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

  • Maryanne Makredes Senna
    Affiliations
    Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Harvard Medical School, Boston, Massachusetts, USA
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  • Erik Peterson
    Affiliations
    Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA
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  • Ivan Jozic
    Affiliations
    Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA
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  • Jérémy Chéret
    Affiliations
    Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA
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  • Ralf Paus
    Correspondence
    Correspondence: Ralf Paus, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, 1600 Northwest 10th Avenue, Miami, Florida 33136, USA.
    Affiliations
    Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Monasterium Laboratory, Münster, Germany

    CUTANEON, Hamburg, Germany
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Open AccessPublished:February 28, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100113
      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.

      Abbreviations:

      5ARI (5α-reductase inhibitor), α-MSH (α-melanocyte-stimulating hormone), AA (alopecia areata), AGA (androgenetic alopecia), CRH (corticotropin-releasing hormone), eHFSC (epithelial hair follicle stem cell), 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)

      The Challenge

      Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are inflammatory scarring hair loss disorders that primarily affect perimenopausal and postmenopausal women. These primary cicatricial alopecias (PCAs) result in disfiguring hair loss, significant scalp symptoms, secondary cutaneous morbidity, (
      • Fertig R.M.
      • Hu S.
      • Maddy A.J.
      • Balaban A.
      • Aleid N.
      • Aldahan A.
      • et al.
      Medical comorbidities in patients with lichen planopilaris, a retrospective case-control study.
      ), severely reduced QOL, and significant psychosocial burden (
      • Chiang Y.Z.
      • Bundy C.
      • Griffiths C.E.M.
      • Paus R.
      • Harries M.J.
      The role of beliefs: lessons from a pilot study on illness perception, psychological distress and quality of life in patients with primary cicatricial alopecia.
      ). Yet, rarely can dermatologists provide these patients with rapid, robust, and meaningful therapeutic interventions today.
      Unfortunately, the evidence-based foundation on which to build treatment guidelines and predict outcomes remains painfully thin, despite laudable attempts by many investigators (for recent examples, see
      • Dadkhahfar S.
      • Araghi F.
      • Tabary M.
      • Moravvej H.
      Considerations of managing lichen planopilaris with hydroxychloroquine during the COVID-19 pandemic.
      ,
      • Fatemi Naeini F.
      • Mohaghegh F.
      • Jelvan M.
      • Asilian A.
      • Saber M.
      Cyclosporine or methotrexate, which one is more promising in the treatment of lichen planopilaris?; a comparative clinical trial.
      ,
      • Fertig R.
      • Tosti A.
      Frontal fibrosing alopecia treatment options.
      ,
      • Peterson E.L.
      • Gutierrez D.
      • Brinster N.K.
      • Lo Sicco K.I.
      • Shapiro J.
      Response of lichen planopilaris to pioglitazone hydrochloride.
      ,
      • Preda-Naumescu A.
      • Bevans S.L.
      • Mayo T.T.
      Pediatric lichen planopilaris treated with pioglitazone: a case study and literature review.
      ,
      • Vañó-Galván S.
      • Trindade de Carvalho L.
      • Saceda-Corralo D.
      • Rodrigues-Barata R.
      • Kerkemeyer K.L.
      • Sinclair R.D.
      • et al.
      Oral minoxidil improves background hair thickness in lichen planopilaris.
      , and
      • Villani A.
      • Fabbrocini G.
      • Ocampo-Candiani J.
      • Ruggiero A.
      • Ocampo-Garza S.S.
      Review of oral minoxidil as treatment of hair disorders: in search of the perfect dose.
      ). Thus, there is an enormous need to improve the field’s understanding of these irreversible and traumatizing alopecias, for which many key parameters remain unclear: the exact prevalence as well as the demographic and ethnic distribution within defined populations; reliable and predictive biomarkers of disease activity, course, and therapeutic response; and genetic, environmental, microbial, cosmetic, and nutritional factors at play in both populations and individuals, which are (i) shared between and (ii) distinct to LPP/FFA.
      Our best bet for overcoming these frustrating limitations arguably is to refocus attention on the underlying shared and distinct pathobiology mechanisms in LPP versus FFA—because this carries the highest likelihood of leading to targeted and effective therapeutic interventions at a justifiable risk-benefit ratio while facilitating management strategies tailored to a given patient’s specific pathobiology constellation and biomarker expression profile. Guided by this overarching goal and the authors’ personal clinical and basic research experience in this field, the current review synthesizes recent progress in LPP and FFA pathobiology research and suggests concrete avenues toward the development of more effective therapeutics.

      Conceptual Pathobiology Considerations

      Let us consider the major distinctive and shared features of LPP and FFA at the level of clinical presentation (Table 1 and Figure 1a and b) and (immuno-)histopathology (Table 1 and Figure 2a and b). These tables and figures show the histopathological similarity of both PCAs in striking contrast to their very distinct clinical phenotypes (although overlap variants do exist [
      • Du X.
      • Li Y.
      • Zhu Q.
      • Zhu J.
      • Xu W.
      • Li Z.
      • et al.
      Focal and diffuse fibrosing alopecias: classical lichen planopilaris, frontal fibrosing alopecia, fibrosing alopecia with a pattern distribution, cicatricial pattern hair loss, and lichen planopilaris diffuse pattern.
      ;
      • Griggs J.
      • Trüeb R.M.
      • Gavazzoni Dias M.F.R.
      • Hordinsky M.
      • Tosti A.
      Fibrosing alopecia in a pattern distribution.
      ;
      • Rigopoulos D.
      • Stamatios G.
      • Ioannides D.
      Primary scarring alopecias.
      ;
      • Vañó-Galván S.
      • Saceda-Corralo D.
      • Blume-Peytavi U.
      • Cucchía J.
      • Dlova N.C.
      • Gavazzoni Dias M.F.R.
      • et al.
      Frequency of the types of alopecia at twenty-two specialist hair clinics: A multicenter study.
      ]). Thus, one key—as yet unanswered—question is how can two histologically deceptively similar diseases be clinically so distinct? Any plausible LPP and FFA pathobiology hypothesis must convincingly explain how such microscopic similarities can yield such distinct clinical features. Next, it helps to reflect the fundamental nature of both PCAs.
      Table 1Clinical and Immunohistopathological Characteristics of FFA and LPP
      DiagnosisDistinct Histopathological Characteristics
      Although several studies have found histopathological differences between LPP and FFA, all concluded that the findings are too subtle to distinguish the entities without clinical correlation.
      Shared Histopathological CharacteristicsDistinct Clinical CharacteristicsShared Clinical Characteristics
      LPPMore severe inflammatory infiltrate and less apoptosis (
      • Poblet E.
      • Jiménez F.
      • Pascual A.
      • Piqué E.
      Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study.
      ;
      • Gálvez-Canseco A.
      • Sperling L.
      Lichen planopilaris and frontal fibrosing alopecia cannot be differentiated by histopathology.
      )

      Concentric lamellar fibroplasia (
      • Gálvez-Canseco A.
      • Sperling L.
      Lichen planopilaris and frontal fibrosing alopecia cannot be differentiated by histopathology.
      )

      More basilar layer and interfollicular epidermal damage (
      • Poblet E.
      • Jiménez F.
      • Pascual A.
      • Piqué E.
      Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study.
      )

      Increased melanocyte counts in the upper hair follicle (
      • Katoulis A.C.
      • Diamanti K.
      • Damaskou V.
      • Pouliakis A.
      • Bozi E.
      • Koufopoulos N.
      • et al.
      Decreased melanocyte counts in the upper hair follicle in frontal fibrosing alopecia compared to lichen planopilaris: a retrospective histopathologic study.
      )

      DIF shows less IgM immunofluorescence and IgG, IgA, and IgM in papillary dermis (
      • Cerqueira E.R.
      • Valente N.
      • Sotto M.N.
      • Romiti R.
      Comparative analysis of immunopathological features of lichen planopilaris and female patients with frontal fibrosing alopecia.
      )

      Increased CD68+ macrophage polarization and upregulated CD163 and IL-4 (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      )
      Lichenoid perifollicular lymphocytic infiltration (most evident in the superior aspects of the hair follicle) (
      • Kurzeja M.
      • Czuwara J.
      • Walecka I.
      • Olszewska M.
      • Rudnicka L.
      Features of classic lichen planopilaris and frontal fibrosing alopecia in reflectance confocal microscopy: a preliminary study.
      ;
      • Stefanato C.M.
      Histopathology of alopecia: a clinicopathological approach to diagnosis.
      )

      Infundibular hyperkeratosis and hypergranulosis.

      Hair epithelium shows vacuolar degeneration, necrotic keratinocytes, and perifollicular loss of elastin fibers with fibrosis (
      • Ma S.A.
      • Imadojemu S.
      • Beer K.
      • Seykora J.T.
      Inflammatory features of frontal fibrosing alopecia.
      )

      Superficial pigment incontinence (
      • Wilk M.
      • Zelger B.G.
      • Zelger B.
      Lichen planopilaris-histologic criteria and clues in vertical sections.
      ;
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Follicular plugging, epidermal/dermal clefts, and sebaceous gland destruction (
      • Kang H.
      • Alzolibani A.A.
      • Otberg N.
      • Shapiro J.
      Lichen planopilaris.
      )

      The chronic stage shows dilated blood vessels and band-like vertical scarring beneath the papillary dermis (
      • Kang H.
      • Alzolibani A.A.
      • Otberg N.
      • Shapiro J.
      Lichen planopilaris.
      )

      The late stage shows extensive perifollicular lamellar fibrosis surrounding the infundibulum (
      • Kang H.
      • Alzolibani A.A.
      • Otberg N.
      • Shapiro J.
      Lichen planopilaris.
      )

      Similar expression profiles of CD1a, CD3, CD4, CD8, CD68, and IDO in immunohistochemical studies (
      • Cerqueira E.R.
      • Valente N.
      • Sotto M.N.
      • Romiti R.
      Comparative analysis of immunopathological features of lichen planopilaris and female patients with frontal fibrosing alopecia.
      )

      Increased CD8+, CXCR3+, FOXP3+ T cells, and CD68+ macrophages (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      )

      Increased total and degranulated mast cells and CD123+ dendritic cells (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      )

      Decreased numbers of CD1a+ and CD209+ dendritic cells in the infundibulum connective tissue sheath (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      )
      Asymmetric multifocal involvement of scarring alopecia (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Perifollicular erythema and keratotic follicular papules (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Most commonly vertex and parietal scalp, but all regions can be involved (
      • Stefanato C.M.
      Histopathology of alopecia: a clinicopathological approach to diagnosis.
      )

