Dermatology: Acne Neena Khanna, Raj Kubba
INDEX
×
Chapter Notes

Save Clear


What's New in Acne Pathogenesis

*,1 Soyun Cho, MD PhD
2 Sewon Kang MD MPH
1 Department of Dermatology, Seoul National University, Seoul, Korea2 Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA

ABSTRACT

In recent years, our knowledge on the classic pathogenic factors of acne, i.e., androgenic control of sebaceous gland, infundibular retention hyperkeratosis, Propionibacterium acnes and inflammatory events, attained a new depth. This article summarizes newer information, including the importance of altered lipid and oxidant/antioxidant ratio in sebum composition, the crucial role of P. acnes as the primary elicitor of host's innate and adaptive immune responses, and the likely involvement of matrix metalloproteinases in scar formation. Furthermore, polymorphisms of genes that function in the steroid hormone metabolism, innate immunity-related genes and fibroblast growth factor receptor 2 (FGFR2) found to be associated with acne are discussed. Emerging evidence demonstrates that dietary triggers, especially the high glycemic load diet and milk consumption, may aggravate acne vulgaris by raising insulin and insulin-like growth factor 1 (IGF-1) levels. Paradigm shifting data show that subclinical inflammation may be the initial driver of follicular hyperkeratinization and hyperproliferation, indicating that our understanding of acne pathogenesis will continue to evolve in the future.
 
INTRODUCTION
Acne, an exclusively human disease, is a very common skin condition which affects as many as 85% of teenagers and 3% of those aged 35–44 years.1 Its pathogenesis is complex and multifactorial, with pubertal androgenic stimulation of the sebaceous gland playing a major role while follicular hyperkeratosis, increased colonization with Propionibacterium acnes, inflammatory events, and dietary and lifestyle factors contributing additionally in variable proportions in genetically susceptible individuals.
2The current body of evidence indicates that the relationship between sebum production, hyperkeratosis, P. acnes and inflammation is more complex than thought previously, with data even suggesting that inflammatory events may precede microcomedone formation and that the plug formation is at least partially influenced by inflammation produced by P. acnes.2 It is clear that these processes are all interrelated since sebum is necessary for P. acnes colonization of the skin and P. acnes is essential in switching on the innate and adaptive immune system leading to the inflammation. Currently, acne is considered primarily an inflammatory skin disease of the pilosebaceous unit, and the precise mechanism by which P. acnes contributes to the pathogenesis of acne remains unknown.
Regarding the role of diet in acne, there is a general perception that non-Western populations have a lower incidence of acne, and that this incidence increases when a Western dietary pattern is adopted, implying that genetic predisposition is not the only relevant factor in the development of acne.3 In this article, we provide a comprehensive review of these notable factors in the pathogenesis of acne.
 
PATHOGENIC FACTORS
 
Role of Sebaceous Gland and Androgens
 
Sebaceous Gland
The function of the sebaceous gland, a holocrine gland, is to excrete sebum and sebum excretion occurs in parallel with acne development. Sebum contains triglycerides (TGs) and fatty acid breakdown products, wax esters, squalene, cholesterol esters and cholesterol.4 The sebaceous gland is a steroidogenic organ that possesses all the enzymes required for sex-hormone synthesis and metabolism. It can synthesize androgens de novo from cholesterol or by locally converting weaker circulating androgens to more potent ones.5 Functional studies on sebocytes have been conducted mainly with cell culture models using mammalian sebocytes, human sebocyte-like cells (human, mouse, hamster and rat) and human sebaceous gland cell lines (SZ95, SEB-1, Seb-E6E7).5,6 Identification of functional receptors for neuropeptides such as corticotropin-releasing hormone (CRH), melanocortins (MCs), β-endorphin, vasoactive intestinal polypeptide, calcitonin gene-related peptide and substance P7,8 gave rise to the notion that human sebaceous gland is like the “brain of the skin”.9 Since CRH is expressed in human sebocytes, stress may affect inflammatory changes in early acne lesions.10 In SZ95 cells that are not stressed, CRH promotes lipogenesis in autocrine fashion.11 However in acne lesions, CRH expression was strongly enhanced, and this further stimulated the release of interleukin (IL)-6 and IL-8 from sebocytes by an IL-1β-independent manner.7 Excessive sebum production is one of the major 3factors in the pathogenesis of acne. Among the MC receptors [melanocortin-1 receptor (MC-1R) and melanocortin-5 receptor (MC-5R)] that are expressed in human sebocytes, MC-1R is expressed in both undifferentiated and differentiated sebocytes, whereas MC-5R is expressed only in the differentiated lipid-containing cells at the center of sebaceous glands,12 and is therefore associated with sebocyte differentiation and sebum production.13 MC-1R expression was shown to be increased in the sebaceous glands of acne lesion in vivo.14 Treatment of cultured sebocytes with substance P led to enhanced IL-1, IL-6, tumor necrosis factor alpha (TNF-α) and peroxisome proliferator-activated receptor gamma (PPARγ) gene and protein expression, further supporting the role of stress in acne development.15
The pilosebaceous unit is an immunocompetent organ, the infundibular keratinocytes and sebocytes being fully equipped with the capacity to elicit innate immune responses.16 The keratinocytes and sebocytes may be activated by P. acnes, via toll-like receptors (TLRs) and cluster of differentiation (CD) 14, recognize altered lipid content in sebum, and produce inflammatory cytokines.17
Among the components of sebum, the TG fraction appears to be responsible for acne development;18,19 bacteria can hydrolyze sebaceous TGs and liberate fatty acids which can penetrate the follicular wall and become incorporated into the surrounding epidermis.20 The application of free fatty acids on rabbit ears or hairless mice was shown to induce hyperkeratinization and epidermal hyperplasia similar to the process of comedogenesis.18,21 Research has shown that among the fatty acids only monounsaturated fatty acids (MUFAs) stimulate the morphological changes in comedo formation whereas TGs and saturated fatty acids (SFAs) have little effect.18 Presumably, MUFAs of sebum interfere with the intracellular calcium dynamics of follicular keratinocytes and the intercellular lipid bilayer structure of epidermal barrier.18 Sebum contains a high proportion of MUFAs, with a characteristic double bond at the Δ6 position19 instead of the standard Δ9 position. Sebum itself is not a direct cause of acne since not everybody gets acne, rather, the compositional changes that occur with increasing sebum production seem to affect events involved in comedo formation.22 Sebum alterations associated with acne include: (1) decrease in linoleic acid which affects the composition of sphingolipids, which may be involved in the follicular hyperkeratosis crucial in comedogenesis;22 (2) incorrect activity of specific desaturase enzymes altering the ratio between Δ6 and Δ9 unsaturated fatty acids, with resultant compositional changes that can drive toward acne development;23 and (3) lipid peroxidation byproducts, such as squalene peroxide, which lead to follicular hyperkeratinization, increased proliferation of sebaceous glands, and upregulation and release of inflammatory mediators such as IL-6.23 When sebum was analyzed in individuals with and without acne, subjects with acne had more (59%) sebum than controls, and free fatty acids were reduced in the sebum of acne subjects whereas squalene was upregulated 2.2-fold in acne subjects,24 suggesting 4potential utility of squalene amount as a lipid marker to diagnose acne-prone skin. Sebaceous gland lipids demonstrate direct proinflammatory and anti-inflammatory properties; specifically the induction of 5-lipoxygenase (5-LOX) and cycloxygenase-2 (COX2) pathways in sebocytes leads to the synthesis of proinflammatory lipids.25 Conversely, the proinflammatory cytokine TNF-α can induce lipogenesis in SZ95 sebocytes through the Jun N-terminal kinase (JNK) and phosphoinositide-3-kinase/Akt (PI3K/Akt) pathways,26 providing rationale for anecdotal reports of dramatic improvement in acne following administration of etanercept, a soluble TNF-α receptor antibody.
Fatty acids also act as ligands of nuclear hormone receptors such as the PPARs, which are transcription factors involved in lipid metabolism and energy homeostasis. Activation of PPARγ and PPARα by their respective specific ligands was found to stimulate lipid droplet accumulation in cultured immature sebocytes but not in keratinocytes, with 5α-dihydrotestosterone (DHT) exhibiting an additive effect only with combination of DHT and PPARγ. This demonstrates that PPARγ influences a step in sebocyte differentiation that is distinct from that influenced by androgen.27 In another study, PPARβ/δ messenger ribonucleic acid (mRNA) was overexpressed in both inflammatory and noninflammatory acne in vivo.28
The sebaceous gland also expresses antimicrobial peptides such as human β-defensin 1 (hBD-1), hBD-2 and cathelicidin (LL-37).29 Although hBD-2 has no direct antimicrobial effects on P. acnes,30 it acts synergistically with cathelicidin.31 Sebum free fatty acids have antibacterial activity against Gram-positive bacteria. When human sebocytes were incubated with free fatty acids, the expression of hBD-2 was dramatically enhanced, suggesting that free fatty acids may provide direct antibacterial activities against P. acnes and enhance the skin's innate antibacterial defense.32
SZ95 sebocytes express liver X receptor (LXR) α and LXRβ, which belong to the nuclear receptor superfamily and play a critical role in cholesterol homeostasis and lipid metabolism.33 Among the two receptors, only LXRα expression was enhanced and lipid synthesis increased by LXR ligands. Furthermore, LXR ligands decreased lipopolysaccharide (LPS)-induced proinflammatory factors COX2 and inducible nitric oxide synthase (iNOS), suggesting the important roles of LXRα in differentiation and inflammatory signaling in the sebaceous gland.34
Acetylcholine receptors (AchR) are also expressed in sebocytes and infundibulum. Stimulation of the receptors by acetylcholine can promote infundibular epithelial hyperplasia and follicular plugging, possibly linking an etiological role of nicotine uptake from smoking in comedonal acne characteristic of smokers.355
 
Androgens
Hormones are undeniably the initiating factor in the pathogenesis of acne. With the surge of androgens in puberty, sebaceous gland is known to mature and begin secreting sebum actively. Androgen receptors (ARs) are expressed in the basal layer of the sebaceous gland and in the outer root sheath keratinocytes of the hair follicle.36 When free testosterone enters the cell, it is quickly reduced to DHT by the 5α-reductase enzyme, whose activity is increased in proportion to the size of the sebaceous gland.37 In primary human sebocyte culture, androgens testosterone and DHT only stimulate sebocyte proliferation38 through sterol-response element-binding proteins (SREBPs), whereas PPAR ligands are required for differentiation and lipogenic activity.39 Exogenous administration of testosterone and dehydroepiandrosterone sulfate (DHEA-S) increases sebaceous gland size and sebum production.40 Serum androgen levels, however, do not correlate with acne severity. Therefore androgens may only serve as a prerequisite for acne development.17 Despite the clinical evidence that androgens stimulate sebaceous gland, the in vitro effect of androgens on the proliferation and differentiation of sebocytes vary in different experiments and cell types.17 The mechanisms by which androgen/AR regulate sebocyte activity in acne vulgaris are still unclear. Androgens might cross talk with IGF-1 activities in controlling acne development.41 At puberty, IGF-1 induces synthesis of androgens and enhances 5α-reductase activity in the skin.42 In addition, IGF-1/PI3K/Akt activity stimulates phosphorylation of FoxO1, an AR corepressor. Upon phosphorylation, FoxO1 translocates from the nucleus to the cytosol and releases its inhibition on AR transactivation.41 Recently, in human sebocyte culture, addition of DHT upregulated IL-6 and TNF-α gene and protein expression, suggesting that DHT may participate in inflammatory acne process as well.43 In addition to affecting sebaceous gland activity, androgens also influence keratinization of follicular corneocytes.44
 
