Overview of the Pathogenesis of Acne (2)

BACTERIAL FACTORS
The skin microflora is greatly influenced by the onset of puberty. Before this hormonal
flood, the sebaceous gland is inactive and bacterial populations are low. The arrival of a
lipid product with about 50% triglyceride on the skin greatly stimulates bacterial
growth and selects bacteria that can effectively metabolize triglycerides. A once
sterile follicle becomes the residence of P. a cne s, an anaerobe, it metabolizes the glycerol
fraction of triglycerides, which sterile follicle liberates with an extracellular lipase (17).
Lipase cleaves triglycerides into fatty acids and glycerol, and the fatty acids remain in
sebum in proportion to the P. a cne s population (18). It was once thought that these fatty
acids were the primary stimulants for inflammation in acne, but now they are believed
to be a relatively minor contributor to the process.
Although tens ofmillions of P. acnes present in a square centimeter area on the
face (19,20), yet infection with the organismis rare and is typically postsurgical. It is
truly a commensal, incapable of surviving in skin without unusual conditions. We
may derive some benefits from P. acnes colonization. Group A streptococci are
inhibited by fatty acids produced by P. acnes (21), which may account for the
rarity of facial streptococcal impetigo after puberty.
P. acnes populations are proportional to the amount of sebum produced but
there is variation amongst the cutaneous microenvironments. Sebum-rich areas
such as the face and upper trunk carry mean log populations between 4.8 and
5.5 cm22
, whereas the lipid deficient legs harbor only 0.5 cm22
(20). Animal skin
does not support the growth of P. acnes, because animal sebum does not contain
triglyceride (22), a major reason why there is no satisfactory animal model available
for inflammatory acne. The distribution of active sebaceous glands and high
P. acnes populations are reason for the distribution of inflammatory acne lesions. The
largest and most active sebaceous glands are located on the face, upper trunk, and
arms, regions where acne is common (23). The lower trunk and distal extremities
have negligible sebaceous activity, trivial P. acnes populations, and no acne (19).
The severity of acne is also somewhat linked to sebaceous secretion and
P. acnes populations. Teenage acne patients have higher levels of bacteria in their
follicles than do age-matched controls (24). Although there is a good degree of
overlap between acne and nonacne groups, in general, teenage acne patients
have higher sebum production than their normal counterparts, accounting for
their greater bacterial populations (25). Interestingly, this difference is less pro-
nounced in older individuals with the disease.
INFLAMMATION IN ACNE
Formation of acne pimples and pustules typically begins at the microcomedones
formation. Kligman (1) has observed that visible comedones only, rarely, become
inflamed and microcomedones have been shown to contain evidence of neutrophil
activity, even though they came fromareas of the skin with no acne lesions (26). The
trigger for the inflammation of the microcomedo is the comedonal resident P. acnes
that has many characteristics that incite the inflammatory and immune responses.
The organism P. acnes is a potent activator of many facets of the innate
immune system, and under the archaic name of Corynebacterium parvum, P. acnes
has been found to be a potent macrophage activator similar to BCG (27). P. acnes
makes chemotactic substances that attract neutrophils and monocytes. Low mol-
ecular weight peptides are produced as a consequence of postsynthetic protein pro-
cessing by the organism. Neutrophils recognize these peptides by the same receptor
as other bacterial chemotactic peptides (28,29) (Tables 1 and 2). These peptides are
,2 kDa in mass and accumulate as the organism grows. Presumably small enough
to leach out from an intact follicle, these compounds may be part of the initial
stimulus for inflammation. P. acnes produces at least one other chemotaxin; the
lipase that cleaves triglycerides in sebum is also attractive to leukocytes (30).
P. acnes is a potent activator of the classic and complement pathways. It is the
major and perhaps sole activator in the comedo (31) and complement deposition
around the inflamed acne lesions is great (32). The alternative pathway activator
is a mannose-containing cell-wall polysaccharide that shares characteristics with
the macrophage-activating factor in P. acnes cell wall (33–35). In the classical
pathway, the activation is through the formation of immune complexes with anti-
P. acnes antibody. The more the antibody present, the more the activation occurs
(36). Thus, complement activation and the subsequent generation ofC5-derived che-
motactic factors are greatest in patients with high levels of anti-P. acnes immunity.
Toll-like receptors (TLRs) are more recently discovered components of innate
immunity,which involve cell-mediated defenses in response to the pathogens in the
absence of an immune response. Vowels et al. (37) have demonstrated that P. acnes
stimulates proinflammatory cytokines such as IL-8, tumor necrosis factor (TNF)-a,
and IL1-b in monocytes. Lee et al. (38) have shown that P. acnes cell-wall
components activate TLR-2 in monocytes, resulting in the production of TNF-a,
IL1-b, and IL-8 that attract both neutrophils and lymphocytes to the follicle. This
process that is involved in acne is supported by the identification of monocytes
in inflamed acne lesions, expressing TLR2 on their surfaces. Activation of TLRs by
P. acnes also accounts for the observation that CD4-bearing lymphocytes appear at
the comedo, early in the initiation of acne inflammation (39).
RESOLUTION OF ACNE LESIONS
Surprisingly, little is known about the processes involved in the healing of acne
lesions, which often takes weeks to occur. Kligman (1) observed the evolution
and healing of acne lesions and noted a late influx of lymphocytes and the for-
mation of granulomas. Electron microscopy has shown these cells to be syntheti-
cally and metabolically active (40). The stimulus for the inflammation is probably
persistence of P. acnes. The organism is unusually difficult for leukocytes to
degrade. Injected P. acnes will remain in tissue for weeks, inciting ongoing inflam-
mation (41,42). In vitro studies find that the organism is far more resistant to degra-
dative enzymes from neutrophils and monocytes than a genuine pathogen such as
Staphylococcus aureus (43) that is degraded within hours. In contrast, P. acnes degra-
dation procedes at a glacial pace, requiring 24 hours for the release of only 10% of
cell-wall mass supporting the observation of persistence of injected organisms after
many weeks.