      Association with oral, ungueal, or cutaneous lichen planus (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Dermoscopy shows elongated concentric blood vessels, violaceous-blue interfollicular areas, and big irregular white dots (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )
      Dermoscopy shows loss of follicular ostia, peripilar white scales, and peripilar erythema (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Symptoms of pruritus, pain, and burning (
      • Vañó-Galván S.
      • Molina-Ruiz A.M.
      • Serrano-Falcón C.
      • Arias-Santiago S.
      • Rodrigues-Barata A.R.
      • Garnacho-Saucedo G.
      • et al.
      Frontal fibrosing alopecia: a multicenter review of 355 patients.
      )
      FFAExtension of the inflammatory infiltrate below the isthmus (
      • Wong D.
      • Goldberg L.J.
      The depth of inflammation in frontal fibrosing alopecia and lichen planopilaris: a potential distinguishing feature.
      )

      Islands of sparing of interfollicular epidermis (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      )

      Less prominent inflammatory infiltrate, with more numerous necrotic keratinocytes and foreign body reaction (
      • Poblet E.
      • Jiménez F.
      • Pascual A.
      • Piqué E.
      Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study.
      )

      More frequent terminal catagen‒telogen hairs (
      • Gálvez-Canseco A.
      • Sperling L.
      Lichen planopilaris and frontal fibrosing alopecia cannot be differentiated by histopathology.
      )

      DIF shows cytoid bodies of IgM in the papillary dermis and epidermal and follicular basement membrane zones (
      • Cerqueira E.R.
      • Valente N.
      • Sotto M.N.
      • Romiti R.
      Comparative analysis of immunopathological features of lichen planopilaris and female patients with frontal fibrosing alopecia.
      )

      Increased Langerhans cells in the infundibuloisthmic region compared with that in LPP (
      • Ma S.A.
      • Imadojemu S.
      • Beer K.
      • Seykora J.T.
      Inflammatory features of frontal fibrosing alopecia.
      )
      Symmetric, progressive frontotemporal hairline recession in a band-like pattern above the patient’s normally pigmented and wrinkled forehead.

      Less frequent recession of preauricular and postauricular areas and occipital scalp.

      Dermoscopy shows peripilar white scales and erythema, regularly distributed red or gray dots in eyebrows, and peripilar erythema (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      Skin-colored facial papules.

      Marked or complete loss of eyebrows, typically beginning laterally (
      • Bolduc C.
      • Sperling L.C.
      • Shapiro J.
      Primary cicatricial alopecia: lymphocytic primary cicatricial alopecias, including chronic cutaneous lupus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome.
      )

      General thinning of the beard and peripheral body hair.

      Absence of vellus hair in the hairline.
      Abbreviations: DIF, direct immunofluoresence; FFA, frontal fibrosing alopecia; LPP, lichen planopilaris.
      1 Although several studies have found histopathological differences between LPP and FFA, all concluded that the findings are too subtle to distinguish the entities without clinical correlation.
      Figure thumbnail gr1
      Figure 1Clinical 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 thumbnail gr2
      Figure 2Immunohistopathologic 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 M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ). (a2) Photographic images of CD68 positivity at the hair follicle bulge region in LPP and FFA (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ). (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 M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ). (b1, b2, b3) H&E staining showing the key similarities of histopathology samples of LPP and FFA (
      • Chiang Y.Z.
      • Tosti A.
      • Chaudhry I.H.
      • Lyne L.
      • Farjo B.
      • Farjo N.
      • et al.
      Lichen planopilaris following hair transplantation and face-lift surgery.
      ). APM, arrector pili muscle; CTS, connective tissue sheath; FFA, frontal fibrosing alopecia; LPP, lichen planopilaris.

      Regional versus systemic diseases

      Specifically, we need to ask whether LPP and FFA are primarily regional (territorial) diseases dominated by localized epithelial hair follicle (HF) stem cell (eHFSC) pathology in defined, predilected skin regions, as we have argued before (
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ), irrespective of whether systemic and genetic elements may substantially modify disease phenotype, triggering, course, and response to therapy, or whether, vice versa, these PCAs are essentially systemic, genetically driven disease entities, where intracutaneous pathobiology elements and/or environmental factors merely modify the location, phenotype, and progression of individual LPP or FFA lesions but not the development and course of the disease as such, a view favored by some investigators (
      • Tziotzios C.
      • Petridis C.
      • Dand N.
      • Ainali C.
      • Saklatvala J.R.
      • Pullabhatla V.
      • et al.
      Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B∗07:02.
      ).
      These conflicting concepts are by no means of mere academic interest because the former implies that optimal disease management primarily demands early and decisive intervention at the local skin level, whereas the latter suggests that systemic therapy will likely be much more effective and is thus more important than anything else if one wishes to halt the progression of these disfiguring hair diseases as soon as possible. Currently, arguments can be invoked that support either view or much further research is needed until it will become clearer which concept is best supported by evidence.
      On the basis of recent studies and as depicted in Figure 3a, intracutaneous pathobiology elements and locally active environmental factors seem to be the key factors in the development of both LPP and FFA (
      • Chiang Y.Z.
      • Bundy C.
      • Griffiths C.E.M.
      • Paus R.
      • Harries M.J.
      The role of beliefs: lessons from a pilot study on illness perception, psychological distress and quality of life in patients with primary cicatricial alopecia.
      ,
      • Chiang Y.Z.
      • Tosti A.
      • Chaudhry I.H.
      • Lyne L.
      • Farjo B.
      • Farjo N.
      • et al.
      Lichen planopilaris following hair transplantation and face-lift surgery.
      ;
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ,
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ). Such environmental factors may include skin trauma due to hair transplantation (triggering LPP development) and/or face lift surgery (inducing FFA) (
      • Chiang Y.Z.
      • Tosti A.
      • Chaudhry I.H.
      • Lyne L.
      • Farjo B.
      • Farjo N.
      • et al.
      Lichen planopilaris following hair transplantation and face-lift surgery.
      ;
      • Lee J.A.
      • Levy D.A.
      • Patel K.G.
      • Brennan E.
      • Oyer S.L.
      Hair transplantation in frontal fibrosing alopecia and lichen planopilaris: a systematic review.
      ;
      • Vañó-Galván S.
      • Villodres E.
      • Pigem R.
      • Navarro-Belmonte M.R.
      • Asín-Llorca M.
      • Meyer-González T.
      • et al.
      Hair transplant in frontal fibrosing alopecia: a multicenter review of 51 patients.
      ), psychoemotional stress and stress mediators (e.g., substance P [SP] induces neurogenic inflammation and immune privilege [IP] collapse of human scalp HFs [
      • Peters E.M.J.
      • Liotiri S.
      • Bodó E.
      • Hagen E.
      • Bíró T.
      • Arck P.C.
      • et al.
      Probing the effects of stress mediators on the human hair follicle: substance P holds central position.
      ], whereas noradrenaline can induce the proliferation and thus exhaustion of HF melanocytes stem cells (SCs) in mice [
      • Zhang B.
      • Ma S.
      • Rachmin I.
      • He M.
      • Baral P.
      • Choi S.
      • et al.
      Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.
      ]; indeed, LPP and FFA HFs show loss of melanocytes [
      • Lin J.
      • Valdebran M.
      • Bergfeld W.
      • Conic R.Z.
      • Piliang M.
      • Atanaskova Mesinkovska N.A.
      Hypopigmentation in frontal fibrosing alopecia.
      ;
      • Salas-Callo C.I.
      • Cajas-García M.S.
      • Pirmez R.
      Hypopigmentation of the eyebrows in frontal fibrosing alopecia.
      ]), and certain leave-on cosmetics whose relevance in FFA is currently intensely being debated (
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      ;
      • Debroy Kidambi A.
      • Dobson K.
      • Holmes S.
      • Carauna D.
      • Del Marmol V.
      • Vujovic A.
      • et al.
      Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens.
      ;
      • Strazzulla L.C.
      • Avila L.
      • Lo Sicco K.
      • Shapiro J.
      Response to “Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens.”.
      ). All these may trigger the recruitment of a pathogenic immune cell infiltrate to the HF, possibly along with dysbiosis of the HF microbiome (
      • Constantinou A.
      • Polak-Witka K.
      • Tomazou M.
      • Oulas A.
      • Kanti V.
      • Schwarzer R.
      • et al.
      Dysbiosis and enhanced beta-defensin production in hair follicles of patients with lichen planopilaris and frontal fibrosing alopecia.
      ;
      • Lousada M.B.
      • Lachnit T.
      • Edelkamp J.
      • Rouillé T.
      • Ajdic D.
      • Uchida Y.
      • et al.
      Exploring the human hair follicle microbiome.
      ), thus further perpetuating the perifollicular inflammation. Intriguingly, the resulting immune-mediated HF destruction may locally activate and recruit ancestral physiological mechanisms whereby isolated irreversibly damaged or malfunctioning HFs can be individually immune eliminated by macrophage (MAC) infiltration of the bulge (programmed organ deletion) (
      • Eichmüller S.
      • van der Veen C.
      • Moll I.
      • Hermes B.
      • Hofmann U.
      • Müller-Röver S.
      • et al.
      Clusters of perifollicular macrophages in normal murine skin: physiological degeneration of selected hair follicles by programmed organ deletion.
      ) but now on a massive pathological scale that affects entire HF collectives in a given skin territory (for discussion, see
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ).
      Figure thumbnail gr3
      Figure 3LPP and FFA: similarities and differences in the pathobiology tree. (a) Cartoon (modified from
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ) 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 I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ) 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.
      Although what remains painfully unclear in this scenario is the initiating primary factor(s) that render(s) the bulge of previously healthy or nonlesional HFs (in patients affected by LPP/FFA) susceptible to IP collapse and/or epithelial SC apoptosis and epithelial‒mesenchymal transition (EMT) (see the section below); however, peroxisome proliferator–activated receptor-γ (PPAR-γ) dysfunction and dysregulation of PPAR-γ‒stimulating lipid mediators have been postulated as such a primary factors (
      • Karnik P.
      • Tekeste Z.
      • McCormick T.S.
      • Gilliam A.C.
      • Price V.H.
      • Cooper K.D.
      • et al.
      Hair follicle stem cell-specific PPARgamma deletion causes scarring alopecia.
      ). PPAR-γ signaling is indeed an important regulator of human HF physiology and a major epithelial SC protectant (see the section below) and is involved in the pathophysiology of several hair diseases (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ;
      • Imanishi H.
      • Ansell D.M.
      • Chéret J.
      • Harries M.
      • Bertolini M.
      • Sepp N.
      • et al.
      Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris.
      ;
      • Ramot Y.
      • Bertolini M.
      • Boboljova M.
      • Uchida Y.
      • Paus R.
      PPAR-γ signalling as a key mediator of human hair follicle physiology and pathology.
      ). However, the bulge PPAR-γ expression does not differ substantially between lesional and nonlesional HFs of patients affected by LPP/FFA (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ). This questions whether insufficient PPAR-γ‒mediated signaling really initiates LPP/FFA pathogenesis but does not rule it out either.
      The most important genetic FFA study published so far has identified several genes to be associated with FFA, whereas some others were overexpressed in full-thickness lesional skin biopsies (see later) (
      • Tziotzios C.
      • Petridis C.
      • Dand N.
      • Ainali C.
      • Saklatvala J.R.
      • Pullabhatla V.
      • et al.
      Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B∗07:02.
      ). Yet, the functional relevance of none of the identified genes has as yet to be established. Therefore, we currently favor the concept that both LPP and FFA are primarily territorial diseases triggered initially by relatively localized intracutaneous pathobiology events, whose clinical phenotype, localization, spread, and course may be modified but is not dictated by environmental, genetic, hormonal, and HF microbiome‒related factors and/or leave-on cosmetics (
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ).