Role of Follicular Epithelial Cells
The initial plugging of the pilosebaceous canal is thought to be from a mechanical effect27 because electron microscopic findings show retention hyperkeratosis with increased number and size of keratohyaline granules and pressure-induced folding of retained squames on themselves.27 Androgen stimulates ductal keratinocytes to multiply; the proliferating keratinocytes are propelled toward the center of the sebaceous duct, which expands to accommodate the increasing volume of lipid droplets until the inelastic “glassy membrane” that encloses the pilosebaceous duct can expand no further. Further accumulation of keratinocytes in this closed system causes an increase in intraluminal pressure, leading to hypoxia in the central part of the duct.27 This produces an anoxic environment that favors intraductal P. acnes 6colony formation, which leads to rupture of the duct walls with release of luminal antigens and resultant inflammation. This was the classic theory of how acne develops. Recent studies using clinically normal follicles from uninvolved skin of acne patients show that vascular endothelial cell activation and inflammatory responses occur prior to and act as possible causal factors in the hyperproliferative changes of acne, as opposed to a secondary event, with increased IL-1 activity occurring prior to follicular hyperproliferation around uninvolved follicles, triggering the “keratinocyte activation cycle”.45
Although the exact cause of follicular hyperkeratinization is still to be elucidated, IL-1α seems to play an important role since it was reported to induce infundibular hyperkeratinization in vitro and in vivo.40 In addition to this change, dysregulated terminal differentiation with increased filaggrin expression46 and follicular keratinocytic hyperproliferation with the hyperproliferative markers of keratin [K6 and K16] was observed.47 Besides IL-1α, increased DHT,44 relative deficiency of linoleic acid and peroxides in sebum,48 and P. acnes extracts46 may all contribute to abnormal hyperkeratinization of infundibular keratinocytes. To elucidate the pathogenesis of closed and open comedo formation, studies have been performed on nevus comedonicus, and the results show association of gain-of-function mutation of fibroblast growth factor receptor 2 (FGFR2), which is also the causative mutation of acne in Apert's syndrome.49,50 This will be dealt with in more detail later in this article.
 
Role of Propionibacterium Acnes
Propionibacterium acnes is a normal commensal in the pilosebaceous units, found to be present in nearly 100% of adults.51 Its population density rises in puberty with an increased sebum excretion rate, keeps increasing until the age of 25 years, and remains constant thereafter through middle age with a declining trend after age 70 years, regardless of race.52 Not everyone gets acne, and there is no relationship between acne severity and follicular population density of P. acnes.53 Therefore, a question rises as to whether P. acnes is a true etiological pathogen or not in acne. There is at present no definitive proof that microorganisms, particularly P. acnes, initiate either comedogenesis or inflammation in acne.54 What exists is circumstantial evidence that a proportion of normal pilosebaceous follicles are colonized by P. acnes; a favorable microenvironment leads to increased colonization of microcomedone by P. acnes which may further aggravate comedogenesis; and an inflamed lesion may further provide an enriched environment for the colonization as well as proliferation of P. acnes. P. acnes can intensify the inflammatory process but is dispensable for its initiation. Nevertheless, we will overview the evidence of the role that P. acnes plays in comedogenesis and inflammation.7
Recently, acne was suggested to be an IGF-1-mediated disease.55 IGF-1 and IGF-1 receptor (IGF-1R) were overexpressed in acne lesions, and P. acnes extracts elevated IGF-1 and IGF-1R expression in the epidermis and induced keratinocyte proliferation, demonstrating that P. acnes can help induce the formation of comedone by stimulating the IGF/IGF-1R system.56 In addition, P. acnes extracts can directly modulate the differentiation of keratinocytes by inducing transglutaminase, K17, integrin (β1, α3, α6x and αVβ6) and filaggrin expression,46 while decreasing K1 and K10 expression.57 Also P. acnes was shown to increase the CRH expression in the epidermis, thereby modulating the differentiation of keratinocytes and increasing local inflammation, hence possibly playing a role in the formation of early microcomedo.58 Furthermore, P. acnes has been shown to form biofilms, a biological glue, that may lead to the increased cohesiveness of corneocytes in acne, leading to comedone.2 A biofilm is a complex aggregation of microorganisms within an extracellular polysaccharide lining, and it is secreted after adherence to a surface.2 The biofilm confers P. acnes increased resistance to antimicrobial agents with enhanced production of virulence factors.59 Indeed, the genome sequence of P. acnes revealed immunogenic and surface-associated genes, confirming the existence of the acne biofilm.60
P. acnes produces various exogenous proteases, and these proteases at least partially elicit cellular responses via proteinase-activated receptor 2 (PAR-2), a sensor for exogenous danger molecules. Increased protease activity and PAR-2 expression was demonstrated in acne lesions. P. acnes induced calcium signaling and stimulated IL-1α, IL-8, TNF-α, hBD-2, LL-37, and matrix metalloproteinase (MMP) 1, 2, 3, 9, and 13 in keratinocytes through PAR-2, indicating that PAR-2 plays an important role in acne pathogenesis by inducing inflammation, innate immune responses and matrix degradation.61
P. acnes is important in the induction and maintenance of the inflammatory phase of acne. The evolving concept of immune response includes microbial invasion, subsequent activation of innate immune system followed by recovery from the microbial infection, or in case this direct recovery is not feasible, secondary activation of adaptive immune system which results in recovery and immune memory with further activation of innate immune system. TLRs are the best studied transmembrane pattern recognition receptors (PRRs) that sense and bind with certain pathogen-associated molecular patterns (PAMPs) such as LPS and CpG DNA and activate the innate immune system. The intracellular portion of TLR has homology with the cytoplasmic domain of the IL-1 receptor; the intracellular portion may trigger a Myd88-dependent pathway that leads to the nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB) and ultimate transcription of many immune response genes.62 TLRs are mainly located in blood and tissue immune cells. Ten TLRs have been identified in humans so far.63 TLR4 is highly specific for LPS from Gram-negative bacteria, 8while TLR2 mediates the recognition of lipopeptides from Gram-positive bacteria.64 TLR2 was expressed on the surface of macrophages surrounding pilosebaceous follicles, and P. acnes, Gram-positive anaerobic bacilli, induced cytokine (IL-1β, IL-8, IL-12 and TNF-α) production in monocytes through a TLR2-dependent pathway.65 The IL-8 produced by the activated monocytes is a potent T cell chemoattractant and neutrophil activator, and as a result, neutrophils release proteins including defensins. Among the six different α-defensins and two β-defensins identified in humans, human neutrophil proteins (HNP) 1-3,66 and hBD 1 and 229 have been found in acne lesions. Interestingly HNPs were expressed only in inflammatory acne lesions suggesting that they may contribute to the development of inflammatory lesions.66 Contrary to the earlier dogma, it has been shown that the initial infiltrating cells in developing inflammatory acne lesions are mononuclear cells which are predominantly CD4+ “memory/effector skin homing” T cells and that neutrophils appear later in the course of inflammation.67,68 Inflammatory events, consisting of IL-1α and increased CD4+ T cells occur in the very earliest stages of acne development, before hyperproliferation or abnormal differentiation of follicular epithelium.69 Once neutrophils infiltrate into the acne lesion, neutrophil α-defensins, in addition to their antimicrobial effects, induce selective chemotaxis of CD45RA/CD4 cells, CD8 T cells and immature dendritic cells at nanomolar concentrations,70 amplifying chronic inflammatory responses.
Normal keratinocytes express TLR1, 2, 4 and 5.71,72 When keratinocytes from acne patients are exposed to P. acnes extract ex vivo, the expressions of TLR2, TLR4 and MMP9 are increased.73 Only certain strains of P. acnes were found to induce selective IL-8 and hBD-2 expression in human keratinocytes via TLR2 and TLR4 and induce keratinocyte growth in vitro.74 P. acnes GroEL (a heat-shock protein) is able to upregulate the proinflammatory cytokine production of keratinocytes.75 In inflammatory acne, the early interaction between keratinocytes and bacteria appears crucial since keratinocytes produce reactive oxygen species (ROS) and proinflammatory cytokines in response to the bacteria.76 SZ95 sebocytes also constitutively express TLR2, TLR4, CD14, IL-1α, IL-1β, IL-6 and IL-8. When exposed to LPS of Gram-negative bacteria and lipoteichoic acid of Gram-positive bacteria,30 SZ95 sebocytes increase the production of IL-6 and IL-8, in addition to antimicrobial lipids48 and antimicrobial peptides (hBD-2, psoriasin and cathelicidin).30,31,31 Therefore, innate immunity can be induced directly in keratinocytes and sebocytes without involving the inflammatory cells, and recruitment of inflammatory cells to the involved sites amplifies the inflammatory process in acne.78 Once the adaptive immune response takes over the innate immunity, the inflammatory reaction is augmented dramatically. However, the magnitude of this response is not related to the amount of bacteria.76 Rather, acne severity is related to the capacity of various P. acnes strains to induce inflammation, and to the host's genetic capacity to respond to P. acnes immunologically.769
Colonization of pilosebaceous unit by P. acnes is the main event that leads to inflammation. Recently a higher prevalence of follicular P. acnes colonization was actually visualized, with greater number of follicles containing P. acnes and the greater numbers of bacteria in macrocolonies/biofilms than in controls.79 P. acnes also directly augments intracellular lipid formation in hamster sebocytes by increasing the de novo synthesis of triacylglycerols.80 LPS directly increases inflammation in sebaceous glands in vivo by augmenting COX2, PGF and PGF-mediated pro-MMP2 productions.81 The production of pro-MMP2 was augmented by P. acnes-derived factors in hamster sebocytes and dermal fibroblasts, suggesting that the bacteria may participate directly in acne scar formation.82
In summary, P. acnes is capable of inducing inflammation by: (1) releasing lytic enzymes and lipases that trigger the rupture of follicular epithelium and inflammatory reaction; (2) producing chemotactic factors that recruit neutrophils through the epithelial wall;83,84 (3) activating the innate immune system through the TLR2 and TLR4 mentioned above; (4) stimulating the formation of C5a by activation of the classical and alternative complement pathways;85 and (5) triggering the adaptive immune response evidenced by the presence of activated T helper 1 (Th1) cells in early inflamed acne lesions.86 In acne vulgaris patients, high serum antibody titers87 directed to several putative surface proteins88 of P. acnes were detected. Infiltrating neutrophils destroy the P. acnes, but the bacteriolysis results in the production of hydrolases that add to further disruption of follicular epithelium and enhanced inflammation. Recently P. acnes was shown to secrete Christie Atkins Munch-Petersen (CAMP) factor, a virulence factor that was cytotoxic to keratinocytes and macrophages in a synergistic manner with the host acid sphingomyelinase. Such observation has led to the possibility of applying vaccine technology that targets both the secreted P. acnes CAMP factor and host acid sphingomyelinase to locally suppress inflammatory acne.89
Gene array expression profiling in acne lesions was conducted for the first time in 2006 and revealed marked upregulation of genes involved in inflammation and matrix remodeling, including MMP1 and 3, IL-8, hBD4, and granzyme B.90 An emerging picture is the chronic inflammatory nature of acne triggered by a pathogen, P. acnes.
 
