Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche

Abstract

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, β2microglobulin; reduced TGFβ2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

Evaluation of the Diagnostic Value of Plasmacytoid Dendritic Cells in Differentiating the Lymphocytic Cicatricial Alopecias

“…While LE-associated alopecia showed increased PDC content (≥10% PDCs in all cases and ≥50% in 94% of cases), PDC clusters (100% of cases), and deeper dermal and perieccrine distribution (100% of cases) with DEJ involvement (94% of cases), the majority of LPP and FFA had <10% PDC content mainly confined to upper dermis surrounding the hair infundibulum with rare DEJ involvement and rare clustering (table 1). The latter findings of PDCs in LPP were similar to those shown in a recent study [13]. …”

“…A recent study also demonstrated PDC recruitment into LPP lesions; however, no study has yet looked into the diagnostic value of PDC presence and distribution patterns in the lymphocytic cicatricial alopecias due to LE, LPP, and frontal fibrosing alopecia (FFA), the latter regarded by many as a clinical LPP variant (fig. 1) with indistinguishable microscopic features [1,13,14,15,16]. …”

Eradication of damaged keratinocytes in cutaneous lichen planus forms demonstrated by evaluation of epidermal and follicular expression of CK15, indices of apoptosis and regulatory protein S100

“…TUNEL reaction findings obtained by us are in accordance with evidence demonstrated by Bloor et al and confirmed by Harries et al reporting on increase of TUNEL positive epithelial cells in LP [14,24,40]. The results of TUNEL reaction supported by AI counting and ultrastructural analysis performed suggest that among patient groups analyzed in this study the basal and suprabasal keratinocyte damage was especially pronounced in the LPP of the scalp region, thus with high probability explaining hair loss.…”

“…Mobini et al suggested that damage of eHFSCs evidenced by diminished or absent immunostaining of CK15 and mediated by cytotoxic CD8 positive cells plays a role in the pathogenesis of LPP [23]. However, the evidence that loss of eHFSCs really does occur in human PCA is poor [24,25,26]. Recent findings suggest that the loss of CK15-positive cells occurs in the hair follicles surrounded by perifollicular lymphocytes, while uninvolved follicles usually retain expression of CK15 [27].…”

Frontal Fibrosing Alopecia and Increased Scalp Sweating: Is Neurogenic Inflammation the Common Link

“…A key event in the permanent HF loss seen in lesional FFA is the destruction of epithelial HF stem cells [2,10], likely due to a Th1-biased inflammatory response and loss of HF immune privilege [11]. However, it is still unclear what predisposes to this inflammatory attack; genetic susceptibility may be important, whereas environmental factors may explain the recent identification, pattern and growing incidence of the condition [12].…”