      Epithelial SC niche immunopathology: The bulge IP collapse concept

      All currently available evidence suggests that LPP and FFA both result from immune targeting and eventually the depletion of the eHFSC reservoir, which ultimately exhausts the HF ability to regenerate and causes loss of HFs. These eHFSCs are located inside the bulge epithelium, an HF compartment that exhibits the classical immune phenotype of a tissue niche that has established a relative IP (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ;
      • Meyer K.C.
      • Klatte J.E.
      • Dinh H.V.
      • Harries M.J.
      • Reithmayer K.
      • Meyer W.
      • et al.
      Evidence that the bulge region is a site of relative immune privilege in human hair follicles.
      ;
      • Ohyama M.
      • Terunuma A.
      • Tock C.L.
      • Radonovich M.F.
      • Pise-Masison C.A.
      • Hopping S.B.
      • et al.
      Characterization and isolation of stem cell-enriched human hair follicle bulge cells.
      ). IP is specific to certain body sites, including the HF, proximal nail fold, eye, brain, testes, ovaries, and the fetotrophoblast, and provides protection from immunologic attack by the downregulation of major histocompatibility complex (MHC) class I and β2-microglobulin molecules and by the creation of an immunoinhibitory environment generated by IP guardians such as IL-10, TGFβ1, TGFβ2, α-melanocyte-stimulating hormone (α-MSH), and IGF-1 (
      • Bertolini M.
      • McElwee K.
      • Gilhar A.
      • Bulfone-Paus S.
      • Paus R.
      Hair follicle immune privilege and its collapse in alopecia areata.
      ;
      • Ito T.
      • Ito N.
      • Bettermann A.
      • Tokura Y.
      • Takigawa M.
      • Paus R.
      Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.
      ;
      • Paus R.
      • Nickoloff B.J.
      • Ito T.
      A “hairy” privilege.
      ).
      Similar to alopecia areata (AA) where the disease cannot develop without the occurrence of the collapse of the anagen hair bulb IP (
      • Gilhar A.
      • Laufer-Britva R.
      • Keren A.
      • Paus R.
      Frontiers in alopecia areata pathobiology research.
      ;
      • Gilhar A.
      • Etzioni A.
      • Paus R.
      Alopecia areata.
      ), the collapse of bulge IP may be an essential first step in the pathogenesis of LPP and FFA (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ) because no lesional LPP or FFA HFs have yet been identified that lack bulge IP collapse when the latter was examined. Moreover, in mice, selectively deleting the no danger signal, CD200, a key element of bulge IP (
      • Meyer K.C.
      • Klatte J.E.
      • Dinh H.V.
      • Harries M.J.
      • Reithmayer K.
      • Meyer W.
      • et al.
      Evidence that the bulge region is a site of relative immune privilege in human hair follicles.
      ;
      • Ohyama M.
      • Terunuma A.
      • Tock C.L.
      • Radonovich M.F.
      • Pise-Masison C.A.
      • Hopping S.B.
      • et al.
      Characterization and isolation of stem cell-enriched human hair follicle bulge cells.
      ), in keratin (K) 15+ eHFSCs induces a murine PCA phenotype that displays the characteristics of both LPP and FFA (
      • Rosenblum M.D.
      • Olasz E.B.
      • Yancey K.B.
      • Woodliff J.E.
      • Lazarova Z.
      • Gerber K.A.
      • et al.
      Expression of CD200 on epithelial cells of the murine hair follicle: a role in tissue-specific immune tolerance?.
      ). As a therapeutic consequence, rapid restoration of bulge IP would be of paramount clinical importance in the management of both LPP and FFA. Furthermore, IFN-γ, the pathogenic cytokine secreted by CD8+ T cells that attacked the bulge in LPP/FFA promotes bulge IP collapse (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ;
      • Imanishi H.
      • Ansell D.M.
      • Chéret J.
      • Harries M.
      • Bertolini M.
      • Sepp N.
      • et al.
      Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris.
      ). However, this fundamentally important LPP and FFA pathobiology concept requires further confirmation.
      Although what remains quite unclear to date is how bulge IP collapse is initiated in the first place, both in LPP and in FFA, and which environmental and/or endogenous signals promote this key pathogenesis event. Although the bulge gene and protein expression profile of established lesional versus nonlesional bulge regions in both patients with LPP and those with FFA is characterized by an upregulation of transcriptional markers of IFN-γ‒related signaling (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ), this does not yet prove that excessive IFN-γ secretion is indeed the proverbial “match that lights the fire.” Yet, IFN-γ currently is the best candidate to fit this bill—not the least because IFN-γ‒secreting cytotoxic perforin-positive CD8+ T cells seem to be the first immunocytes that can be identified on the crime scene, that is, inside the bulge epithelium of lesional LPP or FFA HFs; in addition, other immunocytes involved in immune-mediated damage of the bulge region, such as CXCR3+ (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ,
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ) and FOXP3+ T cells, also prominently secrete IFN-γ (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ).
      Nevertheless, other players that have surfaced in the context of AA research might induce bulge IP collapse as well. These include the neuropeptide, SP, which is released from the dense sensory innervation at the level of the bulge and causes neurogenic skin and HF inflammation (
      • Peters E.M.J.
      • Liotiri S.
      • Bodó E.
      • Hagen E.
      • Bíró T.
      • Arck P.C.
      • et al.
      Probing the effects of stress mediators on the human hair follicle: substance P holds central position.
      ) (see later), and possibly also IL-12, which can induce human hair bulb IP collapse. In addition, human HFs are constantly being policed by γδT cells, namely Vδ1+ T lymphocytes, which can recognize the markers of tissue distress such as MICA protein expression through their NKG2D receptors; activation of the latter induces IFN-γ secretion by these cells, followed by IP collapse in the anagen hair bulb (
      • Uchida Y.
      • Gherardini J.
      • Pappelbaum K.
      • Chéret J.
      • Schulte-Mecklenbeck A.
      • Gross C.C.
      • et al.
      Resident human dermal γδT-cells operate as stress-sentinels: lessons from the hair follicle.
      ,
      • Uchida Y.
      • Gherardini J.
      • Schulte-Mecklenbeck A.
      • Alam M.
      • Chéret J.
      • Rossi A.
      • et al.
      Pro-inflammatory Vδ1+T-cells infiltrates are present in and around the hair bulbs of non-lesional and lesional alopecia areata hair follicles.
      ). NKG2D+ NK cells can exert very similar functions and thereby induce AA lesions (
      • Gilhar A.
      • Keren A.
      • Shemer A.
      • d’Ovidio R.
      • Ullmann Y.
      • Paus R.
      Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata.
      ;
      • Ito T.
      • Ito N.
      • Saatoff M.
      • Hashizume H.
      • Fukamizu H.
      • Nickoloff B.J.
      • et al.
      Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack.
      ).
      Thus, it deserves to be investigated whether autoantigen-specific CD8+ T cells really are always the very first immunocytes that attack and infiltrate the bulge in LPP or FFA or whether IFN-γ‒secreting protagonists of innate or transitional immunity, such as γδTCs or NK cells, first recognize tissue distress signals arising from the bulge epithelium (e.g., in response to trauma, HF dysbiosis, environmental toxins, or allergens that have accumulated in the distal HF epithelium [see later] or to nonspecific danger signals such as selected chemokines secreted by a stressed or damaged bulge epithelium) and then recruit CD8+ T cells only subsequently.
      In any case, whether or not this leads to a functionally relevant collapse of bulge IP may determine whether eHFSCs come under attack, for example, by cytotoxic perforin-positive CD8+ T cells (Figure 3b). Intriguingly, this immune attack is not only associated with substantial eHFSC apoptosis. Initially, some of these SCs even seem to enter into the cell cycle (as a frustrated damage‒repair attempt?), whereas the apoptotic cell machinery has already been activated, thus further expediting the depletion of the eHFSC niche (
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ). A very similar phenomenon also occurs in human scalp HFs that are being exposed to chemotherapy ex vivo (
      • Piccini I.
      • Brunken L.
      • Chéret J.
      • Ghatak S.
      • Ramot Y.
      • Alam M.
      • et al.
      Peroxisome proliferator-activated receptor-γ signaling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition.
      ;
      • Purba T.S.
      • Ng’andu K.
      • Brunken L.
      • Smart E.
      • Mitchell E.
      • Hassan N.
      • et al.
      CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia.
      ). Thus, human eHFSCs may unfortunately be prone to succumb to SC niche‒depletory events, if confronted with cytotoxic cytokines and other agents that the bulge SC niche environment cannot neutralize/inactivate. If further research corroborates this concept, LPP and FFA research is challenged to systematically search for just what these eHFSC cytotoxic agents might be—in addition to the usual suspects, that is, IFN-γ and perforin (
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ,
      • Harries M.J.
      • Meyer K.
      • Chaudhry I.
      • E Kloepper J.
      • Poblet E.
      • Griffiths C.E.
      • et al.
      Lichen planopilaris is characterized by immune privilege collapse of the hair follicle’s epithelial stem cell niche.
      ).

