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The primary cicatricial alopecias have proven to be challenging for the clinician, dermatopathologist and the researcher – let alone the patient. If we are to improve our diagnostic and therapeutic tools for these very difficult disorders, we will need greater insight into their etiology. Recent work with the mouse mutant, asebia, provides a model for cicatricial alopecia. In this model the pathology – perifollicular inflammation, sebaceous gland “destruction”, hair shaft granuloma, and cicatricial follicle drop-out – results from the mutation of one very important sebaceous gland gene. In the absence of this gene, the sebaceous gland is hypoplastic and normal sebum production is minimal to absent. In this paper the relevance of this mutant to human alopecias is discussed and the point emphasized that the pathogenesis of some forms of human cicatricial alopecia could involve the sebaceous gland.
The primary cicatricial alopecias remain a major challenge for the critical diagnostician and therapist. The basis for this challenge is our lack of insight into disease mechanism. Clearly, once we understand that mechanism effective therapy will follow.
The cicatricial alopecias are divided into two groups:1,2 the primary cicatricial alopecias, where the destructive process targets or starts in the pilosebaceous unit itself and not the associated reticular dermis; and the secondary cicatricial alopecias, where the destructive process originates in the surrounding dermis and secondarily affects the pilosebaceous apparatus. In the secondary conditions the follicle is an innocent bystander, caught up in a non-follicular-based process. Examples of the latter include sarcoidosis, lupus vulgaris, and morphea.
The focus in this essay, however, is on the primary cicatricial alopecias which includes pseudopelade, lichen planopilaris, follicular degeneration syndrome, and early stages of cutaneous lupus erythematosus.1 While we do not understand how these disorders come about, we recognize that they have unique clinical and histological presentations.1–4 What they have in common clinically is pilosebaceous apparatus drop-out with loss of follicular orifices. What they have in common histologically, in the early stages, is an inflammatory cell infiltrate about, interfacing or within the mid follicular region, and sebaceous gland destruction. In the late stages all forms show fibrous tissue replacement of follicular structures and absence of sebaceous epithelium with variable number of inflammatory cells.
What and where are the vulnerable elements of the pilosebaceous apparatus, which are critical to hair follicle cycling? The hair follicle arises as an out-pouch of the primitive epidermis during skin morphogenesis in the embryo. After it is fully formed, the follicle cycles through phases of growth (anagen), regression (catagen), resting (telogen), and shedding (exogen).5 It is from the lower follicle that the shaft is formed and it is in this region that the most dramatic changes occur over the cycle.6 The important point here is that the lower follicle recreates itself after each cycle, in other words, the pilosebaceous apparatus has unique and powerful regenerative properties. The regeneration is orchestrated by intimate interactions between the follicular papilla and the very special regenerative epithelium of the lower resting follicle.
What the inductive signals might be, which the papilla or the regenerating epithelium generate, are yet to be defined, but they nonetheless act to periodically renew the follicle. A large body of evidence suggests that there are cells with stem cell-like features in the lower portion of the resting follicle.7–9 In addition, a second major research effort has identified the papilla and the surrounding dermal sheath connective tissue as critical to the cycle and thus regeneration of the inferior follicle.10,11
From what we know today about the biology of the follicle we might surmise that the cicatricial alopecias arise because the regions of the follicle important to normal regeneration and cycling are destroyed. We know from laboratory studies that any physical destruction of the normal connective tissue sheath or the papilla precludes any further cycling. Similarly, destroying the follicular epithelial stem cells by an inflammatory process of the mid-follicle (bulge) could limit or prevent the regenerative ability of that follicle. It has been proposed that repeated episodes of trauma exhaust the follicular stem cell population leading to follicle dropout. In addition, the differentiation and interaction of the cells making up the cycling follicle must be optimal. For example, if proper morphogenetic messages cannot get through, follicle destruction will ensue. These messages may be metabolic or structural. For example, when keratin 6 is overexpressed in the mouse,12 a cicatricial alopecia results.
Recently, we had the opportunity to examine in detail the mutant mouse, asebia. This mouse first found as a spontaneous mutant with autosomal recessive inheritance,13 shows scant to absent hair, fibrous tissue replacement of hair follicles and hypoplastic-to-absent sebaceous glands. Chemical studies of the skin surface show the absence of normal sebaceous gland lipids. Our genetic studies revealed that the asebia mouse lacks the normal expression of a single gene, which generates an enzyme that desaturates fatty acids; the enzyme is a stearoyl CoA desaturase.14 In mouse skin the expression of this gene is restricted to the sebaceous gland.14
Histologically, we found, as Josefowic and Hardy15 had before us, that the anagen follicles of the asebia mouse are abnormally long, extending at an angle into the deep subcutis and that the hair shafts coming out of the skin surface are abnormally short.16 In addition to the atrophic sebaceous glands, we observed that the internal root sheath is retained by the shaft as it courses into and out of the pilary canal and that the outgrowing shaft adheres to the sheath. So, although the shaft itself appears to be of normal size, character, and length, the portion that extends above the skin surface is reduced. We found that in many follicles the shaft appeared to experience resistance in its outward course so that instead of moving distally it moved proximally. Evidence for this reversed movement were the long follicles and the shaft perforation of the inferior, bulb portion of the follicle with resultant foreign body reaction In older mice we found changes of a typical end-stage cicatricial alopecia – fibrosis, inflammation, absent sebaceous glands and focal foreign body reactions.
In earlier studies we and others found that hair follicles grown in culture without their sebaceous glands lead to the retention of the internal root sheath on the outgrowing shaft.17,18 These studies suggested that the sebaceous gland is important to sheath-shaft processing. The asebia mouse takes those observations one step further, namely that a one-gene sebaceous gland defect leads to sebaceous gland hypoplasia and cicatricial alopecia. Collectively, these findings suggest that a novel pathogenetic mechanism causing cicatricial alopecia in mice may be relevant to one or more of the human primary cicatricial alopecias. This correlation is most pertinent recalling that sebaceous glands are characteristically ablated in the early stages of the primary cicatricial alopecias also.1 In the human case, though, we do not know if any of the primary cicatricial alopecias can be reproduced by sebaceous gland pathology alone.
In summary, experiments from our laboratory and others indicate that the sebaceous gland is important to normal shaft sheath processing – it is not just a source of natural emollient, it is necessary for normal follicle cycling. In the absence of sebaceous gland function the sheath adheres to the shaft, prevents shaft exit, and leads to follicle destruction. The pathogenetic lesson here is that there are probably several, if not many, mechanisms causing cicatricial alopecia, one of which is altered sebaceous gland function.