Pathogenesis of Acne: Masahiko Toyoda Masaaki Morohashi

Med Electron Microsc (2001) 34:29–40 © The Clinical Electron Microscopy Society of Japan 2001
REVIEW
Masahiko Toyoda · Masaaki Morohashi
Pathogenesis of acne
Received: March 9, 2001 / Accepted: March 17, 2001
Abstract Acne vulgaris is a skin disorder of the sebaceous induced significant increases in the area of sebaceous
follicles that commonly occurs in adolescence and in young glands. It also increased the size of individual sebaceous
adulthood. The major pathogenic factors involved are hy- cells and the number of sebum vacuoles for each differenti-
perkeratinization, obstruction of sebaceous follicles re- ated sebaceous cell, all of which suggests that substance P
sulting from abnormal keratinization of the infundibular promotes both the proliferation and the differentiation of
epithelium, stimulation of sebaceous gland secretion by an- sebaceous glands. In this review, we introduce the general
drogens, and microbial colonization of pilosebaceous units concept of pathogenic factors involved in acne, including
by Propionibacterium acnes, which promotes perifollicular typical electron microscopic findings and recent evidence of
inflammation. The clinical presentation of acne can range stress-induced exacerbation of acne from a neurological
from a mild comedonal form to severe inflammatory cystic point of view. An improved understanding of the pathogen-
acne of the face, chest, and back. At the ultrastruc- esis of acne should lead to a rational therapy to successfully
tural level, follicular keratinocytes in comedones can be treat this skin disease.
seen to possess increased numbers of desmosomes and
tonofilaments, which result in ductal hypercornification. Key words Acne vulgaris · Sebaceous follicle · Propioni-
The increased activity of sebaceous glands elicited by an- bacterium acnes · Inflammation · Neuropeptides
drogen causes proliferation of P. acnes, an anaerobe present
within the retained sebum in the pilosebaceous ducts. The
organism possesses a ribosome-rich cytoplasm and a rela-
tively thick cell wall, and produces several biologically ac- Introduction
tive mediators that may contribute to inflammation, for
instance, by promoting leukocyte migration and follicular Acne vulgaris is a complex, chronic, and common skin dis-
rupture. In inflamed lesions, numerous neutrophils and order of pilosebaceous units that occurs predominantly in
macrophages infiltrate around hair follicles and sometimes the skin of the face, the upper back, and the upper chest.
phagocytose P. acnes. To examine the participation of neu- This disease usually begins at the time of the sharp increase
rogenic factors in the pathogenesis of acne, we quan- in androgen production that occurs during adolescence. In
titatively assessed the effects of neuropeptides on the recent years, the multifactorial nature of acne has been
morphology of sebaceous glands in vitro using electron elucidated but much remains to be learned. Briefly, acne
microscopy. Substance P, which can be elicited by stress, begins when the pilosebaceous ducts become plugged with
promoted the development of cytoplasmic organelles in se- keratinocytes to form comedones, sebum builds up and dis-
baceous cells, stimulated sebaceous germinative cells, and tends the follicles, and the anaerobe Propionibacterium
acnes (P. acnes) proliferates in the sebum. If the comedo
ruptures into the dermis, inflammation results and a pustule
or papule forms.1 This review article summarizes the patho-
genesis of acne, including the clinicopathological relation-
ship of acne lesions, the fine structural features of P. acnes,
and the pathophysiology of sebaceous follicles. In particu-
M. Toyoda · M. Morohashi (*) lar, we focus on ultrastructural findings that help clarify why
Department of Dermatology, Faculty of Medicine, Toyama Medical and how each therapeutic agent is rationally used for acne
and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194,
treatment. To clarify the participation of neurogenic factors
Japan
Tel. 181-76-434-7305; Fax 181-76-434-5028 in the etiology of acne, the effects of neuropeptides on the
e-mail: [email protected] morphology of sebaceous glands were also studied.
30 N. Matsuda et al.: EGF receptor and osteoblastic differentiation
anaerobic diphtheroid. The yeasts Pityrosporum ovale and