      LPP-/FFA-associated fibrosis by EMT induction of eHFSCs

      Human eHFSCs seem to have yet another Achilles heel: their vulnerability to undergo pathological EMT. Both LPP and FFA are typically associated with scarring/fibrosis (
      • Doche I.
      • Wilcox G.L.
      • Ericson M.
      • Valente N.S.
      • Romiti R.
      • McAdams B.D.
      • et al.
      Evidence for neurogenic inflammation in lichen planopilaris and frontal fibrosing alopecia pathogenic mechanism.
      ;
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ;
      • Ocampo-Garza S.S.
      • Orizaga-Y-Quiroga T.L.
      • Olvera-Rodríguez V.
      • Herz-Ruelas M.E.
      • Chavez-Alvarez S.
      • Vañó-Galván S.
      • et al.
      Frontal fibrosing alopecia: is there a link in relatives?.
      ). This cannot be credibly explained by the apoptosis-induced depletion of the epithelial SCs and their progeny because the loss of epithelial cells induces tissue atrophy but not fibrosis. Therefore, it is an important, relatively new LPP/FFA pathobiology concept that the scarring/fibrosis seen in LPP and FFA results at least in part from pathological EMT of eHFSC within the bulge (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ;
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ;
      • Imanishi H.
      • Ansell D.M.
      • Chéret J.
      • Harries M.
      • Bertolini M.
      • Sepp N.
      • et al.
      Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris.
      ) and not only from pathological fibroblast proliferation and ECM production within the HF mesenchyme and perifollicular dermis.
      The bulge epithelium of lesional LPP HFs is characterized by the upregulation of EMT markers such as vimentin and fibronectin and shows ultrastructural signs of EMT. Most importantly, individual K15+ eHFSC can be identified within the bulge epithelia that are double positive for vimentin, a highly pathological phenomenon compatible with EMT induction. In addition, stimulation of perfectly healthy, organ-cultured human scalp HFs with a cocktail of just four agents well-known to induce EMT in various systems (i.e., the potent E-cadherin antagonist, peptide A, EGF, TGF-β1, and IFN-γ) also does so in the human bulge (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ;
      • Imanishi H.
      • Ansell D.M.
      • Chéret J.
      • Harries M.
      • Bertolini M.
      • Sepp N.
      • et al.
      Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris.
      ). Interestingly, pathological EMT is also seen when healthy human scalp HFs are treated ex vivo with certain chemotherapeutic agents (
      • Piccini I.
      • Brunken L.
      • Chéret J.
      • Ghatak S.
      • Ramot Y.
      • Alam M.
      • et al.
      Peroxisome proliferator-activated receptor-γ signaling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition.
      ). Thus, it is conceivable that pathological bulge EMT might, on the one hand, result from IP collapse‒related excessive IFN-γ secretion but, on the other hand, also from certain environmental or metabolic toxins that can promote eHFSC EMT (yet remain to be identified). In any case, pathological EMT induction within the bulge can explain the LPP-/FFA-associated scarring/fibrosis, at least in part, and is a critical target for early and aggressive therapeutic intervention before eHFSC EMT has progressed beyond the point-of-no-return.

      LPP and FFA: Two distinct branches of the same tree?

      This discussion brings us back to the vexing initial question of how two microscopically very similar diseases can exhibit such a distinct clinical phenotype (Table 1 and Figures 1 and 2). Using the simplistic image of a PCA pathogenesis tree, we have proposed that LPP and FFA share a common initial pathobiology trunk but then prominently bifurcate into clinically distinct branches, with immune-mediated eHFSC apoptosis and lichenoid inflammatory cell HF infiltrates dominating the picture in LPP, whereas EMT and classical fibrosis phenomena predominate in FFA (
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ) (Figure 3a and b). What exactly dictates into which of these two putative PCA branches, the disease develops in a given patient after the initially shared pathobiology events (i.e., bulge IP collapse, eHFSC apoptosis, and EMT) has evolved. However, there are some plausible contenders that may be involved in driving the proposed bifurcation, such as a certain genetic predisposition favoring the FFA phenotype (see the section below), whereas the pathogenic activities of peribulge MACs might promote the development of the LPP phenotype (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ) (Figure 2).
      These general concepts provide guidance for the development of more effective future LPP and FFA treatment strategies. On this background, we conclude this review by discussing specific genetic, hormonal, and environmental factors in the pathobiology of these PCAs before sketching some novel, pathobiology-based therapeutic approaches that we consider particularly promising.

      Genetic Factors

      Although reported pediatric cases of LPP are rare, they outnumber the even rarer reported pediatric cases of FFA (>12:3). There are only three reports of pediatric FFA in the literature: twin sisters aged 14 years who developed FFA at age 5 years and a female aged 7 years with FFA (
      • Atarguine H.
      • Hocar O.
      • Hamdaoui A.
      • Akhdari N.
      • Amal S.
      [Frontal fibrosing alopecia: report on three pediatric cases].
      ). Although the histology of the female aged 7 years was reportedly consistent with FFA, the histology and clinical presentation of what is reported as FFA in the twin sisters is less convincing, showing only depletion of HFs with dermal fibrosis and perivascular infiltrate. In contrast, at least 12 pediatric cases of LPP have been reported, and 33% of these occurred in boys (
      • Christensen K.N.
      • Lehman J.S.
      • Tollefson M.M.
      Pediatric lichen planopilaris: clinicopathologic study of four new cases and a review of the literature.
      ). The lack of pediatric FFA cases despite the significant increase in overall FFA numbers strongly suggests that there is a considerable epigenetic influence in FFA development.
      However, the relatively high number of familial FFA cases also indicates that a genetic predisposition for FFA is likely, a concept that is further supported by the recent
      • Tziotzios C.
      • Petridis C.
      • Dand N.
      • Ainali C.
      • Saklatvala J.R.
      • Pullabhatla V.
      • et al.
      Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B∗07:02.
      ’s study. At least 50 patients across 15 families have been reported to have familial FFA (
      • Dlova N.
      • Goh C.L.
      • Tosti A.
      Familial frontal fibrosing alopecia.
      ;
      • Junqueira Ribeiro Pereira A.F.
      • Vincenzi C.
      • Tosti A.
      Frontal fibrosing alopecia in two sisters.
      ;
      • Navarro-Belmonte M.R.
      • Navarro-López V.
      • Ramírez-Boscà A.
      • Martínez-Andrés M.A.
      • Molina-Gil C.
      • González-Nebreda M.
      • et al.
      Case series of familial frontal fibrosing alopecia and a review of the literature.
      ;
      • Porriño-Bustamante M.L.
      • López-Nevot M.Á.
      • Aneiros-Fernández J.
      • García-Lora E.
      • Fernández-Pugnaire M.A.
      • Arias-Santiago S.
      Familial frontal fibrosing alopecia: a cross-sectional study of 20 cases from nine families.
      ;
      • Tziotzios C.
      • Fenton D.A.
      • Stefanato C.M.
      • McGrath J.A.
      Familial frontal fibrosing alopecia.
      ). These familial FFA cases notably include one report of FFA in six sisters (
      • Rocha V.B.
      • Pires M.C.
      • Contin L.A.
      Familial fibrosing frontal alopecia in six sisters.
      ) and at least seven instances of FFA occurring in male family members. The observed inheritance in these familial FFA cases suggests an autosomal dominant transmission pattern with reduced penetrance. Only one of these reports mentions the potential for common environmental exposures among familial FFA cases, stating that the 10 affected family members either lived in the same home or in the same town; this possibility is not known for the other FFA family cases. One Brazilian study identified susceptibility haplotypes in a cluster of familial cases of FFA and reported that these same haplotypes were identified in five of seven sporadic cases that they included as well (
      • Ramos P.M.
      • Garbers L.E.F.M.
      • Silva N.S.B.
      • Castro C.F.B.
      • Andrade H.S.
      • Souza A.S.
      • et al.
      A large familial cluster and sporadic cases of frontal fibrosing alopecia in Brazil reinforce known human leucocyte antigen (HLA) associations and indicate new HLA susceptibility haplotypes.
      ). Specifically, in the familial cluster of FFA cases in this study, three of four unaffected family members had these alleles present, suggesting a role for the environment in FFA pathogenesis in those who are genetically susceptible. Such a relatively clear genetic predisposition is not documented for LPP (there is only one report of LPP affecting three generations of women in one family [
      • Misiak-Galazka M.
      • Olszewska M.
      • Rudnicka L.
      Lichen planopilaris in three generations: grandmother, mother, and daughter - a genetic link?.
      ]) and may thus constitute at least one driver in the HF pathology bifurcation toward the FFA phenotype (Figure 3a and b).
      What is known about the genetic factors in LPP and FFA? One of the largest genetic studies in LPP was done in 40 Jewish Israeli patients (82.5% of whom were non-Ashkenazi) and 252 controls. Molecular typing revealed that the patients with LPP had a significantly higher frequency of the DRB1∗11 and DQB1∗03 alleles than the controls (
      • Pavlovsky L.
      • Israeli M.
      • Sagy E.
      • Berg A.L.
      • David M.
      • Shemer A.
      • et al.
      Lichen planopilaris is associated with HLA DRB1∗11 and DQB1∗03 alleles.
      ). DQB1∗03 has been implicated as a susceptibility locus for AA and in IP collapse. In yet another study of patients with LPP, increased transcription of HLA DRB1 and DQB1 genes was found in affected but not in unaffected scalp tissue. Interestingly, one report of HLA testing in a daughter with LPP and a mother with FFA showed that both had HLA DRB1 and DQB1 alleles that were identical, suggesting that LPP and FFA may share a common genetic basis but develop different phenotypes depending on environmental, hormonal, or other influences (
      • Rivas M.M.O.
      • Antolín S.C.
      • Sambucety P.S.
      • González E.S.
      • Ruíz de Morales J.M.G.
      • Prieto M.Á.R.
      Frontal fibrosing alopecia and lichen planopilaris in HLA-identical mother and daughter.
      ).
      In addition, microarray analyses of whole affected and unaffected skin biopsies from patients with LPP showed a significant upregulation in the CYP1A1 gene (
      • Karnik P.
      • Tekeste Z.
      • McCormick T.S.
      • Gilliam A.C.
      • Price V.H.
      • Cooper K.D.
      • et al.
      Hair follicle stem cell-specific PPARgamma deletion causes scarring alopecia.
      ). The expression of CYP1A1 is directly controlled by signaling of the AhR, a cellular receptor that plays a role in the processing of xenobiotics, oxidation reactions, and immune regulation, suggesting a role for this receptor in the development of LPP. Increased expression of AhR+ cells was also found in the epidermis of unaffected LPP and FFA scalp specimens compared with that in controls, and 30% of patients with LPP and FFA had increased number of AhR+ cells on the affected scalp compared with that on the unaffected area (
      • Doche I.
      • Pagliari C.
      • Hordinsky M.K.
      • Wilcox G.L.
      • Rivitti-Machado M.C.M.
      • Romiti R.
      • et al.
      Overexpression of the aryl hydrocarbon receptor in frontal fibrosing alopecia and lichen planopilaris: a potential pathogenic role for dioxins?: an investigational study of 38 patients.
      ). A GWAS and meta-analysis in female patients with FFA revealed a significant FFA association at four loci, including a missense variant in CYP1B1, a gene that encodes a xenobiotic processing enzyme and aryl hydrocarbon hydroxylase and has been implicated in the regulation of human immune cells. Other alleles, including HLA-B∗07:02 and ST3GAL1, were also shown to be associated, suggesting that aberrant antigen processing and T-cell homeostasis may play a role in the development of FFA (
      • Tziotzios C.
      • Petridis C.
      • Dand N.
      • Ainali C.
      • Saklatvala J.R.
      • Pullabhatla V.
      • et al.
      Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B∗07:02.
      ).
      Unfortunately, because no study has comprehensively investigated and compared molecular typing and genomics in both conditions, we do not really understand yet where the genetics of LPP and FFA overlap (the trunk as shown in Figure 3a) and diverge (LPP vs. FAA branch as shown in Figure 3b). Also unclear is the pathobiological relevance of the haplotypes and the candidate genes. No functional confirmation, for example, through gene silencing of recently reported candidate genes (
      • Tziotzios C.
      • Petridis C.
      • Dand N.
      • Ainali C.
      • Saklatvala J.R.
      • Pullabhatla V.
      • et al.
      Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B∗07:02.
      ) in organ-cultured human HFs, has been published, even though this has long been possible and is highly instructive in HF genodermatoses (
      • Samuelov L.
      • Sprecher E.
      • Tsuruta D.
      • Bíró T.
      • Kloepper J.E.
      • Paus R.
      P-cadherin regulates human hair growth and cycling via canonical Wnt signaling and transforming growth factor-β2.
      ;
      • Sugawara K.
      • Bíró T.
      • Tsuruta D.
      • Tóth B.I.
      • Kromminga A.
      • Zákány N.
      • et al.
      Endocannabinoids limit excessive mast cell maturation and activation in human skin.
      ;
      • Tiede S.
      • Hundt J.E.
      • Paus R.
      UDP-GlcNAc-1-Phosphotransferase is a clinically important regulator of human and mouse hair pigmentation.
      ), and no persuasive scenario has been proposed on how exactly these genetic elements may contribute to the early stages of FFA versus that of LPP pathogenesis.