Role of Immune Mediators
Clearly, inflammatory cytokines, chemokines and other proteins including IL-1, IL-8 and certain MMPs mediate acne.91 In normal unstressed sebocyte culture, cytokines such as IL-1α, TNF-α, IL-6 and IL-8 are present.25 Treatment of cultured sebocytes with P. acnes and LPS significantly upregulates the expression of proinflammatory cytokines, with P. acnes stimulating IL-8 and TNF-α and LPS stimulating IL-8, TNF-α and IL-1α.3010
P. acnes-stimulated keratinocytes also play an important role in the inflammatory reaction, producing a number of proinflammatory cytokines and chemokines such as IL-1α, IL-1β, IL-8, GM-CSF, TNF-α and hBD-2 through the TLR2 and TLR4 signaling pathways in vitro.65,73 P. acnes activates NF-κB and mitogen-activated protein kinase (MAPK) pathways92 and recruits macrophages and immune cells to the site of infection.
When stimulated by P. acnes surface proteins, keratinocytes were shown to rapidly produce ROS, and especially superoxide anions93 by NAD(P)H (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase (NOX) pathway through activation of the scavenger receptor CD36. The superoxide anions combine with nitric oxide to form peroxynitrites which in turn, activate p38 and extracellular signal-regulated kinase (ERK), MAPKs, leading to IL-8 production. IL-8 production is also activated through P. acnes-induced TLR2 signaling pathway.93 Furthermore, P. acnes-induced superoxide anions abrogated P. acnes growth and were involved in the lysis of keratinocytes through formation of peroxynitrites. Retinoic acid derivatives prevent superoxide anion production, IL-8 release and keratinocyte apoptosis, demonstrating the relevance of this pathway in vivo.
Leukotriene B4 (LTB4), a proinflammatory mediator synthesized from arachidonic acid by 5-LOX, is also implicated in the pathogenesis of acne because systemic treatment with a specific LOX inhibitor resulted in 60% decrease in acne severity index within 3 weeks and 70% reduction in inflammatory lesions at 3 months, with 65% reduction in sebum total lipids.94 LTB4 is also a natural ligand for PPARα; therefore, PPAR regulation can modulate the tissue inflammation in acne lesions by inhibiting the expression of proinflammatory genes.95 On the other hand, COX-2 expression and PGE2 production are increased by PPARγ agonists.81
A decrease in the body's antioxidant activity may also play a role in the pathogenesis of acne. The superoxide dismutase (SOD) levels were significantly lower in leukocytes from acne patients96 in a dose-dependent manner; the more severe the acne, the lower the SOD activity in tissues and blood. Other parameters of oxidative stress such as serum malondialdehyde (MDA) level and xanthine oxidase activity were higher, and serum catalase and SOD activity was lower in acne patients.26 MDA is an end-product of lipid peroxidation induced by oxygen free radicals and is well correlated with the degree of lipid peroxidation.12 When stratum corneum samples from involved and normal skin of acne patients and healthy controls were compared for quantity of glutathione, a component of endogenous antioxidant system, both samples from acne patients contained a significantly lower amount.97 Whether the oxidative stress is the cause or outcome of the inflammatory events is yet to be determined. All these data suggest that P. acnes could modulate host genes, which might in turn influence the inflammatory reaction.11
 
Genetic Factors
Genetic factors, which play a role in the pathogenesis of acne, were initially demonstrated by twin studies and community-based studies.36,98-101 In these studies, the occurrence and severity of acne symptoms showed a strong concordance in identical twins and a familial tendency. In a large British female twin study of 458 monozygotic and 1,099 dizygotic pairs, 47% of acne twins had a family history of at least one non-twin sibling affected with acne compared with 15% in non-acne twins; acne in either parent was reported in 25% of acne twins and 4% of non-acne twins; 41% of acne twins had at least one child affected with acne, in contrast to 17% of controls.99 The authors of this study showed that acne is one of the most heritable skin disorders with 81% of the variance in acne liability attributed to additive genetic factors and only 19% to environmental factors.99
 
Genes Involved in Steroid Metabolism
Serious search for specific genetic susceptibility factors only began in the 1990s.102-104 At that time studies involved genes affecting steroid hormone metabolism, including human cytochrome P-450 1A1 gene (CYP1A1),102 steroid 21-hydroxylase gene (CYP21)103 and AR gene polymorphisms.104 Since cytochrome P-450 enzymes are involved in the metabolism of a wide range of endogenous and foreign compounds and CYP1A1 is involved in vitamin A and endogenous retinoid metabolism, polymorphisms in the regulatory sites of CYP1A1 may impair the biological efficacy of natural retinoids due to their rapid metabolism to inactive compounds, with resultant abnormal sebocyte differentiation and hyperkeratinization of follicular canal, initiating acne in some patients.102 Several years later, two Chinese studies investigated CYP17-34 (T > C) single nucleotide polymorphisms (SNPs) and found that CC homozygote Chinese male patients were at a significantly increased risk of developing severe acne105 and that this mutation increased the risk of postadolescent acne in Chinese female patients with increased androgen levels.106 CYP17 encodes cytochrome P-450c17α which is a key enzyme in androgen biosynthesis, mediating both steroid 17α-hydroxylase and 17,20-lyase activity.107 Therefore, this SNP may result in a higher level of androgen in serum, followed by enhanced sebum production and follicular keratosis. An inadequate activity of steroid 21-hydroxylase, as well as CYP21 mutation, is the most common defect in late-onset congenital adrenal hyperplasia which presents with symptoms of androgenicity including acne. Although a CYP21 mutation was more common in acne patients, there was a poor correlation between the mutation and either elevated steroids or acne, suggesting other factors for the variable phenotype of hyperandrogenism.10312
Androgen works by binding to nuclear ARs which are localized in the basal layer of sebaceous gland and outer root.108 When androgen activates the receptor, the ligand-receptor complex is translocated to the nucleus and transactivation of androgen-regulated genes occurs. The modulatory domain of AR gene includes a polymorphic CAG triplet repeat coding for a polyglutamine tract whose number is inversely correlated with AR's transcriptional activity.109 AR polymorphism of CAG repeat length did not exhibit a correlation with acne in Caucasians,104 but in Chinese Han population the CAG repeat length was significantly shorter in male acne subjects,110 suggesting this variable number of tandem repeat (VNTR) polymorphism as a candidate genetic marker for male acne susceptibility and hinting at genetic differences in each ethnic group.
Since elevated levels of serum IGF-1 correlate with overproduction of sebum and acne55,111 and functional relationship between IGF-1 (CA) 19 polymorphism and circulating IGF-1 levels is known,112 IGF-1 (CA) 19 polymorphism was investigated in Turkish acne patients and a significant association was found between this polymorphism and acne severity regardless of gender.113 The varying frequency of IGF-1 (CA) 19 among different populations, with the highest frequency in Caucasian (65.5%) followed by Asian (33.3%) and African-American (15.6%) population,114 may offer a partial explanation for different susceptibility to acne in each race.
 
Innate Immunity Genes
More recently, a handful of reports on genetic polymorphisms in the innate immunity genes were added.102,103,105,106,110,113,115-123 In the innate immune system, external danger signals including microbes activate pathogen recognition receptors such as TLRs, which leads to the release of early response cytokines including IL-1α and TNF-α. The resultant increased expression of various downstream target genes such as those of adhesion molecules, secondary cytokines and chemokines, and infiltration of professional immune cells, can lead to uncontrolled inflammation.124
Two mutations in the TLR2 gene, Arg677Trp and Arg753Gln, and two SNPs causing Asp299Gly and Thr399Ile changes in the TLR4 gene were investigated in 101 Central European subjects, but no association was found between these mutations and acne, suggesting that carriage of TLR2 or TLR4 SNP allele may not affect susceptibility of patients for acne vulgaris.125 More recently, the carriage of the above SNPs of TLR4 was shown to be protective against the development of acne conglobata in Greek subjects, implying the possibility of modulating TLR4 for therapeutic purposes.115
The gene IL1A encoding IL-1α, a central molecule in cutaneous inflammatory reactions, was also investigated for a relevant mutation in Central Europeans, and 13a positive association was found between IL1A +4845 (G > T) SNP and acne. The severity of inflammatory acne symptoms correlated with the percentage of subjects carrying the homozygote T/T genotype.116 IL-1α is synthesized as pre-IL-1α and processed into mature IL-1α by enzymatic cleavage.55 The IL-1A SNP causes an alanine to serine substitution close to the proteolytic cleavage site and might lead to enhanced cleavage, causing elevated ratio of cytoplasmic/secreted IL-1α to nuclear pre-IL-1α and hence uncontrolled inflammatory reactions and acne symptoms.116 This, together with the same researchers' report on TNF-α regulatory SNP,121 suggests that genetic variations in proinflammatory cytokines contribute to acne development by causing dysregulation of epidermal homeostasis. IL-1A-889 (C > T), but not IL-8-21 (T > A), polymorphism was also a predisposing factor for acne in Polish patients.117 In Saudi population, IL-4R Q551R (A > G) polymorphisms were significantly associated with acne susceptibility but not severity.118
There are several reports on the association of acne and SNPs in TNF-α gene promoter: TNF-α-308 (G > A) in Turkish patients,119 Central Europeans121 and Saudi subjects.122 Interestingly, TNF-α-857 (C > T) minor T allele was found to act as a protective factor against acne in the Central European study.121 The function of TNF-α is mediated mainly by type 2 TNF receptors (TNFR2). TNFR2 M196R (676 T > G) SNPs were associated with acne vulgaris in Han Chinese population,120 further supporting the role of inflammatory cytokines in the pathogenesis of acne.
 
