15 May

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.

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