      Other Factors

      In the venerable history of LPP/FFA pathogenesis discussions (
      • Baibergenova A.
      • Donovan J.
      Lichen planopilaris: update on pathogenesis and treatment.
      ;
      • Harries M.J.
      • Jimenez F.
      • Izeta A.
      • Hardman J.
      • Panicker S.P.
      • Poblet E.
      • et al.
      Lichen planopilaris and frontal fibrosing alopecia as model epithelial stem cell diseases.
      ;
      • Headington J.T.
      Cicatricial alopecia.
      ;
      • Kang H.
      • Alzolibani A.A.
      • Otberg N.
      • Shapiro J.
      Lichen planopilaris.
      ;
      • Kerkemeyer K.L.S.
      • Eisman S.
      • Bhoyrul B.
      • Pinczewski J.
      • Sinclair R.D.
      Frontal fibrosing alopecia.
      ;
      • Tziotzios C.
      • Stefanato C.M.
      • Fenton D.A.
      • Simpson M.A.
      • McGrath J.A.
      Frontal fibrosing alopecia: reflections and hypotheses on aetiology and pathogenesis.
      ), many different potential triggering or aggravating factors besides trauma have been implicated. It remains a wide-open question whether, where, and to which extent the factors discussed in the following sections and listed in Table 2 exert and possibly coalesce in any epigenetic changes that affect LPP/FFA pathogenesis (regrettably, the epigenetic pathology of PCAs essentially is terra incognita).
      Table 2Frequency of Positive Patch Test Results in Patients with LPP and/or FFA Compared with Rates in the European General Population
      Allergen
      • Prasad S.
      • Marks D.H.
      • Burns L.J.
      • De Souza B.
      • Flynn E.A.
      • Scheinman P.
      • et al.
      Patch testing and contact allergen avoidance in patients with lichen planopilaris and/or frontal fibrosing alopecia: a cohort study.
      (N = 42)
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      (N= 40)
      • Rocha V.B.
      • Donati A.
      • Contin L.A.
      • Kakizaki P.
      • Machado C.J.
      • Brito F.F.
      • et al.
      Photopatch and patch testing in 63 patients with frontal fibrosing alopecia: a case series.
      (N = 63)
      • Pastor-Nieto M.A.
      • Gatica-Ortega M.E.
      • Sánchez-Herreros C.
      • Vergara-Sánchez A.
      • Martínez-Mariscal J.
      • De Eusebio-Murillo E.
      Sensitization to benzyl salicylate and other allergens in patients with frontal fibrosing alopecia [published correction appears in Contact Dermatitis 2021;85:385].
      (N = 36)
      • Diepgen T.L.
      • Ofenloch R.F.
      • Bruze M.
      • Bertuccio P.
      • Cazzaniga S.
      • Coenraads P.J.
      • et al.
      Prevalence of contact allergy in the general population in different European regions.
      (N = 3,119)
      Percentage of patients with at least one positive relevant allergen76%52.5%27%80.5%27%
      Gallates26.2%16.6%
      Fragrance Mix I14.3%10.0%5.0%8.3%0.9%
      Linalool19.0%22.5%8.0%5.5%
      Limonene4.8%13.8%
      Ammonium persulfate14.3%
      Benzophenone 414.3%12.5%8.0%
      Benzyl salicylate4.8%22%
      Propolis9.5%16.6%
      MI/MCI11.9%17.5%2.8%0.5%
      Balsam of Peru7.1%12.5%8.0%5.5%0.7%
      Abbreviations: FFA, frontal fibrosing alopecia; LPP, lichen planopilaris; MI/MCI, methylisothiazolinone/methylchloroisothiazolinone.

      Endocrine factors

      Hormones such as androgens, estradiol, thyroid hormones, and prolactin all prominently regulate both human hair growth and epithelial SC functions (
      • Inui S.
      • Itami S.
      Androgen actions on the human hair follicle: perspectives.
      ;
      • Ohnemus U.
      • Uenalan M.
      • Inzunza J.
      • Gustafsson J.A.
      • Paus R.
      The hair follicle as an estrogen target and source.
      ;
      • Paus R.
      • Langan E.A.
      • Vidali S.
      • Ramot Y.
      • Andersen B.
      Neuroendocrinology of the hair follicle: principles and clinical perspectives.
      ;
      • Ramot Y.
      • Böhm M.
      • Paus R.
      Translational neuroendocrinology of human skin: concepts and perspectives.
      ). Among these, the potential role of androgens in FFA has received special attention. The hairline recession in FFA and the frequent concomitant androgenetic alopecia (AGA) that occurs in patients with LPP and FFA have led some authors to propose a role for androgen excess in FFA, largely on the basis of the postmenopausal predominance of affected females (
      • Dawn G.
      • Holmes S.C.
      • Moffat D.
      • Munro C.S.
      Post-menopausal frontal fibrosing alopecia.
      ;
      • Ranasinghe G.C.
      • Piliang M.P.
      • Bergfeld W.F.
      Prevalence of hormonal and endocrine dysfunction in patients with lichen planopilaris (LPP): a retrospective data analysis of 168 patients.
      ). Although definitive evidence for this hypothesis is missing, reports of clinical benefits seen in some patients treated with 5α-reductase inhibitors (5ARIs) such as dutasteride (
      • Jerjen R.
      • Pinczewski J.
      • Sinclair R.
      • Bhoyrul B.
      Clinicopathological characteristics and treatment outcomes of fibrosing alopecia in a pattern distribution: a retrospective cohort study.
      ;
      • Lobato-Berezo A.
      • March-Rodríguez A.
      • Deza G.
      • Bertolín-Colilla M.
      • Pujol R.M.
      Frontal fibrosing alopecia after antiandrogen hormonal therapy in a male patient.
      ;
      • Panchaprateep R.
      • Ruxrungtham P.
      • Chancheewa B.
      • Asawanonda P.
      Clinical characteristics, trichoscopy, histopathology and treatment outcomes of frontal fibrosing alopecia in an Asian population: a retro-prospective cohort study.
      ;
      • Pindado-Ortega C.
      • Saceda-Corralo D.
      • Moreno-Arrones Ó.M.
      • Rodrigues-Barata A.R.
      • Hermosa-Gelbard Á.
      • Jaén-Olasolo P.
      • et al.
      Effectiveness of dutasteride in a large series of patients with frontal fibrosing alopecia in real clinical practice.
      ;
      • Vañó-Galván S.
      • Saceda-Corralo D.
      • Alonso-Castro L.
      • Urech M.
      • Espada J.
      Antiandrogenic drugs, a therapeutic option for frontal fibrosing alopecia patients [published correction appears in J Am Acad Dermatol 2018;78:431].
      ) have been interpreted as supporting it. However, the results of retrospective cohort studies of moderate quality where patients were treated with concomitant therapies in addition to 5ARIs and/or serum androgen and estrogen levels were not measured should be interpreted cautiously (
      • Murad A.
      • Bergfeld W.F.
      Reply to effectiveness of dutasteride in a large series of patients with frontal fibrosing alopecia in real clinical practice.
      ).
      Yet, the involvement of non androgen-dependent scalp hair in LPP and FFA (eyebrows, limb hair) and lack of concomitant hirsutism and acne in this patient population may argue against a major pathogenic role for androgens. That the frontal hairline, the main target HF population in women with FFA, is relatively spared in female, Ludwig-pattern AGA, presumably owing to the decreased density of androgen receptors in female HF at this location further questions a key role of androgens in female FFA development (
      • Grymowicz M.
      • Rudnicka E.
      • Podfigurna A.
      • Napierala P.
      • Smolarczyk R.
      • Smolarczyk K.
      • et al.
      Hormonal effects on hair follicles.
      ;
      • Katoulis A.C.
      • Diamanti K.
      • Sgouros D.
      • Liakou A.I.
      • Bozi E.
      • Avgerinou G.
      • et al.
      Is there a pathogenetic link between frontal fibrosing alopecia, androgenetic alopecia and fibrosing alopecia in a pattern distribution?.
      ;
      • MacDonald A.
      • Clark C.
      • Holmes S.
      Frontal fibrosing alopecia: a review of 60 cases.
      ). One retrospective study of 168 female patients investigated the association of androgen excess or deficiency with LPP and FFA. A total of 69% of the subjects were postmenopausal, and 31% had a history of polycystic ovary syndrome. A total of 41.7% of patients had LPP, 31.5% had FFA, and 26.8% had LPP/FFA overlap. Notably, androgen excess was seen in 40% of patients with LPP and in 35.6% of patients with LPP/FFA but surprisingly not in the FFA only group; in contrast, androgen deficiency was seen in 32.1% of patients with FFA (
      • Ranasinghe G.C.
      • Piliang M.P.
      • Bergfeld W.F.
      Prevalence of hormonal and endocrine dysfunction in patients with lichen planopilaris (LPP): a retrospective data analysis of 168 patients.
      ). In a cross-sectional study of 711 female patients with FFA, 5.6% of women had a history of estrogen deficiency, and 2.3% were exposed to selective estrogen receptor modulators such as tamoxifen or clomiphene (
      • McSweeney S.M.
      • Christou E.A.A.
      • Dand N.
      • Boalch A.
      • Holmes S.
      • Harries M.
      • et al.
      Frontal fibrosing alopecia: a descriptive cross-sectional study of 711 cases in female patients from the UK.
      ). Thus, more robust data are needed before the role of sex steroids in FFA and/or LPP pathogenesis can be fully judged.