Clinical aspects of acne
Pityrosporum orbiculare colonize the upper acroinfundi-
bulum. Aerobic cocci, usually Staphylococcus epidermidis,
From the clinical point of view, acne is divided into non- reside on the skin surface around the follicles.6
inflammatory or inflammatory lesions.2 Noninflammatory
acne is characterized by the presence of open or closed
comedones, which begin as invisible microcomedones that
proceed all other acne lesions. Microcomedo formation is Pathogenesis of acne
caused by the abnormal keratinization of the infundibular
epithelium of hair follicles. Further retention of a dense There is general agreement that acne is of multifactorial
material composed of sebum and keratinous debris dilates origin. The four most significant pathogenic factors of
the follicles of microcomedones, which leads to the forma- acne have been identified as previously stated: (1) an andro-
tion of comedones. Two types of comedones can be distin- gen-stimulated increase in the production of sebum, (2)
guished morphologically, one being a closed comedo, or hyperkeratinization and obstruction of sebaceous follicles
whitehead, and the other being a open comedo, or black- resulting from abnormal desquamation of follicular epithe-
head. In contrast, inflammatory lesions consist of papules, lium, (3) proliferation of Propionibacterium acnes, and (4)
which are raised erythematous lesions measuring less than inflammation.2
0.5 cm, and pustules, which are papules with a visible collec-
tion of white pus at the surface. These lesions often enlarge, Sebaceous secretion
becoming firm or indurated, and are termed nodules. Cysts
are a similar type of lesion with noted fluctuations. Scarring The first factor in the genesis of acne is the androgen-
may be associated with any form of severe inflammatory induced hypertrophy of sebaceous glands and the overpro-
acne. Clinical manifestations of acne vulgaris range from duction of sebum, which is the by-product of the holocrine
noninflammatory comedones to inflammatory papules, pus- rupture of mature sebocytes. Androgens are the major
tules, and cyst. In most patients with acne, these lesions are sebotropic hormones; sebaceous glands are very sensitive to
usually intermingled to various extent. The goal of treat- androgens and are less sensitive to estrogens.7,8 Acne gener-
ment is to reduce the numbers of both types of lesions, with ally begins at puberty, when androgen levels increase
minimal or no side effects.3 significantly and stimulate excess sebum secretion.9 In a
microcomedo, the sebum is trapped behind a keratin plug.
The follicle then becomes enlarged and contains a mixture
of sebum and keratinous squamae, which leads to the oblit-
Histology eration of the normal architecture of the follicle and to the
formation of a thin-walled cystic lesion, the comedo. The
Acne is a disease of the sebaceous follicles, which are hormonal control of sebaceous gland function is complex.
equipped with large sebaceous glands and produce only fine The pituitary is the main driver, and as a result of its influ-
vellus hairs. Sebaceous follicles are most common in the ence on the adrenal and gonads, there is an interplay of
acne-prone areas such as the cheeks, the nose, and the hormones that control the pilosebaceous units.10,11 The most
forehead, as well as on the midline chest and the back. The important androgen is testosterone, which is converted to
follicular canal is considerably wider than that of a normal dihydrotestosterone by the iso-enzyme 5α-reductase type
hair follicle and is lined with stratified squamous epithe- 112 (Fig. 1). On the other hand, it has been recognized that
lium. At the proximal end of the canal, deep in the dermis, the adrenal androgen dehydroepiandrostenedione corre-
are sebaceous glands connected to the canal by short ducts. lates well with early features of acne, in particular, the
The outer part of the follicular canal comprises two histo- presence of comedones.13 There are increased levels of 5α-
logically distinct regions. The distal region is termed the reductase in the sebaceous glands of acne patients.12 An
acroinfundibulum and the proximal region is the infrain- increased number of androgen receptors is also found in
fundibulum, the latter portion being important to the sebaceous glands.14 Acne patients are not endocrine misfits,
pathogenesis of acne. The acroinfundibulum is essentially a and an end-organ hyperresponse of the glands to androgens
continuation of the usual surface epithelium. There is a is probably the most likely explanation for the seborrhea.8
similar granular layer and a stratum corneum, and des- Sebum, when first secreted, consists principally of triglyceri-
quamation of cornified cells proceeds normally. In the des, with significant quantities of wax esters and squalene
infrainfundibulum, the epithelial cells have fewer desmo- and very small amounts of cholesterol and cholesterol
somes and tonofilaments,4,5 the granular layer is diminished, esters.1 However, as the secretion moves up the follicular
and the horny layer is much thinner. The cornified cells do canal, its composition is modified by microbial lipase hy-
not form a coherent layer, and they slough readily into the drolysis of the triglycerides to yield free fatty acids and
follicular canal. The resulting keratinous squamae are car- glycerol.15 P. acnes produces a lipase, and it has been re-
ried to the skin surface with the secreted sebum. In addition ported that 95% of the free fatty acids at the surface of the
to sebum and shed cells, the canal normally contains a skin results from P. acnes activity.16,17 Free fatty acids pro-
mixed microbial population. In the infrainfundibulum, the duced by P. acnes metabolism contribute to microcomedo
most common organism is Propionibacterium acnes, an formation as well as to inflammatory reactions in acne.

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Med Electron Microsc (2001) 34:29–40 © The Clinical Electron Microscopy Society of Japan 2001

Masahiko Toyoda · Masaaki Morohashi

Received: March 9, 2001 / Accepted: March 17, 2001

anaerobic diphtheroid. The yeasts Pityrosporum ovale and

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