New Study Suggests there is More in Common with Primary Scarring Alopecias than Realized

New Data Highlights Shared Gene Signatures Between Scarring Alopecias

There are several primary scarring alopecias. We spend a considerable amount of time and effort trying to understand how they all differ and if there are specific treatments that might help each one. More often than not, treatments that help one scarring alopecia often help another scarring alopecia. For example, topical steroids, doxycycline, steroid injections, calcineurin inhibitors and JAK inhibitors are known to help LPP, FFA and folliculitis decalvans despite the fact that the pathogenesis of these conditions may differ.

Wang EHC et al. 2022

Authors of a new study performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures. They collected scalp tissue samples from a cohort of 30 LPP, 36 FFA, 9 CCCA patients, and 12 normal controls. The authors wanted to determine if there are shared transcriptomic signatures among LPP, FFA, and CCCA and to determine the degree of association with different immune cell types. They performed morphological and cytokine analysis to define the immune cell populations found in primary scarring alopecia subtypes.

The authors identified common PCA gene expression signatures that were shared between LPP, FFA, and CCCA and differed from normal controls. Pathway analyses and immunopanel on these gene signatures revealed changes in three main pathways: (1) cholesterogenesis; (2) fibrosis; and (3) MCs

This included:

a) a significant over-representation of mast cell (MC) genes

The immunopanel analysis revealed a striking and highly significant MC signature. Many genes such as TPSAB1, MS4A2, and CMA1 appear involved in LPP, FFA and CCCA.

The authors found strong positive staining for mast cells (via MC tryptase and Toluidine Blue) in biopsy samples from LPP, FFA, and CCCA. This staining was seen around the sebaceous gland and within fibrotic tissue. In contrast, the normal control skin, did not show a large number of MCs in the bulb and sebaceous gland region. Taken together, this data is consistent with the overrepresentation of the MC signature in primary scarring alopecias like LPP, CCCA and FFA.

The authors found that plasma mast cell marker levels were similar among the different disease groups, and showed data to support the notion that mast cell activity was primarily restricted to the skin and was not a systemic feature of primary scarring alopecia.

The presence of mast cells in the pathogenesis of LPP, FFA and CCCA suggests a possible trigger of innate immune responses in scarring alopecia that potentially involve allergic mechanisms. This gives further fuel to the hypothesis that environmental factors such as allergens may be involved in the pathogenesis of PCAs. Mast cells also play a role in fibrosis and the authors propose that sustained activation of mast cells could also result in the development of fibrosis.

The authors point out a recent 2018 study by Hobo et al which found a high number IL-17A positive mast cells in LPP lesions and suggested autoactivation of the IL-23/IL-17 axis

b) downregulation of cholesterogenic pathways.

The authors computational analysis revealed a core set of differentially expressed genes involved in cholesterol biosynthesis, fatty acid biosynthesis and metabolism pathways. Specifically, there was a decrease of cholesterol biosynthesis. This was thought to reflect the loss of sebaceous glands and/or decreased sebum production.

The authors found a significant downregulation of cholesterol biosynthesis genes such as CYP51A1, DHCR7, and MSMO1 in scarring alopecia biopsies. The authors remind us that these particular genes are involved in different stages cholesterol biogenesis, lipid synthesis and some are even involved in drug metabolism. The defect in cholesterol biosynthesis may result in accumulation of sterol intermediates which can initiate inflammatory response.

c) upregulation of fibrosis genes.

Pathway analysis revealed upregulation of many genes involved in fibrosis

FROM Wang EHC et al. Primary cicatricial alopecias are characterized by dysregulation of shared gene expression pathways. PNAS Nexus . 2022 Jul 11;1(3):pgac111. Data presented with creative commons license.

Conclusion

Overall, the authors showed there are many indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA. These data are indeed encouraging as they suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss. In particular, the data here suggest that LPP, FFA and CCCA share similar pathogenic pathways and that new treatments that upregulate chlosterogenic pathways, reduce fibrosis, and target mast cells may be helpful to treat these diseases.

The role of the mast cell is indeed interesting. It has been suggested that allergy may have a role in some patients with LPP and FFA. Indeed, antihistamines are showing benefit in these diseases.

REFERENCE

Wang EHC et al. Primary cicatricial alopecias are characterized by dysregulation of shared gene expression pathways. PNAS Nexus . 2022 Jul 11;1(3):pgac111

Hobo A, et al. 2018. IL-17-positive mast cell infiltration in the lesional skin of lichen planopilaris: possible role of mast cells in inducing inflammation and dermal fibrosis in cicatricial alopecia. Exp Dermatol.29:273–277