      Environmental chemical exposure

      Several of the earliest cases of follicular spinous eruptions affecting the scalp in the setting of generalized lichen planus—deemed to be the first published cases of LPP—were reported in otherwise healthy postmenopausal women (
      • Little E.G.
      Folliculitis decalvans et atrophicans.
      ;
      • Pringle J.J.
      Lichenous eruption for diagnosis (pityriasis rubra pilaris).
      ). However, in 1909, a case of patchy scarring alopecia affecting only the scalp with perifollicular scale and erythema was described in a healthy male lithographer aged 34 years exposed to occupational chlorinated hydrocarbons, heavy metals, and strong acids (
      • Macleod J.M.H.
      Case of pseudo-pelade (Brocq) or cicatricial alopecia, affecting chiefly the vertex of the scalp.
      ). Later, another report of a sudden eruption of follicular inflammatory lesions on the abdomen that quickly generalized to involve the scalp was reported in a female aged 43 years just 1 month after undergoing a dilatation and curettage for menorrhagia (
      • Peters A.D.
      Lichen pilaris seu spinulosus.
      ). Perhaps most striking is a recent case of a male construction worker aged 35 years who acutely developed biopsy-proven LPP 2 weeks after high-concentration exposure to trichloroethylene and perchloroethylene during ground intrusive work at a previous dry-cleaning facility site. Despite treatment, this patient had rapid progression and loss of all scalp hair within 3 years (
      • Marks D.H.
      • Hagigeorges D.
      • Manatis-Lornell A.J.
      • Foreman R.K.
      • Senna M.M.
      Development of lichen planopilaris-like alopecia following occupational exposure to trichloroethylene and tetrachloroethylene.
      ). Although these anecdotal cases reflect atypical and more severe presentations of LPP, the coincident occurrences of LPP after exposure to occupational or perioperative substances raise interest in the potential role of environmental influences in LPP development.
      Instead, recent reports have focused mainly on the association between FFA and environmental exposures, likely fostered by reports of the emerging epidemic of FFA cases (
      • Mirmirani P.
      • Tosti A.
      • Goldberg L.
      • Whiting D.
      • Sotoodian B.
      Frontal fibrosing alopecia: an emerging epidemic.
      ) and owing to the distribution of hair loss being in areas of frequent contact with personal care products (PCPs) (moisturizers, cosmetics) and sunscreens. PubMed analysis trends have been used by authors to show the increase in FFA numbers by reporting the surge in FFA publications over time (
      • Mirmirani P.
      • Tosti A.
      • Goldberg L.
      • Whiting D.
      • Sotoodian B.
      Frontal fibrosing alopecia: an emerging epidemic.
      ). However, as of September 2021, similar trends are seen in this PubMed analysis for LPP, with 39 and 609 total articles published through 1994 and 2021, respectively, compared with 1 and 633 articles published on FFA over this same time course. Notably, a 2019 multicenter study of specialty alopecia clinics across four continents reported that the frequency of patients with FFA was 10.8%, followed closely by that of LPP (7.6%) (
      • Vañó-Galván S.
      • Saceda-Corralo D.
      • Blume-Peytavi U.
      • Cucchía J.
      • Dlova N.C.
      • Gavazzoni Dias M.F.R.
      • et al.
      Frequency of the types of alopecia at twenty-two specialist hair clinics: A multicenter study.
      ). Although it is undeniable that cases of FFA have increased over time, it should not be overlooked that LPP diagnoses have similarly risen.
      It is also important to consider that since 2010, there has been a significantly increased reporting of adverse effects from haircare products to the United States Food and Drug Administration, with above-average reports of serious health outcomes associated with items used for personal-cleanliness haircare and hair-coloring products (
      • Kwa M.
      • Welty L.J.
      • Xu S.
      Adverse events reported to the US Food and Drug Administration for cosmetics and personal care products.
      ). Furthermore, three hair product lines have been subjects of class action lawsuits in the United States, namely Brazilian Blowout, Chaz Dean’s Wen products, and DevaCurl, with consumers reporting hair loss and scalp inflammation after use of these products (
      ClassAction.org
      Class action alleges DevaCurl hair products contain several ‘Known’ allergens, irritants.
      ). Although these certainly do not prove an association between these products and LPP or FFA development, they do suggest that selected hair products may stimulate immune responses leading to HF pathology, whose downstream effects require further investigation.

      PCPs

      The increase in the cases of FFA, the distribution of its involvement, and that it largely affects postmenopausal women have stimulated research into the possibility that PCPs could play a role in pathogenesis. The association between FFA and increased use of leave-on facial products, including sunscreens, was initially reported in case-control survey studies. A subset of these patients with FFA underwent patch testing that revealed an increased allergy to fragrance (
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      ;
      • Debroy Kidambi A.
      • Dobson K.
      • Holmes S.
      • Carauna D.
      • Del Marmol V.
      • Vujovic A.
      • et al.
      Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens.
      ), and subsequent patch testing studies conducted in other countries in patients with FFA identified other potentially relevant allergens (
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      ;
      • Pastor-Nieto M.A.
      • Gatica-Ortega M.E.
      • Sánchez-Herreros C.
      • Vergara-Sánchez A.
      • Martínez-Mariscal J.
      • De Eusebio-Murillo E.
      Sensitization to benzyl salicylate and other allergens in patients with frontal fibrosing alopecia [published correction appears in Contact Dermatitis 2021;85:385].
      ;
      • Rocha V.B.
      • Donati A.
      • Contin L.A.
      • Kakizaki P.
      • Machado C.J.
      • Brito F.F.
      • et al.
      Photopatch and patch testing in 63 patients with frontal fibrosing alopecia: a case series.
      ) (Table 2).
      Although these studies did not include patients with LPP, another patch testing study of 42 patients with LPP and FFA reported that 76% had at least one relevant positive allergic reaction to ingredients in their PCPs used on the head and neck (
      • Prasad S.
      • Marks D.H.
      • Burns L.J.
      • De Souza B.
      • Flynn E.A.
      • Scheinman P.
      • et al.
      Patch testing and contact allergen avoidance in patients with lichen planopilaris and/or frontal fibrosing alopecia: a cohort study.
      ). There were no differences in the rates of allergy between patients with LPP and those with FFA, and the most common allergens identified were gallates, linalool, and Fragrance Mix I (Table 2). Notably, diligent avoidance of known allergens for 3 months led to decreased scalp symptoms and clinical signs of LPP and FFA. Most remarkable about these contact allergy reports in patients with LPP and FFA is how the rates of allergy compare with what is known about the rates of these allergens in the general population. In a study of patch testing responses in the European general population, only 0.9% of people had positive reactions to Fragrance Mix I compared with 14.3%, 10%, 5%, and 8.3% reported in the LPP and FFA populations (
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      ;
      • Pastor-Nieto M.A.
      • Gatica-Ortega M.E.
      • Sánchez-Herreros C.
      • Vergara-Sánchez A.
      • Martínez-Mariscal J.
      • De Eusebio-Murillo E.
      Sensitization to benzyl salicylate and other allergens in patients with frontal fibrosing alopecia [published correction appears in Contact Dermatitis 2021;85:385].
      ;
      • Prasad S.
      • Marks D.H.
      • Burns L.J.
      • De Souza B.
      • Flynn E.A.
      • Scheinman P.
      • et al.
      Patch testing and contact allergen avoidance in patients with lichen planopilaris and/or frontal fibrosing alopecia: a cohort study.
      ;
      • Rocha V.B.
      • Donati A.
      • Contin L.A.
      • Kakizaki P.
      • Machado C.J.
      • Brito F.F.
      • et al.
      Photopatch and patch testing in 63 patients with frontal fibrosing alopecia: a case series.
      ) (Table 2).
      Further research into the exact role of these allergens or other PCP ingredients and the downstream effects of sensitization to these agents on HF biology and immune status is necessary before the ongoing controversial debate on the role of leave-on cosmetics in LPP and/or FFA pathogenesis (
      • Aldoori N.
      • Dobson K.
      • Holden C.R.
      • McDonagh A.J.
      • Harries M.
      • Messenger A.G.
      Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study.
      ;
      • Debroy Kidambi A.
      • Dobson K.
      • Holmes S.
      • Carauna D.
      • Del Marmol V.
      • Vujovic A.
      • et al.
      Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens.
      ;
      • Strazzulla L.C.
      • Avila L.
      • Lo Sicco K.
      • Shapiro J.
      Response to “Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens.”.
      ;
      • Tavakolpour S.
      • Mahmoudi H.
      • Abedini R.
      • Kamyab Hesari K.
      • Kiani A.
      • Daneshpazhooh M.
      Frontal fibrosing alopecia: an update on the hypothesis of pathogenesis and treatment.
      ) can be laid to rest, in one way or another. Certainly, it would be instructive to clarify in this context whether any of the incriminated candidate agents impairs bulge IP and/or eHFSC functions by testing these directly in full-length HF organ culture (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ;
      • Purba T.S.
      • Ng’andu K.
      • Brunken L.
      • Smart E.
      • Mitchell E.
      • Hassan N.
      • et al.
      CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia.
      ).

      Odorants and olfactory receptors

      Many leave-on cosmetics contain natural or synthetic odorants, for which human scalp HFs prominently express functional olfactory receptors and whose stimulation both regulates hair growth (
      • Chéret J.
      • Bertolini M.
      • Ponce L.
      • Lehmann J.
      • Tsai T.
      • Alam M.
      • et al.
      Olfactory receptor OR2AT4 regulates human hair growth.
      ) and can affect tissue pathology in various systems (
      • Maßberg D.
      • Hatt H.
      Human olfactory receptors: novel cellular functions outside of the nose.
      ). Olfactory receptor stimulation with a synthetic odorant contained in many perfumes and aftershaves also stimulates the production of potent antimicrobial peptides in human scalp HFs ex vivo (
      • Chéret J.
      • Bertolini M.
      • Ponce L.
      • Lehmann J.
      • Tsai T.
      • Alam M.
      • et al.
      Olfactory receptor OR2AT4 regulates human hair growth.
      ) and thus may impact the composition of the HF microbiome (
      • Lousada M.B.
      • Lachnit T.
      • Edelkamp J.
      • Rouillé T.
      • Ajdic D.
      • Uchida Y.
      • et al.
      Exploring the human hair follicle microbiome.
      ). Olfactory receptors are expressed by many immune cell populations, including CD8+ T cells and MACs (
      • Clark A.A.
      • Nurmukhambetova S.
      • Li X.
      • Munger S.D.
      • Lees J.R.
      Odorants specifically modulate chemotaxis and tissue retention of CD4+ T cells via cyclic adenosine monophosphate induction.
      ), and activation of specific MAC surface olfactory receptors can induce chemokine secretion (
      • Li J.J.
      • Tay H.L.
      • Plank M.
      • Essilfie A.T.
      • Hansbro P.M.
      • Foster P.S.
      • et al.
      Activation of olfactory receptors on mouse pulmonary macrophages promotes monocyte chemotactic protein-1 production.
      ) and polarization into M2 MACs (
      • Vadevoo S.M.P.
      • Gunassekaran G.R.
      • Lee C.
      • Lee N.
      • Lee J.
      • Chae S.
      • et al.
      The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages.
      ). This is interesting because the M2 phenotype is preferentially increased around lesional LPP HFs (Figure 2a) (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ), raising the question whether this or other olfactory receptors might be involved in the development of LPP.
      Recently, we found that patients with LPP are allergic to gallates and linalool, an odorant known to specifically activate OR1C1 (
      • Mainland J.D.
      • Li Y.R.
      • Zhou T.
      • Liu W.L.L.
      • Matsunami H.
      Human olfactory receptor responses to odorants.
      ) and that there was a direct correlation between the use of products containing these molecules and disease development (
      • Prasad S.
      • Marks D.H.
      • Burns L.J.
      • De Souza B.
      • Flynn E.A.
      • Scheinman P.
      • et al.
      Patch testing and contact allergen avoidance in patients with lichen planopilaris and/or frontal fibrosing alopecia: a cohort study.
      ). Interestingly, OR1C1 has been found to be expressed in the testis (
      • Flegel C.
      • Vogel F.
      • Hofreuter A.
      • Schreiner B.S.P.
      • Osthold S.
      • Veitinger S.
      • et al.
      Characterization of the olfactory receptors expressed in human spermatozoa.
      ), another key site of IP such as the HF bulge. Therefore, the potential role of odorant-induced, olfactory receptor‒dependent mechanisms in LPP/FFA chemosensation pathobiology deserves systematic exploration.

