitor; AA, alopecia areata; AGA, androgenetic alopecia; CRH, corticotropin-releasing hormone; EMT, epithelial‒mesenchymal transition; FFA, frontal fibrosing alopecia; HF, hair follicle; IP, immune privilege; K, keratin; KC, keratinocyte; LPP, lichen planopilaris; MAC, macrophage; MHC, major histocompatibility complex; PCA, primary cicatricial alopecia; PCP, personal care product; PPAR-γ, peroxisome proliferator–activated receptor-γ; SC, stem cell; SP, substance P; eHFSC, epithelial hair follicle stem cell; α-MSH, α-melanocyte-stimulating hormone.

Figure 1

Clinical characteristics of LPP and FFA. Macroscopic and dermatoscopic views of biopsy-proven (a) FFA and (b) LPP, showing the key clinical characteristics features. All subjects consented to the publication of the images. FFA, frontal fibrosing alopecia; LPP, lichen planopilaris.

Figure 2

Immunohistopathologic characteristics of LPP and FFA. (a1) Quantitative display of the median cell counts for all statistically significant results of CD68⁺ macrophages in the key parts of follicular anatomy involved in LPP group, FFA group, and control groups (Harries et al., 2020). (a2) Photographic images of CD68 positivity at the hair follicle bulge region in LPP and FFA (Harries et al., 2020). (a3) CD68 macrophage M1 marker is downregulated, and M2 marker CD163 is upregulated in lesional LPP skin compared with that in nonlesional LPP and FFA. The percentages of macrophages (CD68⁺) expressing each marker in the CTS were calculated and expressed as the fold change calculated from patient-matched nonlesional skin (Harries et al., 2020). (b1, b2, b3) H&E staining showing the key similarities of histopathology samples of LPP and FFA (Chiang et al., 2012). APM, arrector pili muscle; CTS, connective tissue sheath; FFA, frontal fibrosing alopecia; LPP, lichen planopilaris.

Figure 3

LPP and FFA: similarities and differences in the pathobiology tree. (a) Cartoon (modified from Harries et al. [2018]) exhibits the actual known key pathways shared by LPP and FFA, such as PPAR-γ deficiency, immune privilege collapse and EMT, but also additional pathways more recently identified such as dysbiosis, increased FOXP3 expression, or mitochondrial dysfunction. Despite sharing many common pathways, these two hair diseases diverge at some point. Indeed, CD8⁺ T cells have been shown to attack the bulge of LPP, and recent evidence tends also to show that LPP HFs showed increased M2 macrophage number but also increased CYP1A1 expression. On the other hand, FFA development is associated with environmental and epigenetic factors as well as abnormal hormonal (steroids) levels. (b) Proposed diagram (modified from Jozic et al. [2021b]) of the key processes involved in LPP and FFA development from healthy HFs until the occurrence of permanent scarring alopecia. We showed the progression of healthy HFs possessing some predisposing factors (in blue). When these predisposed HFs are affected by any of the amplifying factors (in orange), HF IP will collapse. At this point, specific factors related to FFA or LPP will guide the HFs in one or the other pathology. EMT, epithelial‒mesenchymal transition; FFA, frontal fibrosing alopecia; HF, hair follicle; IP, immune privilege; K15, keratin 15; LPP, lichen planopilaris; MC, mast cells; PPAR-γ, peroxisome proliferator-activated receptor-γ.