Webinar p acnes


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p. Acnes plays more of a pathogenic role in the development of acne then previously thought. In this webinar you will learn more about how specifically p.Acnes helps to form the microcomedone. Why fruit acids work with acne....and it's not the reason you think it is.

Why some companies treat all acne the same and why this is successful.

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Webinar p acnes

  1. 1. Propionibacterium acnes has a major role in the development of acne lesions. Antibiotic therapy directed against p. acnes has been a mainstay treatment for over 30 years. Resistance was not seen though until the early 1980’s. Molecular Basis for p.acnes Resistance In general bacteria develop antibiotic resistance by acquiring genetic elements such as plasmids, which can be transferred between strains of a species and even between species in some instances. With tetracyclines and erythromycin, mobile plasmids and transposons encode for pump proteins that efflux antibiotics away from ribosomes. Types of p.Acnes Two main P. acnes classification systems are described in the literature: The first is based on gene sequences and identifies two phenotypes (Type I and II). The proportion of P. acnes Types I and II in different situations suggest that different P. acnes clones may have different biological activities with different clinical consequences. Of those, a certain number were associated with moderate to severe acne whereas others were considered related to other skin infections or simply to healthy skin conditions. P. acnes type I was isolated from the majority of acne lesions in one study, favouring the hypothesis that a specific P. acnes phenotype might be more common in acne patients. They also found a subdivision of group I (I-1) to be significantly associated with moderate to severe acne A second classification system is based on biological characteristics. There is a correlation between the severity of acne and lipase activity. Among the five P. acnes biotypes identified, P. acnes B3, corresponding to Type I, predominates in isolates from more severe acne. It produces higher quantities of propionic and butyric acids than other P. acnes biotypes. This suggests that different P. acnes strains may have different proinflammatory profiles and hence the ability to modulate differently the innate immunity. Hence, profiles of skin microbiomes and more specifically that of P. acnes strains may differ between mild, moderate and severe acne and obviously for non-acneic skin. Therefore, and according to the evolutionary lineages of P. acnes in the follicle, a certain number of teenagers may develop mild acne, whereas other may develop moderate, severe or even no acne. This confirms the hypothesis that pathogenic vs. truly commensal lineages of P. acnes exist resulting in important therapeutic and diagnostic considerations p.Acnes and Comedones P. acnes has been isolated from comedones. Interleukin 1 (IL-1) promotes comedone formation and P. acnes produced IL-1 and stimulated IL-1 secretion by keratinocytes participating in the comedone formation.
  2. 2. So what are some of the mechanisms that p.Acnes can induce comedone formation? Biofilms and p.Acnes Most microorganisms exist in nature not as plankton nor as free-floating microorganisms in suspension, but as biofilms. The production of extracellular polysaccharide is essential for development of the architecture of any biofilm matrix. While classic examples include dental plaques, and infections on implanted prosthetic devices and urinary catheters, biofilms occur in dermatologic conditions as well. By definition, biofilms are composed of populations (or communities) of bacteria that adhere to environmental surfaces, such as the pilosebaceous lining. These microorganisms encase themselves in an extracellular polysaccharide, which they secrete after adherence to a surface. The extracellular matrix usually comprises two-thirds of the biofilm mass, and is composed of polysaccharides, water, extracellular DNA, and excreted cellular products. Propionibacterium acnes reside within the pilosebaceous unit in a biofilm. This gylcocalyx polymer acts as a protective exoskeleton and serves as a physical barrier, limiting effective antimicrobial concentrations within the biofilm microenvironment. Bacteria in the protected microenvironment of a biofilm are 50 to 500 times more resistant to antibacterial therapies. Biofilm formation is a process during which microorganisms irreversibly attach to and grow on a surface and produce extracellular polymers facilitating adherence and matrix formation. This process results in an alteration of the phenotype of the organisms with respect to their growth rate and gene transcription. The biofilm created by P. acnes contributes to the forming of an adhesive glue leading to the binding of corneocytes resulting in microcomedones The P. acnes’ biofilm model explains many aspects of acne pathogenesis and therapy, including why prolonged antibiotic treatment is needed. Biofilm infections tend to be persistent. The P. acnes biofilm can explain why antibiotics are often used for numerous months in treating acne, whereas much shorter courses are utilized for standard bacterial infections. In short, P. acnes reveal great tolerance to even high concentrations of antibiotics as a result of its existence in a biofilm matrix. Resistance within the biofilms may relate to delayed penetration of antimicrobial agents into the biofilm polysaccharide matrix, the slow growth rate of organisms within the biofilms, and the phenotypes of bacteria expressed within the biofilms that are distinct from planktonic cells. Typically a wide range of enzymatic activities by bacteria can be found within a biofilm. In the case of P. acnes , the organism secretes an array of
