The epidermis forms an effective barrier, however, the hair canal, the distal ORS of the hair follicle, and the pilosebaceous duct constitute major ports of entry for microbial invasion in humans and harbor a rich residential microflora such as P. acnes, Staphylococcus epidermidis, Demodex folliculorum, and Malassezia furfur. The distal ORS and the pilosebaceous duct are also characterized by many features of innate and adaptive immunological activity such as classical and nonclassical MHC class 1 expression, ICAM-1 expression, and the presence of intraepithelial Langerhans cells and perifollicular macrophages (28 – 30). It is of considerable inter- est, therefore, that this area of the pilosebaceous unit is also a “hot spot” in the development of “acne vulgaris” lesions.
Acne, a disease of the pilosebaceous unit is characterized by hypercornifica- tion and hyperkeratosis of the ORS and sebaceous duct and perilesional infiltrate (PI). Lesions may be characterized as “non”inflammatory versus inflammatory and their increasing inflammatory infiltrate may be classified as: comedones, papules, and pustules. In acne (Fig. 2), there is marked upregulation of hBD1 and hBD2 as follows: hBD1, healthy follicular skin pustule comedo , papule; hBD2, healthy follicular skin comedo , papule , pustule. The fact that intensity of upregulation of hBD2 is identical to the classification of inflammatory infiltrate correlates with other inflammatory disorders such as psoriasis and mastitis, which also exhibit marked upregulation of hBD2 (31 – 33).
From the published studies to date, it is clear that b-defensins are expressed in regions of the pilosebaceous unit that are exposed to microorganisms and more- over, in regions that may provide access routes for these organisms into the skin. Moreover, it is also apparent that some b-defensins are upregulated in acne (9). What, therefore, is the role of antimicrobial peptides in acne? Major factors in the pathogenesis of acne include hypercornification of the distal ORS and the pilosebac- eous duct in concert with increased sebum production and abnormalities of the microbial flora (34).
There is increasing evidence that proinflammatory cytokines, such as IL-1b, TNF-a, and bacterial LPS, can upregulate b-defensins (4,6,32). P. acnes produces many likely candidates for inflammation such as lipases, neuramidases, phospha- tases, and proteases (35). Therefore, the observed upregulation of b-defensins in acne vulgaris lesions is most likely a secondary response to the marked PI. It has been suggested that, variation in the microenvironment of the duct is likely to influ- ence the production and activity of inflammatory mediators (36,37) and this may influence defensin production. Although hBD1 has been reported to be constitu- tively expressed and not upregulated under inflammatory conditions in oral
FIGURE 2 (See color insert.) Human beta-defensin 1 (hBD1) and hBD2 immunoreactivity in acne lesions. In comedones (A and B), hBD1 (A) is found in the hyperkeratotic plug (HP), the suprabasal layers of the lesional epithelium (LE), the pilosebaceous duct, and the sebaceous gland (SG). Strong hBD2 expression (B) is found in the suprabasal layers of the LE and the SG and duct. In papules (C and D), strong hBD1 expression is present in the HP, suprabasal layers of the epidermis, and LE, including the pilosebaceous duct and SG. Strong hBD2 expression (D) is present in the HP, the upper suprabasal layers of the epidermis, and LE including the pilosebaceous duct. In pustules (E and F), virtually no hBD1 (E) is found in the inflammatory area of the pustule. Moderate expression of hBD1 is present in the suprabasal layers of the epidermis, the LE and the pilosebaceous duct and SG. Intense hBD2 expression (F) is detected in the inflammatory area of the pustule, the suprabasal layers of the perilesional epidermis and LE, the pilosebaceous duct, and sebaceous gland. Abbreviations: EG, eccrine gland; HP, hyperkeratotic plug; LE, lesional epithelium; P, pustule proper; PI, perilesional infiltrate; SG, sebaceous gland. Source: From Ref. 9.
mucosa (38). Moderate upregulation of hBD1 has been reported in acne vulgaris lesions when compared to nonlesional skin of the same patient and also when com- pared to pilosebaceous follicles from healthy back skin controls (9). However, in contrast to the intense hBD2 upregulation found in and around pustules, including the area of maximal inflammation, relatively little upregulation of hBD1 IR is seen.
Because of the suggested antimicrobial function of AM in skin and in line with the proposed role of P. acnes in the pathogenesis of acne vulgaris, we have
investigated AM immunoreactivity in inflammatory acne lesions compared to healthy pilosebaceous follicles. However, in contrast to b-defensins, AM does not appear to be upregulated in acne (21).
We have proposed (9,39) that acne vulgaris patients may suffer from a dysregu- lation of the production of innate and specific antimicrobial peptides. This is based on our own observations that substantial variations in the intensity of hBD1 and hBD2 IR occur between sex- and age-matched patients, between face and back skin as well as between different hair follicle types (terminal hair follicles and pilo- sebaceous follicles). Colonization of the pilosebaceous duct is a feature of established comedones and early inflammatory lesions (40,41). Why some colonized ducts become inflamed and others do not is uncertain. Variation in the microenvironment of the duct could be important. Likewise, it is possible that differences in levels or induction of defensins may explain why some colonized ducts become inflamed and others do not and may also explain why some individuals are prone to more severe acne than others. P. acnes is likely to be the major organism since selective anti- biotic studies have shown that only those antibiotics which suppress P. acnes in vivo, are associated with clinical benefit. However, what is not clear is why some patients are good responders to antibiotic treatment and other not. An interesting line of study would be to investigate whether good responders to antibiotic antiacne treat- ment differ in their b-defensin levels and/or activity from bad responders.
From published studies, it is clear that there is marked variation in defensin expression, both between different body sites as well as between individuals. It has been reported that hBD-1 promotes keratinocyte differentiation in vitro (42). It is intriguing, therefore, to speculate whether defensins may play a role in the hypercornification of the sebaceous duct and whether perhaps individuals that are high producers of defensins may in fact be more prone to acne.
Defensins play a major role in innate immunity of epithelial tissues. It is clear that they are expressed in skin and are upregulated in inflammatory conditions. Their role in acne is still subject to much speculation and it is hoped that future studies will address whether individuals who suffer from severe acne or are poor respon- ders to antibiotic treatment do produce lower levels of defensins.
I would like to thank Dr. Sven Muller Roever and Catherine Chronnell for carrying out the research on defensins and acne in my laboratory; Professor Tony Quinn for many useful discussions; Dr. Bill Cunliffe and Dr. Diane Holland for supplying the acne biopsies; Dr. Thomas Ganz for donating the hBD1 and hBD2 antibodies, and Dr. Veronique Bataille for her valuable contributions to the study concept. I would also like to acknowledge the European Union (EU) for financial assistance.