MUC1 Gene
Polymorphisms of genes with antiinflammatory properties were also investigated. Polymorphic epithelial mucin (PEM) or MUC1 is a cell surface glycoprotein secreted from various epithelial gland tissues, including sweat glands and sebaceous glands of the skin. During pathogen infection, the mucins initiate active protection mainly by interfering with the NF-κB signal transduction. VNTR polymorphisms are present in the extracellular domain of MUC1, and compared to controls, a higher percentage of longer length alleles were seen in severe Japanese acne patients.123 Long alleles may be more efficient in pathogen binding and hence result in enhanced bacterial colonization and susceptibility to various infectious diseases in the carriers.126
 
Fibroblast Growth Factor Receptor 2 Gene
Evidence for the role of FGFR2 signaling in the pathogenesis of acne has been provided by confirming FGFR2 gain-of-function mutations in unilateral acneiform nevus49 and nodulocystic acne seen in Apert's syndrome, a dominantly 14inherited condition with craniosynostosis and syndactyly.127 FGFR2 Ser252Trp or Pro253Arg mutations cause epidermal thickening seen in epidermal nevi,128 and androgen-dependent dermal-epithelial FGFR2 signaling seems to be important in acne development; fibroblasts, in response to DHT, synthesize FGF7 and FGF10, which are ligands for FGFR2b found on suprabasal keratinocytes and sebocytes.129 FGFR2b binding causes transcription of IL-1α, which stimulates follicular hyperkeratinization and in sebocytes, proliferation and fatty acid synthesis. Importantly, FGFR2b shares with IGF1R common downstream signaling cascades,130 which are MAPK and PI3K/Akt, sonic hedgehog (Shh) and MC-5R pathways.131
 
Genes Involved in Autoinflammatory Syndromes
Acne may also be a manifestation of autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndromes. In PAPA syndrome a heterozygous point mutation in proline-serine-threonine-phosphatase-interactive protein 1 (PSTPIP1) gene on chromosome 15q encoding CD2-binding protein 1 (CD2BP1) has been verified.132 PSTPIP1 and pyrin are coexpressed as part of nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome in granulocytes and monocytes, and the mutation leads to increased binding of PSTPIP1 to pyrin and resulting in reduced free pyrin. Pyrin is an inhibitor of the inflammatory process that recruits caspase-1. Consequent increased recruitment of caspase-1 leads to increased IL-1 production,133,134 leading to inflammation in the joint and skin. In conclusion, multiple genes are involved in the development of acne.
 
Environmental Factors
In addition to genetic propensity, varying prevalence of acne in different countries and cultures may reflect different lifestyles including dietary factors, smoking, face washing and sunlight exposure.
 
Diet
For several decades, there has been a general consensus in the dermatology community that diet plays no role in the pathogenesis of acne. Earlier small, uncontrolled studies looking into the effects of chocolate, milk or peanuts found no effect of these foods on acne.28,135,135 These few, old, poorly designed studies have been referenced time and again to support the non-association of diet and acne in the literature. In the last decade, however, the general thinking regarding diet and 15acne has been revisited following a large cross-sectional study of acne in native, non-Westernized New Guinean and Paraguayan populations3 in whom acne is nonexistent, in contrast to the prevalence of acne in Western populations. The diet of these indigenous people has low glycemic index (GI), consisting of fresh fruits and vegetables, lean protein and healthy fats. The GI is the potential of various foods to increase blood glucose, and glycemic load is calculated by multiplying the GI by the carbohydrate content/serving size.137 Western diet characterized by high GI, i.e. high carbohydrate diet (> 55% of energy from carbohydrates), leads to reactive hyperinsulinemia and results in increased androgens and IGF-1, which are involved in acne pathogenesis.138 Since then, several studies have been conducted that directly implicate diet as the most likely environmental factor underlying pathogenesis of acne.
In the last two decades, a growing body of evidence has shown that the course of acne corresponds more closely to plasma growth hormone (GH) and IGF-1 levels than the traditionally associated androgen levels.139 GH, secreted by the anterior pituitary, binds to GH receptor expressed on most peripheral cells of the body140 and induces hepatic synthesis and secretion of IGF-1, the key regulator of growth. During puberty, GH-driven rise in IGF-1 stimulates 5α-reductase,141 adrenal and gonadal androgen synthesis, AR signal transduction,142 and sebocyte proliferation and lipogenesis,42 thereby potentiating peripheral androgen signaling. In human sebocytes, IGF-1 is most strongly expressed in maturing sebocytes and suprabasal cells of sebaceous ducts,143 suggesting its role as a sebaceous mitogen and morphogen. More than 90% of circulating IGFs are bound to IGF-binding protein 3 (IGFBP-3), the rest to IGFBP-1, 2, 4, 5 and 6, and less than 1% of IGFs circulate as free IGFs. IGF signal transduction is mediated by IGF1R and IGF2R. IGF1R is a tyrosine kinase receptor which can form heterodimers with insulin receptor (IR). Insulin and IGFs overlap substantially in signal transduction due to their receptor cross-reactivity.140,144 Insulin and IGF-1 increase SREBP-1 expression, and this transcription factor in turn stimulates lipogenesis.145 Endocrine or nutritional conditions including puberty, precocious pubarche, polycystic ovary syndrome, acromegaly, insulin resistance, high glycemic food and skim milk consumption which cause increased insulin and IGF-1 serum levels are frequently associated with acne.42 Furthermore, individuals with congenital deficiency of IGF-1 (Laron syndrome) were found to be almost free of acne,146 and in male acne patients receiving a low-glycemic-load diet, IGFBP-1 and IGFBP-3 increased significantly, reflecting reduced free IGF-1 activity and bioavailability.147 Increased insulin/IGF-1 signaling activates PI3K/Akt pathway, reducing the nuclear content of the transcription factor FoxO1, the key nutrigenomic regulator of acne target genes. In the absence of GH, nuclear FoxO1 suppresses nuclear receptors (AR, PPARγ), key genes and transcription factors of cell proliferation (cyclin D2), matrix breakdown (MMPs), 16lipid biosynthesis (SREBP-1) and inflammatory signaling (NF-κB). Nuclear FoxO1 deficiency results in AR transactivation, increased follicular proliferation, increased sebaceous lipogenesis and follicular inflammation, all of which occur in acne development.41
The first randomized controlled trial (RCT) to demonstrate a therapeutic effect of dietary intervention on acne came from Australia in 2007 and reported that a 12-week low-glycemic-load diet in male patients aged 15–25 years led to a decrease in total acne lesion counts, body weight and free androgen index with an increase in IGFBP-1 compared to control group.148 This dietary intervention was also high in protein and fiber, and test diet group lost more body weight and body mass index (BMI) at the end of the 12 weeks. As part of this dietary intervention trial, skin surface lipids were collected from 31 subjects; at 12 weeks the experimental diet group showed increased ratio of SFAs to MUFAs of skin surface TGs compared to controls, and this increase correlated with decreased acne lesion counts.20 As MUFAs, but not SFAs and TGs, have been shown to induce abnormal keratinization and epidermal hyperplasia seen in comedo formation,18 improvement of acne following this dietary intervention seems relevant. MUFAs presumably led to an influx of calcium through N-methyl-D-aspartate glutamate ionic channels on the cellular membrane of keratinocytes and cause hypercornification.149 Although the precise mechanism by which dietary glycemic load influences the sebum composition is unknown, it is possible that low-glycemic-load diet may both decrease the glycogen stores in sebaceous glands, which may be a limiting factor in sebaceous lipogenesis, and lower insulin levels,3 thereby reducing testosterone bioavailability and DHEA-S concentrations.148 A recent study from Korea showed beneficial effects of a low-glycemic-load diet of 10 week duration in both noninflammatory and inflammatory acne lesions assessed clinically and histopathologically.150 Clinical improvement was accompanied by histologic reduction in sebaceous gland size, less inflammation and lowered expression of SREBP-1 and IL-8, demonstrating for the first time objective evidence for decreased lipogenesis and inflammation following a low-glycemic-load diet. In another Australian study of low GI and high GI parallel design for 8 weeks, there was no significant difference between the two groups in the improvement of acne, and the authors suspected that probably 8 weeks is too short a time to see any difference.151 The results of these studies indicate that future trials would need to be designed with at least a 10 week duration.
Milk is an exception to the seemingly beneficial effects of food with low GI. Milk has low GI of 15–30 and yet produces high insulinemic index of 90–98.152 This disproportionately high insulinotropic effect of milk was attributable to the whey fraction which comprises 20% of milk protein; casein which accounts for 80% of protein fraction of cow's milk had a stronger IGF-1 stimulating effect than whey.153 Two cohort studies from the US demonstrated association of milk 17consumption, especially skim milk, with acne in teenage girls and boys,154,155 and a recent Italian case-control study reached the same conclusion, with the risk increasing with more than three portions per week milk consumption and the association more marked for skim than for whole milk.155 The higher association of skim milk with acne indicates that the hydrophilic protein fraction, not the lipophilic androgenic steroids in milk fat, might have a stronger influence on aggravation of acne.143 A recent Malaysian case-control study also confirmed a higher dietary glycemic load and frequency of milk and ice-cream consumption in cases compared to controls.156 Cow's milk contains active IGF-1 and IGF-2.157 High levels of IGF-1 are detected after homogenization and pasteurization of milk, and there is evidence that IGFs in milk may survive digestion and remain bioactive in the plasma after intake.143 Since bovine and human IGF-1 shares the same amino acid sequence, bovine IGF-1 binds to the human IGF1R.143 Milk consumption has been shown to increase serum IGF-1 levels,158-161 with increased ratio of IGF-1/IGFBP-3,159 leading to increased bioavailability of IGF-1. In addition, milk contains androgens, 5-alpha reduced steroids and other growth factors that may affect the pilosebaceous unit. The results of these studies may justify recommending restriction of milk to acne patients.
In the above mentioned Italian study, the risk was reduced in people with lower BMI and people who consumed fish.162 As high BMI has been identified as a risk factor for acne development,163,164 the beneficial effects of lowered BMI can be expected. Since fish oil, high in omega-3 fatty acids, is known to inhibit LTB4, this inhibition may lead to reduced sebum production and improved inflammatory acne.165 Polyunsaturated fats, and omega-3 from fish oil in particular, are inversely correlated with androgen levels.166 A Korean case-control study showed protective effects of vegetable and fish intake and exacerbating effects of a high-glycemic-load diet, dairy food, high fat and iodine consumption and irregular intermeal intervals in acne patients.167 Notably Korean diet has traditionally included seaweed consumption, which is high in iodine, and iodine intake is well known to aggravate acne.168 Another community-based case-control study from Italy demonstrated a protective effect of Mediterranean diet toward acne.169 In contrast, familial hypercholesterolemia, diabetes and hypertension were strong risk factors for acne.169 Nonetheless, further elucidation on the roles of omega-3 fatty acids, antioxidants, zinc, vitamin A and dietary fiber in acne vulgaris remains.170
Based on the existing body of data, convincing evidence exists that high GI foods and dairy products play an important role in the exacerbation of acne. Considering the simultaneous protective effects of low-glycemic-load diet against cardiovascular diseases, type II diabetes and even obesity, there is no reason not to recommend it to acne patients.18
 
Cigarette Smoking
Regarding smoking and acne, conflicting results have been reported101,171-179 with six studies demonstrating a negative171-173 or no association101,175,175 and four studies observing a positive association.174,177-179 In the largest cohort study conducted to date in which 27,083 young Israeli men were interviewed and acne diagnosed by dermatologists, an inverse dose-dependent relationship between severe acne prevalence and daily cigarette consumption (21 or more cigarettes a day) was found.171 The negative association or protective effect of smoking against acne may possibly be due to the anti-inflammatory180 and immunosuppressive181 action of nicotine. Therefore, smoking is more likely to inhibit the inflammatory acne than the comedonal acne. This may be an explanation for the so called “smoker's acne” which is characterized by predominantly noninflammatory microcomedones and macrocomedones in mostly adult female smokers.182 Keratinocytes have nicotine AchR, and they induce cutaneous hyperkeratinization at high concentration.183 In addition, through production of ROS, smoking was shown to increase the grade of sebum peroxidation with an associated reduction in vitamin E.182 Squalene peroxides are comedogenic and can cause hyperproliferation of keratinocytes.184 In a German study of smoking and acne, positive correlation was seen only when the entire age range was considered (up to 87 years).175 When analysis was restricted to patients between 15 years and 40 years of age no association was found. In a retrospective case-control study of Hong Kong and Indian subjects, smoking was correlated with acne only in men.178 In a cross-sectional study of 17,345 Chinese subjects acne was correlated with smoking in adolescents (< 25 years of age) but not in adults.174 Recently benzo(a)pyrene, a major environmental contaminant in cigarette smoke, was found to induce oxidative stress-mediated IL-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway, providing a plausible partial explanation for correlation of smoking and acne severity.185 The conflicting results of the previous studies may be due to the different ways of recruiting study subjects, subject gender/age, sample size and ascertainment of smoking and/or acne.
 