      Caveolins/caveolae

      Most recently, specialized membrane microdomains (caveolae) have also emerged as a promising, previously overlooked target in future LPP/FFA management. The scaffolding protein, CAV1, a key structural component of caveolae, not only colocalizes with K15 in the outer root sheath and eHFSCs of human scalp HFs, but its expression is also significantly elevated in lesional FFA compared with that in healthy scalp HFs (
      • Jozic I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ). Furthermore, it is well established that CAV1 inhibits TGFβ- and α-MSH‒mediated (
      • He K.
      • Yan X.
      • Li N.
      • Dang S.
      • Xu L.
      • Zhao B.
      • et al.
      Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes.
      ) signaling and thus antagonizes the activity of these key guardians of HF IP.
      In addition, CAV1 upregulates the expression of IFN-γ, the key inducer of bulge HF IP collapse, as well as SP and MICA (
      • Oakley F.D.
      • Smith R.L.
      • Engelhardt J.F.
      Lipid rafts and caveolin-1 coordinate interleukin-1beta (IL-1beta)-dependent activation of NFkappaB by controlling endocytosis of Nox2 and IL-1beta receptor 1 from the plasma membrane.
      ;
      • Stang E.
      • Kartenbeck J.
      • Parton R.G.
      Major histocompatibility complex class I molecules mediate association of SV40 with caveolae.
      ;
      • Tomassian T.
      • Humphries L.A.
      • Liu S.D.
      • Silva O.
      • Brooks D.G.
      • Miceli M.C.
      Caveolin-1 orchestrates TCR synaptic polarity, signal specificity, and function in CD8 T cells.
      ). Moreover, the SP receptor, neurokinin (NK1), localizes to caveolae, and disruption of caveolae by cholesterol-depleting agents significantly reduces SP reactivity and activation of NK1 receptor in mice (
      • Monastyrskaya K.
      • Hostettler A.
      • Buergi S.
      • Draeger A.
      The NK1 receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity.
      ). Additional arguments in support of elucidating the role of caveolins and caveolae in FFA/LPP pathobiology arise from the fact that CAV1 expression is upregulated during EMT (
      • Bailey K.M.
      • Liu J.
      Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase.
      ;
      • Gai X.
      • Lu Z.
      • Tu K.
      • Liang Z.
      • Zheng X.
      Caveolin-1 is up-regulated by GLI1 and contributes to GLI1-driven EMT in hepatocellular carcinoma.
      ;
      • Liang W.
      • Hao Z.
      • Han J.L.
      • Zhu D.J.
      • Jin Z.F.
      • Xie W.L.
      CAV-1 contributes to bladder cancer progression by inducing epithelial-to-mesenchymal transition.
      ) and that the overexpression of CAV1 can lead to the downregulation of E-cadherin and upregulation of vimentin (
      • Cokakli M.
      • Erdal E.
      • Nart D.
      • Yilmaz F.
      • Sagol O.
      • Kilic M.
      • et al.
      Differential expression of Caveolin-1 in hepatocellular carcinoma: correlation with differentiation state, motility and invasion.
      ) and thus promotes EMT. Thus, pharmacologically downregulating caveolins might help to protect the bulge from both IP collapse and pathological EMT (
      • Jozic I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ).

      Dysbiosis

      There is an increasing interest in the role of HF dysbiosis in various hair diseases, such as AA and AGA, whereas very little is as yet known about the HF microbiome in LPP and FFA (
      • Constantinou A.
      • Kanti V.
      • Polak-Witka K.
      • Blume-Peytavi U.
      • Spyrou G.M.
      • Vogt A.
      The potential relevance of the microbiome to hair physiology and regeneration: the emerging role of metagenomics.
      ,
      • Constantinou A.
      • Polak-Witka K.
      • Tomazou M.
      • Oulas A.
      • Kanti V.
      • Schwarzer R.
      • et al.
      Dysbiosis and enhanced beta-defensin production in hair follicles of patients with lichen planopilaris and frontal fibrosing alopecia.
      ;
      • Gaber H.D.
      • Mohamed A.M.
      • Abdel Gaber R.M.
      Presence of Alternaria in scalp of patients with alopecia areata: triggering factor or coexistence?.
      ;
      • Lousada M.B.
      • Lachnit T.
      • Edelkamp J.
      • Rouillé T.
      • Ajdic D.
      • Uchida Y.
      • et al.
      Exploring the human hair follicle microbiome.
      ;
      • Pinto D.
      • Sorbellini E.
      • Marzani B.
      • Rucco M.
      • Giuliani G.
      • Rinaldi F.
      Scalp bacterial shift in alopecia areata.
      ;
      • Polak-Witka K.
      • Rudnicka L.
      • Blume-Peytavi U.
      • Vogt A.
      The role of the microbiome in scalp hair follicle biology and disease.
      ). Because Staphylococcus aureus overcolonization is thought to be one of the main pathogenic factors in the neutrophilic PCA, folliculitis decalvans (
      • Chiarini C.
      • Torchia D.
      • Bianchi B.
      • Volpi W.
      • Caproni M.
      • Fabbri P.
      Immunopathogenesis of folliculitis decalvans: clues in early lesions.
      ;
      • Otberg N.
      • Kang H.
      • Alzolibani A.A.
      • Shapiro J.
      Folliculitis decalvans.
      ), it is important to characterize the effect of bacterial colonization and HF dysbiosis also on LPP and FFA.
      Interestingly, in female patients with LPP and FFA, Cutibacterium acnes reportedly is absent from the lesional FFA scalp surface but was present on LPP lesional scalp and in healthy controls (
      • Constantinou A.
      • Polak-Witka K.
      • Tomazou M.
      • Oulas A.
      • Kanti V.
      • Schwarzer R.
      • et al.
      Dysbiosis and enhanced beta-defensin production in hair follicles of patients with lichen planopilaris and frontal fibrosing alopecia.
      ). Instead, Actinobacteria were significantly reduced in lesional skin of both patients with FFA and those with LPP compared with that in healthy controls, whereas the amount of Firmicutes was strongly upregulated. Moreover, S. aureus was the most abundant bacteria in plucked lesional hair shafts from lesional LPP and FFA areas compared with that from healthy controls, suggesting a role for an imbalance between these bacterial species in the development of these PCAs (
      • Constantinou A.
      • Polak-Witka K.
      • Tomazou M.
      • Oulas A.
      • Kanti V.
      • Schwarzer R.
      • et al.
      Dysbiosis and enhanced beta-defensin production in hair follicles of patients with lichen planopilaris and frontal fibrosing alopecia.
      ). This was accompanied by a strong upregulation of both β-defensin 1 and 2 in patients with LPP and FFA (these β-defensins are well-known T-cell attractants [
      • Kanda N.
      • Kamata M.
      • Tada Y.
      • Ishikawa T.
      • Sato S.
      • Watanabe S.
      Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells.
      ;
      • Niyonsaba F.
      • Ogawa H.
      • Nagaoka I.
      Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils.
      ]). Thus, dissecting the role of HF dysbiosis and the related abnormalities in chemokine secretion, bulge expression of danger signals such as MICA, and changes in the local production of proinflammatory antimicrobial peptides in the early stages of LPP/FFA pathogenesis promise to be a particularly fertile and translationally relevant research frontier.

      Stress and neurogenic inflammation

      Although our understanding of how psychological stress and hair loss might be related is still quite incomplete (
      • Paus R.
      • Arck P.
      Neuroendocrine perspectives in alopecia areata: does stress play a role?.
      ), human HFs exhibit a fully functional, local hypothalamic‒pituitary‒adrenal axis (
      • Ito N.
      • Ito T.
      • Kromminga A.
      • Bettermann A.
      • Takigawa M.
      • Kees F.
      • et al.
      Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.
      ), including the key stress-related neurohormone, corticotropin-releasing hormone (CRH) (
      • Ito N.
      • Ito T.
      • Betterman A.
      • Paus R.
      The human hair bulb is a source and target of CRH.
      ), which promotes perifollicular mast cell degranulation and the local maturation of mast cells from resident progenitors (
      • Ito N.
      • Sugawara K.
      • Bodó E.
      • Takigawa M.
      • van Beek N.
      • Ito T.
      • et al.
      Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme.
      ). Thus, activation of this intrafollicular neuroendocrine stress responses axis by perceived stress may promote perifollicular neurogenic inflammation, thereby facilitating bulge IP collapse in LPP and FFA.
      In mice, perceived stress rapidly induces prominent perifollicular neurogenic inflammation that centers around the bulge region; causes premature HF regression (catagen induction); is dependent on NGF, mast cells, and signaling through the SP receptor, NK1 (
      • Arck P.C.
      • Handjiski B.
      • Kuhlmei A.
      • Peters E.M.J.
      • Knackstedt M.
      • Peter A.
      • et al.
      Mast cell deficient and neurokinin-1 receptor knockout mice are protected from stress-induced hair growth inhibition.
      ,
      • Arck P.C.
      • Handjiski B.
      • Hagen E.
      • Joachim R.
      • Klapp B.F.
      • Paus R.
      Indications for a “brain-hair follicle axis (BHA)”: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
      ); and also upregulates intrafollicular CRH expression. SP+ nerve fibers are densely situated around the human HF bulge (
      • Peters E.M.
      • Botchkarev V.A.
      • Botchkareva N.V.
      • Tobin D.J.
      • Paus R.
      Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.
      ), and SP is a known fibroblast GF and can promote fibrosis (
      • Słoniecka M.
      • Danielson P.
      Substance P induces fibrotic changes through activation of the RhoA/ROCK pathway in an in vitro human corneal fibrosis model.
      ). Moreover, SP induces (bulb) IP collapse also in human HFs where it activates perifollicular mast cells and upregulates HF production of the mast cell secretagogue, NGF, and expression of p75NTR (
      • Peters E.M.J.
      • Liotiri S.
      • Bodó E.
      • Hagen E.
      • Bíró T.
      • Arck P.C.
      • et al.
      Probing the effects of stress mediators on the human hair follicle: substance P holds central position.
      ), whose activation by NGF triggers the apoptosis of HF keratinocytes (KCs); SP also stimulates TNF-α release, which further promotes HF KC apoptosis and catagen development (
      • Botchkarev V.A.
      • Botchkarev N.V.
      • Albers K.M.
      • van der Veen C.
      • Lewin G.R.
      • Paus R.
      Neurotrophin-3 involvement in the regulation of hair follicle morphogenesis.
      ;
      • Paus R.
      • Lüftl M.
      • Czarnetzki B.M.
      Nerve growth factor modulates keratinocyte proliferation in murine skin organ culture.
      ;
      • Tron V.A.
      • Coughlin M.D.
      • Jang D.E.
      • Stanisz J.
      • Sauder D.N.
      Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212).
      ). Furthermore, SP greatly increases the number of CD68+ tissue-resident MACs in human skin (
      • Gherardini J.
      • Uchida Y.
      • Hardman J.A.
      • Chéret J.
      • Mace K.
      • Bertolini M.
      • et al.
      Tissue-resident macrophages can be generated de novo in adult human skin from resident progenitor cells during substance P-mediated neurogenic inflammation ex vivo.
      ), whose number is significantly increased around the bulge of LPP, notably more than around FFA-affected scalp HFs (Figure 2a) (
      • Harries M.
      • Hardman J.
      • Chaudhry I.
      • Poblet E.
      • Paus R.
      Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?.
      ). Therefore, SP-dependent neurogenic (stress-induced?) peribulbar inflammation could also play a role in triggering and/or aggravating LPP and FFA pathobiology; however, this remains to be conclusively shown.

