Immune-mediated alopecias and their mechanobiological aspects

Abstract

Alopecia is a non-specific term for hair loss clinically diagnosed by the hair loss pattern and histological analysis of patient scalp biopsies. The immune-mediated alopecia subtypes, including alopecia areata, lichen planopilaris, frontal fibrosing alopecia, and central centrifugal cicatricial alopecia, are common, significant forms of alopecia subtypes. For example, alopecia areata is the most common autoimmune disease with a lifetime incidence of approximately 2% of the world's population. In this perspective, we discuss major results from studies of immune-mediated alopecia subtypes. These studies suggest the key event in disease onset as the collapse in immune privilege, which alters the hair follicle microenvironment, e.g., upregulation of major histocompatibility complex molecules and increase of cytokine production, and results in immune cell infiltration, inflammatory responses, and damage of hair follicles. We note that previous studies have established that the hair follicle has a complex mechanical microenvironment, which may regulate the function of not only tissue cells but also immune cell infiltrates. This suggests a potential for mechanobiology to contribute to alopecia research by adding new methods, new approaches, and new ways of thinking, which is missing in the existing literature. To fill this a gap in the alopecia research space, we develop a mechanobiological hypothesis that alterations in the hair follicle microenvironment, specifically in the mechanically responsive tissues and cells, partially due to loss of immune privilege, may be contributors to disease pathology. We further focus our discussion on the potential for applying mechanoimmunology to the study of T cell infiltrates in the hair follicle, as they are considered primary contributors to alopecia pathology. To establish the connection between the mechanoimmunological hypothesis and immune-mediated alopecia subtypes, we discuss what is known about the role of T cells in immune-mediated alopecia subtypes, using the most extensively studied AA as our model.

Keywords: Alopecia; Autoimmunity; Hair loss; Mechanobiology; Mechanoimmunology.

Fig. 1.

Clinical presentation of immune-mediated alopecia subtypes. Immune-mediated alopecias have various subtypes and can be distinguished by the extent and severity of hair loss. Representative images show typical phenotypes. A) Alopecia Areata (AA).¹ B) Central Centrifugal Cicatricial Alopecia (CCCA). C) Frontal Fibrosing Alopecia (FFA). D) Lichen Planopilaris (LPP)². ¹Image retrieved from: “Alopecia Areata.” Docs4Hair, 2018, https://www.docs4hair.com/alopecia-areata. Date accessed: March, 01, 2022. ²Image retrieved from: “Lichen Planopilaris.: Docs4-Hair, 2018, https://www.docs4hair.com/lichen-planopilaris. Date accessed: March, 01, 2022. Permission to reproduce and copyright transfer will be requested upon the acceptance of the manuscript.

Fig. 2.

Lymphocyte infiltration of immune-mediated alopecias. Hematoxylin and eosin (H&E) stained tissue sections of embedded tissues from alopecia patients. H&E stains use the combination of two stains to label cell nuclei and non-specific staining of proteins, respectively. H&E staining can be used to distinguish differences in microenvironment alterations between alopecia subtypes. Panels A) AA³ B) CCCA⁴ C) FFA⁵ D) LPP⁶ show histology of respective alopecia subtypes. ³Image retrieved from: Dy, L. C., & Whiting, D. A. (2011). Histopathology of alopecia areata, acute and chronic: Why is it important to the clinician? Dermatologic Therapy, 24(3), 369–374. https://doi.org/10.1111/J.1529-8019.2011.01414.X. ⁴Image retrieved from: “Destructive Perifollicular Inflammation in Central Centrifugal Cicatricial Alopecia.” Uptodate 2018, Wolters Kluwer, 2018, https://ykhoa.org/d/image.htm?imageKey=DERM%2F91789. Date accessed: March 1, 2022. ^5,6Image retrieved from: Gálvez-Canseco, A., & Sperling, L. (2018). Lichen planopilaris and frontal fibrosing alopecia cannot be differentiated by histopathology. Journal of Cutaneous Pathology, 45(5), 313–317. https://doi.org/10.1111/CUP.13112. Permission to reproduce and copyright transfer will be requested upon the acceptance of the manuscript.

Fig. 3.

The immunological aspects of alopecia subtypes. A. Alopecia arises from the loss of hair follicle immune privilege resulting in disease-prone cytokine environment, upregulated MHC expression, and immune cell infiltrates. B. Alopecia subtypes as well as their common and different features are indicated by the overlapping and non-overlapping regions of the three circles. The callout shows a comparative venn-diagram of immune-mediated alopecia subtypes, where cytokines and immune cell infiltrates are compared. Common to all alopecia subtypes is the loss in HFIP, which resides in the center of the graph.

Fig. 4.

Interplay of mechanobiology with the hair cycle. Contributions to hair follicle homeostasis involve responses to mechanical stimuli. On the tissue level, the attachment of the arrector pilli muscle to scalp hair contributes to follicular mechanical regulation. On the cellular level, dermal sheath contraction facilitates stem cell relocation for hair cycle progression. Constituent follicular stem cells include mesenchymal stem cells, which are known to be mechanically responsive. More importantly, molecular bonds across intercellular junctions to bridge stem cells or stem cells to the extracellular matrix are likely subject to mechanical forces. Depicted are concentric cycles intended to convey the involvement of mechanobiology in the various stages of the hair cycle.

Fig. 5.

The hypothetical disease progressive pathological response of immune-mediated alopecia. Tissue homeostasis is perturbed by the loss of HFIP, leading to antigen recognition, immune activation, inter- and intra-cellular signaling, cellular response, and effector function. Points where mechanoimmunology has been shown useful are indicated. These include the changes of mechanical microenvironment and perhaps more importantly, the sensing, response, and adaptation of the immune cells to such changes, contributing to the pathology of the disease.