Sunlight (Seasonal Influence)
There is no consensus regarding the influence of sunlight on acne. In a survey of 139 acne patients, one-third of patients reported aggravation in winter, one-third in summer, and the remaining one-third saw no seasonality,186 but this retrospective study is subject to recall bias. Potential beneficial effects of sunlight may be inferred from encouraging results of clinical trials performed using artificial light sources such as ultraviolet B (UVB), UVA, blue, red, green, violet and full-spectrum light;187-190 however, lack of blinding or control in these studies limits the credibility of their acne-ameliorating effects. In view of the sun's well-established 19harmful effects on the skin and the lack of convincing evidence of its beneficial effects on acne, advocating light therapy as treatment for acne cannot be justified.
 
Stress
There is a dearth of research on the effects of stress on acne. In the only cohort study that investigated the relationship between stress and acne exacerbation, increased acne severity was significantly correlated with increased stress levels during examinations in 22 university students,191 and this association remained significant even after controlling for changes in diet and sleep habits during the test period. Increased levels of glucocorticoids and adrenal androgens that are released during periods of emotional stress,192 and secretion of neuroactive substances within the epidermis activating cutaneous inflammatory processes193 have been proposed as mechanisms of stress-induced aggravation of acne.
 
Skin Hygiene
Personal hygienic factors may also affect the progression of inflammatory acne. However, existing studies are scarce in this area. In an RCT, the effects of chlorhexidine gluconate skin cleanser and 5% benzoyl peroxide in acne were similar at 8 weeks and 12 weeks, whereas chlorhexidine cleanser led to significantly less acne lesions compared to vehicle placebo.194 In contrast to chlorhexidine, povidone-iodine cleanser showed no significant superiority to control.195 In another study of mild-to-moderate acne in men, the effect of face washing frequency of 1, 2 or 4 times a day with a mild cleanser was evaluated over a 6 week period. Significant improvements in total noninflammatory lesions was observed in the group washing twice a day, whereas worsening of acne with increases in erythema and total inflammatory lesions was observed in the group washing once a day; excessive face washing 4 times daily did not improve or worsen acne.196 This study was limited by the fact that clinical assessment was performed without blinding of the treatment groups and that non-wash control arm was lacking. In a cross-sectional study of 2,300 Turkish subjects, daily facial washing of 3 times or more significantly lowered risk for acne.197 Despite their limitations, the results of these studies offer some evidence to recommend face washing at least twice daily for acne patients. In a different study, when two groups of patients with a similar degree of mild inflammatory acne were compared after 4 weeks of twice daily use of an acidic syndet bar or a conventional alkaline soap bar, the number of inflammatory lesions decreased in the former group, whereas it increased in the latter group. Symptoms of irritation were seen in 2% of syndet group and 40% of soap group,198 suggesting associated irritation caused by alkaline soap may aggravate inflammatory acne.20
 
ACNE SCAR FORMATION
Although our understanding of acne pathogenesis has increased substantially in recent years, it is in the area of its scar formation that significant advances have been made. Classic teachings had included, based on strong clinical impression, that the more inflamed acne lesions are, the more likely acne scars will result. However, how inflammation may lead to scar formation was considered “unknown”.
The first report of dermal matrix degradation in inflamed acne lesion was published in 2005.199 Compared to uninvolved facial skin from acne patients, involved lesions were found to contain markedly elevated levels of matrix degrading MMPs of several types—1, 3, 8 and 9. MMP8, also known as neutrophil collagenase, was due to significant number of neutrophils that had infiltrated acne lesions. Three other MMPs (1, 3 and 9) are known to be activator protein-1 (AP-1) transcription factor-regulated genes. Coincident increase in c-Jun protein (a key element of AP-1) in cells lining the sebaceous follicles and in some dermal cells implicated the participation of MAPK. In the same report, in vivo demonstration of NF-κB activation (nuclear translocation of p50/p65), and consistent elevation of primary proinflammatory cytokines (IL-1B, TNF-α, etc.) suggested the likely involvement of TLRs in initiating the signaling cascade.
Applying computer software program to accurately superimpose high quality clinical photographs over time has allowed investigators to follow the natural history of acne lesions.200 In one study, development of atrophic scars was carefully documented every 2 weeks, in over a 12 week observation period. About 20% of atrophic scars arose from acne lesions, mostly from inflammatory lesions, but also from large comedones. Remarkably, about half of the atrophic scars arose in previously normal appearing skin. These findings suggest that aggressive and rapid treatment plans should be implemented to reduce scar formation.
 
CONCLUSION
The classic pathogenic factors of acne, i.e. androgenic control of sebaceous gland, infundibular retention hyperkeratosis, P. acnes and inflammatory events, undoubtedly play a major role in the breakout of this common cutaneous disorder. They withstood the test of time and still provide a foundational framework in thinking about acne pathogenesis. In the last few years however, we have gained refined insight into the role of these classic factors, as well as additional potential triggers (such as genetic and dietary) through molecular studies and well-designed prospective RCTs.
Sebaceous gland is crucial in the initiation of acne since it possesses all the enzymatic machinery for the production of hormones and cytokines.201 We now appreciate that more than seborrhea, it is the altered lipid composition and the oxidant/antioxidant ratio that are important in acne pathogenesis.21
Colonization of the pilosebaceous unit by P. acnes is the primary event that elicits both innate and adaptive immune responses in the host. Interaction of P. acnes in the skin's microflora with keratinocytes, sebocytes and other cells that comprise of the cutaneous immune system must be important in acne. Recent research that suggests a link between the clinical severities of acne, the host's ability to neutralize ROS generated by P. acnes is consistent with this view.93 Therefore, the use of antioxidants to mitigate this process may be a novel treatment option in the future.
Complementing molecular studies that looked at genetic risk factors (investigating polymorphisms of genes that function in the steroid hormone metabolism, innate immunity-related genes and FGFR2), epidemiologic inquiry revealed important lifestyle factors (such as diet and smoking) that impact the development of acne. Compelling evidence that high-glycemic-load diet and milk consumption contribute to aggravation of acne vulgaris by raising insulin and IGF-1 levels allow us to recommend behavior modifications to improve the outcome of acne. The influence of dietary fatty acids, vitamin A, antioxidants, iodine and dietary fiber on acne is less clear and warrant further investigation. Since diet is an important factor which influences one's hormonal, inflammatory and oxidation status, assessing diet history should be included in the evaluation of acne patients.17 The existing literature on the effects of smoking and sunlight is controversial and no conclusions can be drawn at this time.
In the classic theory on acne development, inflammation is considered a late stage event. Emerging body of evidence however, points to inflammation (subclinical) as an early, almost necessary step in driving follicular hyper- keratinization and hyperproliferation, supporting the notion that even comedonal acne is an inflammatory skin disease. Such evidence-based assessment of acne has implications on treatment strategy. Treating uninvolved skin in acne patients becomes important, as well as the choice of pharmacologic agents. Inclusion of medications that possess antiinflammatory properties may reduce or even prevent the appearance of visible acne lesions. Improved clinical outcome of our acne patients can be realized through continued research into its pathogenesis.
REFERENCES
  1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34–7.
  1. Burkhart CG, Burkhart CN. Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes biofilm produces biological glue that holds corneocytes together to form plug. J Am Acad Dermatol. 2007;57:722–4.
  1. Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138:1584–90.
  1. Downing DT, Stewart ME, Wertz PW, Colton SW, Abraham W, Strauss JS. Skin lipids: an update. J Invest Dermatol. 1987;88:2s–6s.
  1. Thiboutot D, Jabara S, McAllister JM, Sivarajah A, Gilliland K, Cong Z, et al. Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1). J Invest Dermatol. 2003;120:905–14.
  1. Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol. 1999;113:1011–20.
  1. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol. 2004;22:360–6.
  1. Toyoda M, Nakamura M, Morohashi M. Neuropeptides and sebaceous glands. Eur J Dermatol. 2002;12: 422–7.
  1. Ganceviciene R, Graziene V, Fimmel S, Zouboulis CC. Involvement of the corticotropin-releasing hormone system in the pathogenesis of acne vulgaris. Br J Dermatol. 2009;160:345–52.
  1. Zouboulis CC. Propionibacterium acnes and sebaceous lipogenesis: a love-hate relationship? J Invest Dermatol. 2009;129:2093–6.
  1. Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, et al. Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci U S A. 2002; 99:7148–53.
  1. Latha B, Babu M. The involvement of free radicals in burn injury: a review. Burns. 2001;27:309–17.
  1. Zhang L, Li WH, Anthonavage M, Pappas A, Rossetti D, Cavender D, et al. Melanocortin-5 receptor and sebogenesis. Eur J Pharmacol. 2011;660:202–6.