      Future Directions and Therapeutic Interventions

      On the basis of our limited current understanding of LPP and FFA pathobiology (Figure 3a and b), it is possible to envision novel therapeutic intervention strategies that could greatly enhance the arsenal for managing these disfiguring PCAs in the future. To conclude, we briefly highlight some particularly promising avenues for how we might translate recent LPP/FFA pathobiology insights into concrete therapeutic benefits.
      Arguably, the lowest-hanging fruit in substantially advancing both LPP and FFA therapy is to finally develop a good topical application vehicle for tacrolimus (FK506) and similar immunophilin ligands that greatly enhances HF penetration. Because FK506 both prevents experimentally induced IP collapse in the human anagen hair bulb and promotes HF IP restoration ex vivo (
      • Ito T.
      • Ito N.
      • Bettermann A.
      • Tokura Y.
      • Takigawa M.
      • Paus R.
      Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.
      ), it is to be expected that it will also do so in the (more easily accessible) bulge—if it can only reach a sufficient concentration there. That FK506 treatment with a suboptimal vehicle reportedly already has some therapeutic benefit in selected patients with FFA or LPP (
      • Blazek C.
      • Megahed M.
      [Lichen planopilaris. Successful treatment with tacrolimus].
      ;
      • Giorgio C.M.
      • Briatico G.
      • Licata G.
      • Babino G.
      • Di Brizzi E.V.
      • Pellerone S.
      • et al.
      Frontal fibrosing alopecia: a successful treatment with tacrolimus 0,2% in topical solution [e-pub ahead of print].
      ;
      • Mahmoudi H.
      • Rostami A.
      • Tavakolpour S.
      • Nili A.
      • Teimourpour A.
      • Salehi Farid A.
      • et al.
      Oral isotretinoin combined with topical clobetasol 0.05% and tacrolimus 0.1% for the treatment of frontal fibrosing alopecia: a randomized controlled trial.
      ) strongly encourages one to pursue HF-targeting vehicle development for this drug and other candidate bulge IP guardians, such as extended-activity α-MSH (afamelanotide) (
      • Ito T.
      • Ito N.
      • Bettermann A.
      • Tokura Y.
      • Takigawa M.
      • Paus R.
      Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.
      ), which might be repurposed for topical LPP/FFA treatment.
      Given the potential role of SP and NK1 in peribulge neurogenic inflammation, it also deserves to be tested whether clinically available NK1 antagonists such as aprepitant (
      • Chen S.
      • Lu M.
      • Liu D.
      • Yang L.
      • Yi C.
      • Ma L.
      • et al.
      Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography.
      ) can be repurposed in the management of LPP/FFA.
      If the proposed role for caveolins in FFA pathogenesis (
      • Jozic I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ) is confirmed, this warrants investigation whether topical perturbation of intrafollicular CAV1, either pharmacologically (e.g., through cyclodextrins/statins) (
      • Jozic I.
      • Abujamra B.A.
      • Elliott M.H.
      • Wikramanayake T.C.
      • Marjanovic J.
      • Stone R.C.
      • et al.
      Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.
      ,
      • Jozic I.
      • Sawaya A.P.
      • Pastar I.
      • Head C.R.
      • Wong L.L.
      • Glinos G.D.
      • et al.
      Pharmacological and genetic inhibition of caveolin-1 promotes epithelialization and wound closure.
      ;
      • Sawaya A.P.
      • Jozic I.
      • Stone R.C.
      • Pastar I.
      • Egger A.N.
      • Stojadinovic O.
      • et al.
      Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signaling.
      ) or by nanoparticle-mediated small interfering RNA delivery, can halt the—often relentless—progression of FFA/LPP and can be used as an auxiliary therapy to the other candidate therapeutics discussed in this paper. Interestingly, the OR2AT4 agonist, Sandalore, which prolongs anagen ex vivo (
      • Chéret J.
      • Bertolini M.
      • Ponce L.
      • Lehmann J.
      • Tsai T.
      • Alam M.
      • et al.
      Olfactory receptor OR2AT4 regulates human hair growth.
      ), also downregulates the expression of CAV1 at both mRNA and protein levels (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ;
      • Jozic I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ). Besides targeting CAV1 therapeutically, it may also be an overlooked candidate biomarker of disease progression and activity (
      • Jozic I.
      • Chéret J.
      • Abujamra B.A.
      • Miteva M.
      • Gherardini J.
      • Paus R.
      A cell membrane-level approach to cicatricial alopecia management: is Caveolin-1 a viable therapeutic target in frontal fibrosing alopecia?.
      ).
      The PPAR-γ modulator, NAGED, not only prevents and partially reverses experimentally induced EMT in the human bulge (
      • Imanishi H.
      • Ansell D.M.
      • Chéret J.
      • Harries M.
      • Bertolini M.
      • Sepp N.
      • et al.
      Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris.
      ) and upregulates K15 expression in eHFSCs ex vivo (
      • Ramot Y.
      • Mastrofrancesco A.
      • Herczeg-Lisztes E.
      • Bíró T.
      • Picardo M.
      • Kloepper J.E.
      • et al.
      Advanced inhibition of undesired human hair growth by PPARγ modulation?.
      ) but also protects K15+ eHFSC from apoptosis, reduces the number of CD8+ and MHCII+ cells in the bulge region of LPP HFs, and reduces EMT ex vivo (
      • Chéret J.
      • Piccini I.
      • Hardman-Smart J.
      • Ghatak S.
      • Alam M.
      • Lehmann J.
      • et al.
      Preclinical evidence that the PPARγ modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.
      ). Preliminary recent evidence suggests that the bulge of lesional LPP HFs contains dysfunctional mitochondria, including the downregulation of the key TFAM (
      • Hardman-Smart J.A.
      • Purba T.S.
      • Panicker S.
      • Farjo B.
      • Farjo N.
      • Harries M.J.
      • et al.
      Does mitochondrial dysfunction of hair follicle epithelial stem cells play a role in the pathobiology of lichen planopilaris?.
      ). Because TFAM is upregulated by PPAR-γ (
      • Miglio G.
      • Rosa A.C.
      • Rattazzi L.
      • Collino M.
      • Lombardi G.
      • Fantozzi R.
      PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss.
      ), PPAR-γ agonists/modulators may also help to prevent or reverse LPP-associated mitochondrial dysfunction.
      Additional future interventions should consider prophylactic avoidance of potentially immune-stimulating environmental factors, including allergenic and certain olfactory receptors‒stimulating fragrances in PCPs, namely in genetically or otherwise FFA- or LPP-predisposed individuals. This will become mandatory if experimental evidence becomes available that some fragrances stimulate pathogenic MAC and dendritic cell activities at the level of the bulge and/or alter the physiological composition of the HF microbiome through olfactory receptors‒controlled changes in the intrafollicular production of antimicrobial peptides (
      • Chéret J.
      • Bertolini M.
      • Ponce L.
      • Lehmann J.
      • Tsai T.
      • Alam M.
      • et al.
      Olfactory receptor OR2AT4 regulates human hair growth.
      ).
      Importantly, directions for future research must investigate the genetic and pathogenic mechanisms of LPP, FFA, and LPP/FFA overlap in tandem because this is the only way that we will truly begin to appreciate how these conditions are similar and where they diverge. For example, when the genetics of FFA are examined using one method and the genetics of LPP are evaluated in a different way, an important opportunity is missed to understand the similarities and differences between these conditions. Robust research will rely heavily on diagnoses performed by expert dermatologist hair specialists collaborating with colleagues in basic science to yield comprehensive data from reliable samples. Correlating the clinical features of patients with LPP and/or FFA who provide such research samples, including the degree of severity and disease activity, will provide important information to help guide the interpretation of disease processes. It is only through such vigorous clinical and scientific collaboration that the much needed answers for our elusive questions surrounding LPP and FFA will finally become clearer.
      In summary, this review shows that refocusing attention on the pathobiology of LPP and FFA along the system of coordinates delineated here and the specific suggestions we have made has substantial translational value. Indeed, it promises to greatly accelerate the development of long-awaited, much more effective LPP/FFA therapies and will likely supply us with robust molecular biomarkers of both, disease activity/subtype and response to therapy.

      Data availability statement

      No datasets were generated or analyzed during this study.

      Author Contributions

      Visualization: MMS, RP, EP, JC, IJ; Writing - Original Draft Preparation: MMS, RP; Writing - Review and Editing: EP, JC, IJ

      Acknowledgments

      The writing of this review was supported by a Frost Endowed Scholarship to RP and an American Skin Association Research Scholar Award to IJ.

      Conflict of Interest

      For the record, RP is the chief executive officer of a skin and hair research company (www.monasteriumlab.com) that has performed contract research on the impact of peroxisome proliferator–activated receptor-γ and olfactory receptor ligands on human hair follicles but holds no patents and does not develop products in this area. The remaining authors state no conflict of interest.

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