  1. 23 Ganceviciene R, Graziene V, Böhm M, Zouboulis CC. Increased in situ expression of melanocortin-1 receptor in sebaceous glands of lesional skin of patients with acne vulgaris. Exp Dermatol. 2007;16:547–52.
  1. Lee WJ, Jung HD, Lee HJ, Kim BS, Lee SJ, Kim do W. Influence of substance-P on cultured sebocytes. Arch Dermatol Res. 2008;300:311–6.
  1. Koreck A, Pivarcsi A, Dobozy A, Kemény L. The role of innate immunity in the pathogenesis of acne. Dermatology. 2003;206:96–105.
  1. Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18:821–32.
  1. Katsuta Y, Iida T, Inomata S, Denda M. Unsaturated fatty acids induce calcium influx into keratinocytes and cause abnormal differentiation of epidermis. J Invest Dermatol. 2005;124:1008–13.
  1. Nicolaides N. Skin lipids: their biochemical uniqueness. Science. 1974;186:19–26.
  1. Smith RN, Braue A, Varigos GA, Mann NJ. The effect of a low glycemic load diet on acne vulgaris and the fatty acid composition of skin surface triglycerides. J Dermatol Sci. 2008;50:41–52.
  1. Maeda T. An electron microscopic study of experimentally-induced comedo and effects of vitamin A acid on comedo formation. J Dermatol. 1991;18:397–407.
  1. Downing DT, Stewart ME, Wertz PW, Strauss JS. Essential fatty acids and acne. J Am Acad Dermatol. 1986; 14:221–5.
  1. Ottaviani M, Camera E, Picardo M. Lipid mediators in acne. Mediators Inflamm. 2010;2010. pii: 858176.
  1. Pappas A, Johnsen S, Liu JC, Eisinger M. Sebum analysis of individuals with and without acne. Dermatoendocrinol. 2009;1:157–61.
  1. Alestas T, Ganceviciene R, Fimmel S, Müller-Decker K, Zouboulis CC. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med (Berl). 2006;84:75–87.
  1. Sarici G, Cinar S, Armutcu F, Altinyazar C, Koca R, Tekin NS. Oxidative stress in acne vulgaris. J Eur Acad Dermatol Venereol. 2010;24:763–7.
  1. Knutson DD. Ultrastructural observations in acne vulgaris: the normal sebaceous follicle and acne lesions. J Invest Dermatol. 1974;62:288–307.
  1. Fulton JE, Plewig G, Kligman AM. Effect of chocolate on acne vulgaris. JAMA. 1969;210:2071–4.
  1. Chronnell CM, Ghali LR, Ali RS, Quinn AG, Holland DB, Bull JJ, et al. Human beta defensin-1 and −2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions. J Invest Dermatol. 2001; 117:1120–5.
  1. Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, McDowell A, et al. Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. Microbes Infect. 2006;8:2195–205.
  1. Lee DY, Yamasaki K, Rudsil J, Zouboulis CC, Park GT, Yang JM, et al. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill propionibacterium acnes. J Invest Dermatol. 2008;128:1863–6.
  1. Nakatsuji T, Kao MC, Zhang L, Zouboulis CC, Gallo RL, Huang CM. Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression. J Invest Dermatol. 2010;130:985–94.
  1. Russell LE, Harrison WJ, Bahta AW, Zouboulis CC, Burrin JM, Philpott MP. Characterization of liver X receptor expression and function in human skin and the pilosebaceous unit. Exp Dermatol. 2007;16:844–52.
  1. Hong I, Lee MH, Na TY, Zouboulis CC, Lee MO. LXRalpha enhances lipid synthesis in SZ95 sebocytes. J Invest Dermatol. 2008;128:1266–72.
  1. Hana A, Booken D, Henrich C, Gratchev A, Maas-Szabowski N, Goerdt S, et al. Functional significance of non-neuronal acetylcholine in skin epithelia. Life Sci. 2007;80:2214–20.
  1. Findlay GH. The age incidence of common skin diseases in the white population of the Transvaal. Br J Dermatol. 1967;79:538–42.
  1. Findlay GH, Lups JG. Findlay The incidence and pathogenesis of chronic discoid lupus erythematosus. An analysis of 191 consecutive cases from the Transvaal. S Afr Med J. 1967;41:694–8.

  1. 24 Akamatsu H, Zouboulis CC, Orfanos CE. Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands. J Invest Dermatol. 1992;99:509–11.
  1. Janssen R, Prpic NM, Damen WG. Gene expression suggests decoupled dorsal and ventral segmentation in the millipede Glomeris marginata (Myriapoda : Diplopoda). Dev Biol. 2004;268:89–104.
  1. Guy R, Ridden C, Kealey T. The improved organ maintenance of the human sebaceous gland: Modeling in vitro the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic acid, and phenol red. J Invest Dermatol. 1996;106:454–60.
  1. Melnik BC. FoxO1-the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges. 2010;8:105–14.
  1. Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18:833–41.
  1. Lee WJ, Jung HD, Chi SG, Kim BS, Lee SJ, Kim do W, et al. Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured sebocytes. Arch Dermatol Res. 2010;302:429–33.
  1. Thiboutot DM, Knaggs H, Gilliland K, Hagari S. Activity of type 1 5 alpha-reductase is greater in the follicular infrainfundibulum compared with the epidermis. Br J Dermatol. 1997;136:166–71.
  1. Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M. Keratins and the keratinocyte activation cycle. J Invest Dermatol. 2001;116:633–40.
  1. Jarrousse V, Castex-Rizzi N, Khammari A, Charveron M, Dréno B. Modulation of integrins and filaggrin expression by Propionibacterium acnes extracts on keratinocytes. Arch Dermatol Res. 2007;299(9):441–7.
  1. Hughes BR, Morris C, Cunliffe WJ, Leigh IM. Keratin expression in pilosebaceous epithelia in truncal skin of acne patients. Br J Dermatol. 1996;134:247–56.
  1. Georgel P, Crozat K, Lauth X, Makrantonaki E, Seltmann H, Sovath S, et al. A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria. Infect Immun. 2005;73:4512–21.
  1. Munro CS, Wilkie AO. Epidermal mosaicism producing localised acne: somatic mutation in FGFR2. Lancet. 1998;352:704–5.
  1. Melnik BC, Vakilzadeh F, Aslanidis C, Schmitz G. Unilateral segmental acneiform naevus: a model disorder towards understanding fibroblast growth factor receptor 2 function in acne? Br J Dermatol. 2008;158:1397–9.
  1. McGinley KJ, Webster GF, Leyden JJ. Regional variations of cutaneous propionibacteria. Appl Environ Microbiol. 1978;35:62–6.
  1. Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Age-related changes in the resident bacterial flora of the human face. J Invest Dermatol. 1975;65:379–81.
  1. Leeming JP, Holland KT, Cuncliffe WJ. The microbial colonization of inflamed acne vulgaris lesions. Br J Dermatol. 1988;118:203–8.
  1. Shaheen B, Gonzalez M. A microbial aetiology of acne: what is the evidence? Br J Dermatol. 2011;165:474–85.
  1. Aizawa H, Niimura M. Elevated serum insulin-like growth factor-1 (IGF-1) levels in women with post-adolescent acne. J Dermatol. 1995;22:249–52.
  1. Isard O, Knol AC, Ariès MF, Nguyen JM, Khammari A, Castex-Rizzi N, et al. Propionibacterium acnes activates the IGF-1/IGF-1R system in the epidermis and induces keratinocyte proliferation. J Invest Dermatol. 2011;131:59–66.
  1. Akaza N, Akamatsu H, Kishi M, Mizutani H, Ishii I, Nakata S, et al. Effects of Propionibacterium acnes on various mRNA expression levels in normal human epidermal keratinocytes in vitro. J Dermatol. 2009; 36:213–23.
  1. Isard O, Knol AC, Castex-Rizzi N, Khammari A, Charveron M, Dréno B. Cutaneous induction of corticotropin releasing hormone by Propionibacterium acnes extracts. Dermatoendocrinol. 2009;96–9.
  1. Coenye T, Peeters E, Nelis HJ. Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors. Res Microbiol. 2007;158:386–92.
  1. Brüggemann H, Henne A, Hoster F, Liesegang H, Wiezer A, Strittmatter A, et al. The complete genome sequence of Propionibacterium acnes, a commensal of human skin. Science. 2004;305:671–3.

  1. 25 Lee SE, Kim JM, Jeong SK, Jeon JE, Yoon HJ, Jeong MK, et al. Protease-activated receptor-2 mediates the expression of inflammatory cytokines, antimicrobial peptides, and matrix metalloproteinases in keratinocytes in response to Propionibacterium acnes. Arch Dermatol Res. 2010;302:745–56.
  1. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell. 1998;2:253–8.
  1. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004;303:1522–6.
  1. Köllisch G, Kalali BN, Voelcker V, Wallich R, Behrendt H, Ring J, et al. Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology. 2005;114:531–41.
  1. Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002;169:1535–41.
  1. Adişen E, Yüksek J, Erdem O, Aksakal FN, Aksakal AB. Expression of human neutrophil proteins in acne vulgaris. J Eur Acad Dermatol Venereol. 2010;24:32–7.
  1. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol. 2003;121:20–7.
  1. Norris JF, Cunliffe WJ. A histological and immunocytochemical study of early acne lesions. Br J Dermatol. 1988;118:651–9.
  1. Aldana OL, Holland DB, Cunliffe WJ. A role for interleukin 1 alpha comedogenesis. J Invest Dermatol. 1998; 110:558.
  1. Yang D, Chen Q, Chertov O, Oppenheim JJ. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J Leukoc Biol. 2000;68:9–14.
  1. Baker BS, Ovigne JM, Powles AV, Corcoran S, Fry L. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol. 2003;148:670–9.
  1. Pivarcsi A, Bodai L, Réthi B, Kenderessy-Szabó A, Koreck A, Széll M, et al. Expression and function of Toll-like receptors 2 and 4 in human keratinocytes. Int Immunol. 2003;15:721–30.
  1. Jugeau S, Tenaud I, Knol AC, Jarrousse V, Quereux G, Khammari A, et al. Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol. 2005;153:1105–13.
  1. Nagy I, Pivarcsi A, Koreck A, Széll M, Urbán E, Kemény L. Distinct strains of Propionibacterium acnes induce selective human beta-defensin-2 and interleukin-8 expression in human keratinocytes through toll-like receptors. J Invest Dermatol. 2005;124:931–8.
  1. Graham GM, Farrar MD, Cruse-Sawyer JE, Holland KT, Ingham E. Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL. Br J Dermatol. 2004;150:421–8.
  1. Grange PA, Weill B, Dupin N, Batteux F. Does inflammatory acne result from imbalance in the keratinocyte innate immune response? Microbes Infect. 2010;12:1085–90.
  1. Ganceviciene R, Fimmel S, Glass E, Zouboulis CC. Psoriasin and follicular hyperkeratinization in acne comedones. Dermatology. 2006;213:270–2.
  1. Chen W, Yang CC, Sheu HM, Seltmann H, Zouboulis CC. Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes. J Invest Dermatol. 2003;121:441–7.
  1. Jahns AC, Lundskog B, Ganceviciene R, Palmer RH, Golovleva I, Zouboulis CC, et al. An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case-control study. Br J Dermatol. 2012;167:50–8.
  1. Iinuma K, Sato T, Akimoto N, Noguchi N, Sasatsu M, Nishijima S, et al. Involvement of Propionibacterium acnes in the augmentation of lipogenesis in hamster sebaceous glands in vivo and in vitro. J Invest Dermatol. 2009;129:2113–9.
  1. Zhang Q, Seltmann H, Zouboulis CC, Konger RL. Involvement of PPARgamma in oxidative stress-mediated prostaglandin E(2) production in SZ95 human sebaceous gland cells. J Invest Dermatol. 2006;126:42–8.
  1. Sato T, Kurihara H, Akimoto N, Noguchi N, Sasatsu M, Ito A. Augmentation of gene expression and production of promatrix metalloproteinase 2 by propionibacterium acnes-derived factors in hamster sebocytes and dermal fibroblasts: a possible mechanism for acne scarring. Biol Pharm Bull. 2011;34:295–9.

  1. 26 Leyden JJ, McGinley KJ, Vowels B. Propionibacterium acnes colonization in acne and nonacne. Dermatology. 1998;196:55–8.
  1. Jappe U, Ingham E, Henwood J, Holland KT. Propionibacterium acnes and inflammation in acne; P. acnes has T-cell mitogenic activity. Br J Dermatol. 2002;146:202–9.
  1. Webster GF, Leyden JJ, Norman ME, Nilsson UR. Complement activation in acne vulgaris: in vitro studies with Propionibacterium acnes and Propionibacterium granulosum. Infect Immun. 1978;22:523–9.
  1. Mouser PE, Baker BS, Seaton ED, Chu AC. Propionibacterium acnes-reactive T helper-1 cells in the skin of patients with acne vulgaris. J Invest Dermatol. 2003;121:1226–8.
  1. Basal E, Jain A, Kaushal GP. Antibody response to crude cell lysate of Propionibacterium acnes and induction of pro-inflammatory cytokines in patients with acne and normal healthy subjects. J Microbiol. 2004;42:117–25.
  1. Lodes MJ, Secrist H, Benson DR, Jen S, Shanebeck KD, Guderian J, et al. Variable expression of immuno reactive surface proteins of Propionibacterium acnes. Microbiology. 2006;152:3667–81.
  1. Nakatsuji T, Tang DC, Zhang L, Gallo RL, Huang CM. Propionibacterium acnes CAMP factor and host acid sphingomyelinase contribute to bacterial virulence: potential targets for inflammatory acne treatment. PloS one. 2011;6:e14797.
  1. Trivedi NR, Gilliland KL, Zhao W, Liu W, Thiboutot DM. Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling. J Invest Dermatol. 2006;126:1071–9.
  1. Taylor M, Gonzalez M, Porter R. Pathways to inflammation: acne pathophysiology. Eur J Dermatol. 2011; 21:323–33.
  1. Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-kappa B and MAPK pathways. J Dermatol Sci. 2009;56:106–12.
  1. Grange PA, Chéreau C, Raingeaud J, Nicco C, Weill B, Dupin N, et al. Production of superoxide anions by keratinocytes initiates P. acnes-induced inflammation of the skin. PLoS Pathog. 2009;5:e1000527.
  1. Zouboulis CC, Nestoris S, Adler YD, Orth M, Orfanos CE, Picardo M, et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139:668–70.
  1. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169:453–9.
  1. Basak PY, Gultekin F, Kilinc I. The role of the antioxidative defense system in papulopustular acne. J Dermatol. 2001;28:123–7.
  1. Ikeno H, Tochio T, Tanaka H, Nakata S. Decrease in glutathione may be involved in pathogenesis of acne vulgaris. J Cosmet Dermatol. 2011;10:240–4.
  1. Friedman GD. Twin studies of disease heritability based on medical records: application to acne vulgaris. Acta Genet Med Gemellol (Roma). 1984;33:487–95.
  1. Bataille V, Snieder H, MacGregor AJ, Sasieni P, Spector TD. The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women. J Invest Dermatol. 2002;119:1317–22.
  1. Walton S, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion and acne—a twin study. Br J Dermatol. 1988;118:393–6.
  1. Ghodsi SZ, Orawa H, Zouboulis CC. Prevalence, severity, and severity risk factors of acne in high school pupils: a community-based study. J Invest Dermatol. 2009;129:2136–41.
  1. Paraskevaidis A, Drakoulis N, Roots I, Orfanos CE, Zouboulis CC. Polymorphisms in the human cytochrome P-450 1A1 gene (CYP1A1) as a factor for developing acne. Dermatology. 1998;196:171–5.
  1. Ostlere LS, Rumsby G, Holownia P, Jacobs HS, Rustin MH, Honour JW. Carrier status for steroid 21-hydroxylase deficiency is only one factor in the variable phenotype of acne. Clin Endocrinol (Oxf). 1998; 48:209–15.
  1. Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg. 1998;3:9–15.
  1. He L, Yang Z, Yu H, Cheng B, Tang W, Dong Y, et al. The relationship between CYP17–34T/C polymorphism and acne in Chinese subjects revealed by sequencing. Dermatology. 2006;212:338–42.

  1. 27 Tian LM, Xie HF, Yang T, Hu YH, Li J. [Correlation between CYP17 gene polymorphisms and female post adolescent acne in Han population in Hunan Province]. Nan Fang Yi Ke Da Xue Xue Bao. 2010;30:1590–2, 6.
  1. Janssen JP, Verlinden I, Gungor N, Raus J, Michiels L. Different gene expression in the breast after pregnancy. J Clin Oncol. 2004;22:1019.
  1. Liang T, Hoyer S, Yu R, Soltani K, Lorincz AL, Hiipakka RA, et al. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J Invest Dermatol. 1993;100:663–6.
  1. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22:3181–6.
  1. Yang Z, Yu H, Cheng B, Tang W, Dong Y, Xiao C, et al. Relationship between the CAG repeat polymorphism in the androgen receptor gene and acne in the Han ethnic group. Dermatology. 2009;218:302–6.
  1. Cappel M, Mauger D, Thiboutot D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women. Arch Dermatol. 2005;141:333–8.
  1. Rietveld I, Janssen JA, van Rossum EFC, Houwing-Duistermaat JJ, Rivadeneira F, Hofman A, et al. A polymorphic CA repeat in the IGF-I gene is associated with gender-specific differences in body height, but has no effect on the secular trend in body height. Clin Endocrinol (Oxf). 2004;61:195–203.
  1. Tasli L, Turgut S, Kacar N, Ayada C, Coban M, Akcilar R, et al. Insulin-like growth factor-I gene polymorphism in acne vulgaris. J Eur Acad Dermatol Venereol. 2011.
  1. Chen X, Guan J, Song Y, Chen P, Zheng H, Tang C, et al. IGF-I (CA) repeat polymorphisms and risk of cancer: a meta-analysis. J Hum Genet. 2008;53:227–38.
  1. Grech I, Giatrakou S, Damoraki G, Pistiki A, Kaldrimidis P, Giamarellos-Bourboulis EJ, et al. Single nucleotide polymorphisms of toll-like receptor-4 protect against acne conglobata. J Eur Acad Dermatol Venereol. 2012;26:1538–43.
  1. Szabó K, Tax G, Kis K, Szegedi K, Teodorescu-Brinzeu DG, Diószegi C, et al. Interleukin-1A +4845(G > T) polymorphism is a factor predisposing to acne vulgaris. Tissue Antigens. 2010;76:411–5.
  1. Sobjanek M, Zablotna M, Glen J, Michajlowski I, Nedoszytko B, Roszkiewicz J. Polymorphism in interleukin 1A but not in interleukin 8 gene predisposes to acne vulgaris in Polish population. J Eur Acad Dermatol Venereol. 2013;27:259–60.
  1. Al Robaee AA, AlZolibani A, Al Shobaili H, Settin A. Association of interleukin 4 (-590 T/C) and interleukin 4 receptor (Q551R A/G) gene polymorphisms with acne vulgaris. Ann Saudi Med. 2012;32:349–54.
  1. Baz K, Emin Erdal M, Yazici AC, Söylemez F, Güvenç U, Ta°delen B, et al. Association between tumor necrosis factor-alpha gene promoter polymorphism at position -308 and acne in Turkish patients. Arch Dermatol Res. 2008;300:371–6.
  1. Tian L, Xie H, Yang T, Hu Y, Li J, Wang W. TNFR 2 M196R polymorphism and acne vulgaris in Han Chinese: a case-control study. J Huazhong Univ Sci Technolog Med Sci. 2010;30:408–11.
  1. Szabó K, Tax G, Teodorescu-Brinzeu D, Koreck A, Kemény L. TNFalpha gene polymorphisms in the pathogenesis of acne vulgaris. Arch Dermatol Res. 2011;303:19–27.
  1. Al-Shobaili HA, Salem TA, Alzolibani AA, Robaee AA, Settin AA. Tumor necrosis factor-α -308 G/A and interleukin 10 -1082 A/G gene polymorphisms in patients with acne vulgaris. J Dermatol Sci. 2012;68:52–5.
  1. Ando I, Kukita A, Soma G, Hino H. A large number of tandem repeats in the polymorphic epithelial mucin gene is associated with severe acne. J Dermatol. 1998;25:150–2.
  1. Szabó K, Kemény L. Studying the genetic predisposing factors in the pathogenesis of acne vulgaris. Hum Immunol. 2011;72:766–73.
  1. Koreck A, Kis K, Szegedi K, Paunescu V, Cioaca R, Olariu R, et al. TLR2 and TLR4 polymorphisms are not associated with acne vulgaris. Dermatology. 2006;213:267–9.
  1. Rivadeneira F, Houwing-Duistermaat JJ, Beck TJ, Janssen JA, Hofman A, Pols HA, et al. The influence of an insulin-like growth factor I gene promoter polymorphism on hip bone geometry and the risk of nonvertebral fracture in the elderly: the Rotterdam Study. J Bone Miner Res. 2004;19:1280–90.
  1. Melnik B, Schmitz G. FGFR2 signaling and the pathogenesis of acne. J Dtsch Dermatol Ges. 2008;6:721–8.

  1. 28 Werner S, Weinberg W, Liao X, Peters KG, Blessing M, Yuspa SH, et al. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 1993;12:2635–43.
  1. Melnik BC, Schmitz G, Zouboulis CC. Anti-acne agents attenuate FGFR2 signal transduction in acne. J Invest Dermatol. 2009;129:1868–77.
  1. Kaushansky A, Gordus A, Chang B, Rush J, MacBeath G. A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R. Mol Biosyst. 2008;4:643–53.
  1. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermato-endocrinology. 2009;1:141–56.
  1. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11:961–9.
  1. Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601–18.
  1. McDermott MF, Aksentijevich I. The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol. 2002; 2:511–6.
  1. Grant JD, Anderson PC. Chocolate as a cause of acne: A dissenting view. Mo Med. 1965;62:459–60.
  1. Anderson PC. Foods as the cause of acne. Am Fam Physician. 1971;3:102–3.
  1. Willett W, Manson J, Liu S. Glycemic index, glycemic load, and risk of type 2 diabetes. Am J Clin Nutr. 2002;76:274S-80S.
  1. Thiboutot DM, Strauss JS. Diet and acne revisited. Arch Dermatol. 2002;138:1591–2.
  1. Cara JF, Rosenfield RL, Furlanetto RW. A longitudinal study of the relationship of plasma somatomedin-C concentration to the pubertal growth spurt. Am J Dis Child. 1987;141:562–4.
  1. Edmondson SR, Thumiger SP, Werther GA, Wraight CJ. Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev. 2003;24:737–64.
  1. Horton R, Pasupuletti V, Antonipillai I. Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I. Endocrinology. 1993;133:447–51.
  1. Fan W, Yanase T, Morinaga H, Okabe T, Nomura M, Daitoku H, et al. Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. J Biol Chem. 2007;282:7329–38.
  1. Rudman SM, Philpott MP, Thomas GA, Kealey T. The role of IGF-I in human skin and its appendages: morphogen as well as mitogen? J Invest Dermatol. 1997;109:770–7.
  1. Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev. 2005;16:421–39.
  1. Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol. 2008; 128:1286–93.
  1. Melnik BC, John SM, Schmitz G. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome. Nutr Metab (Lond). 2011;8:41.
  1. Smith R, Mann N, Makelainen H, Roper J, Braue A, Varigos G. A pilot study to determine the short-term effects of a low glycemic load diet on hormonal markers of acne: a nonrandomized, parallel, controlled feeding trial. Mol Nutr Food Res. 2008;52:718–26.
  1. Smith RN, Mann NJ, Braue A, Mäkeläinen H, Varigos GA. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial. J Am Acad Dermatol. 2007;57:247–56.
  1. Fuziwara S, Inoue K, Denda M. NMDA-type glutamate receptor is associated with cutaneous barrier homeostasis. J Invest Dermatol. 2003;120:1023–9.
  1. Kwon HH, Yoon JY, Hong JS, Jung JY, Park MS, Suh DH. Clinical and histological effect of a low glycaemic load diet in treatment of acne vulgaris in Korean patients: a randomized, controlled trial. Acta Derm Venereol. 2012;92:241–6.
  1. Reynolds RC, Lee S, Choi JY, Atkinson FS, Stockmann KS, Petocz P, et al. Effect of the glycemic index of carbohydrates on Acne vulgaris. Nutrients. 2010;2:1060–72.

  1. 29 Ostman EM, Liljeberg Elmståhl HG, Björck IM. Inconsistency between glycemic and insulinemic responses to regular and fermented milk products. Am J Clin Nutr. 2001;74:96–100.
  1. Hoppe C, Mølgaard C, Michaelsen KF. Cow's milk and linear growth in industrialized and developing countries. Ann Rev Nutr. 2006;26:131–73.
  1. Adebamowo CA, Spiegelman D, Danby FW, Frazier AL, Willett WC, Holmes MD. High school dietary dairy intake and teenage acne. J Am Acad Dermatol. 2005;52:207–14.
  1. Adebamowo CA, Spiegelman D, Berkey CS, Danby FW, Rockett HH, Colditz GA, et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol. 2008;58:787–93.
  1. Ismail NH, Manaf ZA, Azizan NZ. High glycemic load, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study. BMC Dermatol. 2012;12:13.
  1. Blum JW, Baumrucker CR. Insulin-like growth factors (IGFs), IGF binding proteins, and other endocrine factors in milk: role in the newborn. Adv Exp Med Biol. 2008;606:397–422.
  1. Hoppe C, Udam TR, Lauritzen L, Mølgaard C, Juul A, Michaelsen KF. Animal protein intake, serum insulin-like growth factor I, and growth in healthy 2.5-y-old Danish children. Am J Clin Nutr. 2004;80:447–52.
  1. Hoppe C, Molgaard C, Juul A, Michaelsen KF. High intakes of skimmed milk, but not meat, increase serum IGF-I and IGFBP-3 in eight-year-old boys. Eur J Clin Nutr. 2004;58:1211–6.
  1. Rogers IS, Gunnell D, Emmett PM, Glynn LR, Dunger DB, Holly JM. Cross-sectional associations of diet and insulin-like growth factor levels in 7- to 8-year-old children. Cancer Epidemiol Biomarkers Prev. 2005; 14:204–12.
  1. Esterle L, Sabatier JP, Guillon-Metz F, Walrant-Debray O, Guaydier-Souquières G, Jehan F, et al. Milk, rather than other foods, is associated with vertebral bone mass and circulating IGF-1 in female adolescents. Osteoporosis Int. 2009;20:567–75.
  1. Di Landro A, Cazzaniga S, Parazzini F, Ingordo V, Cusano F, Atzori L, et al. Family history, body mass index, selected dietary factors, menstrual history, and risk of moderate to severe acne in adolescents and young adults. J Am Acad Dermatol. 2012;67:1129–35.
  1. Tsai MC, Chen W, Cheng YW, Wang CY, Chen GY, Hsu TJ. Higher body mass index is a significant risk factor for acne formation in schoolchildren. Eur J Dermatol. 2006;16:251–3.
  1. Bourne S, Jacobs A. Observations on acne, seborrhoea, and obesity. Br Med J. 1956;1:1268–70.
  1. Logan AC. Omega-3 fatty acids and acne. Arch Dermatol. 2003;139:941–2.
  1. Nagata C, Takatsuka N, Kawakami N, Shimizu H. Relationships between types of fat consumed and serum estrogen and androgen concentrations in Japanese men. Nutr Cancer. 2000;38:163–7.
  1. Jung JY, Yoon MY, Min SU, Hong JS, Choi YS, Suh DH. The influence of dietary patterns on acne vulgaris in Koreans. Eur J Dermatol. 2010;20:768–72.
  1. Hitch JM. Acneform eruptions induced by drugs and chemicals. JAMA. 1967;200:879–80.
  1. Skroza N, Tolino E, Semyonov L, Proietti I, Bernardini N, Nicolucci F, et al. Mediterranean diet and familial dysmetabolism as factors influencing the development of acne. Scand J Public Health. 2012;40:466–74.
  1. Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol. 2010;63:124–41.
  1. Klaz I, Kochba I, Shohat T, Zarka S, Brenner S. Severe acne vulgaris and tobacco smoking in young men. J Invest Dermatol. 2006;126:1749–52.
  1. Mills CM, Peters TJ, Finlay AY. Does smoking influence acne? Clin Exp Dermatol. 1993;18:100–1.
  1. Rombouts S, Nijsten T, Lambert J. Cigarette smoking and acne in adolescents: results from a cross-sectional study. J Eur Acad Dermatol Venereol. 2007;21:326–33.
  1. Shen Y, Wang T, Zhou C, Wang X, Ding X, Tian S, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40–4.
  1. Firooz A, Sarhangnejad R, Davoudi SM, Nassiri-Kashani M. Acne and smoking: is there a relationship? BMC Dermatol. 2005;5:2.
  1. Jemec GB, Linneberg A, Nielsen NH, Frølund L, Madsen F, Jørgensen T. Have oral contraceptives reduced the prevalence of acne? a population-based study of acne vulgaris, tobacco smoking and oral contraceptives. Dermatology. 2002;204:179–84.
  1. Schäfer T, Nienhaus A, Vieluf D, Berger J, Ring J. Epidemiology of acne in the general population: the risk of smoking. Br J Dermatol. 2001;145:100–4.

  1. 30 Chuh AA, Zawar V, Wong WC, Lee A. The association of smoking and acne in men in Hong Kong and in India: a retrospective case-control study in primary care settings. Clinl Exp Dermatol. 2004;29:597–9.
  1. Capitanio B, Sinagra JL, Ottaviani M, Bordignon V, Amantea A, Picardo M. Acne and smoking. Dermato endocrinol. 2009;1:129–35.
  1. Misery L. Nicotine effects on skin: are they positive or negative? Exp Dermatol. 2004;13:665–70.
  1. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002;2:372–7.
  1. Capitanio B, Sinagra JL, Ottaviani M, Bordignon V, Amantea A, Picardo M. ‘Smoker's acne’: a new clinical entity? Br J Dermatol. 2007;157:1070–1.
  1. Theilig C, Bernd A, Ramirez-Bosca A, Görmar FF, Bereiter-Hahn J, Keller-Stanislawski B, et al. Reactions of human keratinocytes in vitro after application of nicotine. Skin Pharmacol. 1994;7:307–15.
  1. Ottaviani M, Alestas T, Flori E, Mastrofrancesco A, Zouboulis CC, Picardo M. Peroxidated squalene induces the production of inflammatory mediators in HaCaT keratinocytes: a possible role in acne vulgaris. J Invest Dermatol. 2006;126:2430–7.
  1. Tsuji G, Takahara M, Uchi H, Takeuchi S, Mitoma C, Moroi Y, et al. An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J Dermatol Sci. 2011;62:42–9.
  1. Gfesser M, Worret WI. Seasonal variations in the severity of acne vulgaris. Int J Dermatol. 1996;35:116–7.
  1. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973–8.
  1. Kawada A, Aragane Y, Kameyama H, Sangen Y, Tezuka T. Acne phototherapy with a high-intensity, enhanced, narrow-band, blue light source: an open study and in vitro investigation. J Dermatol Sci. 2002;30:129–35.
  1. Sigurdsson V, Knulst AC, vanWeelden H. Phototherapy of acne vulgaris with visible light. Dermatology. 1997;194:256–60.
  1. Mills OH, Kligman AM. Ultraviolet phototherapy and photochemotherapy of acne vulgaris. Arch Dermatol. 1978;114:221–3.
  1. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol. 2003;139:897–900.
  1. Lee SW, Tsou AP, Chan H, Thomas J, Petrie K, Eugui EM, et al. Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA. Proc Natl Acad Sci U S A. 1988;85:1204–8.
  1. O'Sullivan RL, Lipper G, Lerner EA. The neuro-immuno-cutaneous-endocrine network: relationship of mind and skin. Arch Dermatol. 1998;134:1431–5.
  1. Stoughton RB, Leyden JJ. Efficacy of 4 percent chlorhexidine gluconate skin cleanser in the treatment of acne vulgaris. Cutis. 1987;39:551–3.
  1. Millikan LE. A double-blind study of Betadine skin cleanser in acne vulgaris. Cutis. 1976;17:394–8.
  1. Choi JM, Lew VK, Kimball AB. A single-blinded, randomized, controlled clinical trial evaluating the effect of face washing on acne vulgaris. Pediatr Dermatol. 2006;23:421–7.
  1. Aksu AE, Metintas S, Saracoglu ZN, Gurel G, Sabuncu I, Arikan I, et al. Acne: prevalence and relationship with dietary habits in Eskisehir, Turkey. J Eur Acad Dermatol Venereol. 2012;26:1503–9.
  1. Korting HC, Ponce-Pöschl E, Klövekorn W, Schmötzer G, Arens-Corell M, Braun-Falco O. The influence of the regular use of a soap or an acidic syndet bar on pre-acne. Infection. 1995;23:89–93.
  1. Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ. Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo. Am J Pathol. 2005;166:1691–9.
  1. Do TT, Zarkhin S, Orringer JS, Nemeth S, Hamilton T, Sachs D, Voorhees JJ, Kang S. Computer-assisted alignment and tracking of acne lesions indicate that most inflammatory lesions arise from comedones and de novo. J Am Acad Dermatol. 2008;58:603–8.
  1. Makrantonaki E, Ganceviciene R, Zouboulis C. An update on the role of the sebaceous gland in the pathogenesis of acne. Dermatoendocrinol. 2011;3:41–9.