  3. 3. extracellular products, including hyaluronidase, proteases, lipases, and chemotactic factors for neutrophils, lymphocytes, and macrophages. The Furthermore, P.acnes is not pathogenic by normal standards because there is no correlation between the number of bacteria and severity and type of acne. Nevertheless, P. acnes is the target of oral and topical antibiotic usage possibly because of its affect on the P. acnes biofilm. In terms of antibiotics, minocycline is more fat-soluble than other antimicrobials and achieves high therapeutic success, which might be explained by means of this biofilm concept. Indeed, tetracycline-derivatives proved to have the highest synergistic effect when used in combination with another antibiotic when investigated in biofilms. Ideally, acne agents would alter the physicochemical environment of the pilosebaceous unit in which P. acnes live. 30 mM azelaic acid, 2.5% or 5% benzoyl peroxide does not result in a significantly decreased biofilm. Benzoyl peroxide alone had no effect on P. acnes biofilms. p.Acnes stimulates the production of Sebum P. acnes increases the production of sebum. P. acnes stimulates the sebaceous glands and sebum synthesis via the corticotropin-releasing hormone/CRH-receptor (CRH/CRH-R) system increasing the lipogenic activity of human sebocytes. An increase in CRH/CRH-R1 expression was observed in the sebaceous glands of acne patients and in that of healthy individuals. It also stimulates in a similar manner the sebum production through the IGF/IGF-R pathway present in sebocytes. p.Acnes and IGF-1 IGF-1 stimulates the proliferation of keratinocytes via an activation of the IGF1 receptor (IGF-1R). Recent studies describe a correlation between IGF-1 serum levels and the severity of acne in women. IGF-1 serum levels also correlate directly with the amount of facial sebum in both men and women. In the skin, IGF-1 induces keratinocyte proliferation and it induces lipid production in human sebocytes. In acne biopsies there is a strong expression of IGF-1 and IGF-1R in the epidermis as compared with healthy skin. In addition, Ki-67 expression was strongly increased in the basal layer of the epidermis of acne lesions as compared with healthy skin. In comparison with healthy skin, in which filaggrin expression is located only in the stratum corneum, among the acne lesions, we observed expression in the stratum corneum and the suprabasal layers of the epidermis.
  4. 4. P. acnes has been shown to stimulate IGF-1 and IGF-1R expression in keratinocytes and increases IGF-1 secretion. IGF-1 and IGF-1R are over expressed in both acne lesions and subsequently have an Ki-67 and filaggrin expression in the epidermis, confirming that the IGF-1/IGF-1R system is associated with the modulation of both proliferation and differentiation of keratinocytes. It was previously noted that Ki-67 expression is higher in acne patients’ epidermis than in normal healthy skin. So differentiation of keratinocytes is modulated by P. acnes through an induction of filaggrin and integrin expression. P. acnes has a significant role in the formation of comedones and that one of the mechanisms is the IGF1/IGF-1R pathway. P. acnes acts not only in the inflammatory step of acne pathogenesis but also in the retentional stage. p.Acnes and Cytokines P. acnes also induces the activation of Toll-like receptors-2 and -4 in keratinocytes. Inflammation resulted from the immune response targeting p. acnes plays a significant role in the pathogenesis of acne vulgaris. P. acnes induces IL-12 and IL-8 protein production by primary human monocytes via a Tolllike receptor 2 (TLR2)-regulated pathway and that TLR2 is expressed on the cell surface of macrophages surrounding pilosebaceous follicles of acne lesions. TLR2 is also expressed in human keratinocytes and sebocytes. TLR2 and TLR4 expression was increased in the epidermis of acne lesions, and P. acnes was found to induce TLR expression in human keratinocytes. The major difference is the ability of P. acnes and its products to induce human B-defensin-2 (hBD2) expression in keratinocytes and sebocytes, which may simulate immune cells by virtue of pathogen recognition and abnormal sebum lipid production, followed by inflammatory cytokine production. p.Acnes and FFA After colonization, P. acnes can potentiate comedogenesis by various mechanisms. It is known that P. acnes produces lipases which hydrolyse triglycerides, thereby releasing FFAs. These FFAs have been found to be irritant and contribute significantly to inflammation. FFA have been found to be comedogenic in the rabbit ear model. In addition, the lipase itself can act as a neutrophil attractant. FFA increase the adhesion of P. acnes cells and promote colonization of the sebaceous follicle.
  5. 5. Oxidized squalene is another substance that has been found to be comedogenic in the rabbit ear model. P. acnes, through its production of porphyrins, may act as a catalytic agent in the oxidation of squalene. This, along with the fact that keratinocytes stimulated by P. acnes have been shown to produce significantly more IL-1a compared with unstimulated keratinocytes, might signify other potential pathways through which P. acnes may be involved in comedogenesis. p.Acnes and Aberrant Integrin Expression Integrins play an important role in the modulation of both differentiation and proliferation of keratinocytes in the epidermis. Thus abnormal keratinocyte differentiation induces alterations of the expression of b1, a3, a6 integrins. Interestingly, on biopsies of acne lesions, it has been demonstrated that the alteration of keratinocytes differentiation is associated with abnormal integrins expression. Filaggrin is a cationic (basic) protein named for its ability to aggregate filaments of keratin into fibers. Filaggrin is synthesized in the granular cells of the epidermis as a large, highly phosphorylated precursor, profilaggrin, which accumulates in the keratohyalin granules. A number of keratinization disorders are associated with dysregulation in the formation of keratohyalin granules and in the processing of profilaggrin. Seborrhoeic and acne skin revealed considerable amounts of filaggrin in the intermediate layers of the sebaceous duct and the infundibulum indicating a premature terminal keratinization process in these areas. Furthermore it has been observed in studies an increased number of keratohyaline granules in acne skin. P. acnes extracts modulate the expression of b1 integrin and filaggrin. Thus the induction of b1 integrin by P. acnes, by modulating the proliferation of keratinocytes can play a role in the formation of micro-comedon. Concerning a3 and a6 integrins, acne patients have shown an aberrant a2 and a3 integrins expression around comedones and uninvolved pilosebaceous follicles from acne lesions. Thus, these results suggest that P. acnes modulates the terminal phase of differentiation of keratinocytes P. acnes induce B1 integrin expression significantly on both proliferating keratinocytes and differentiated keratinocytes. In addition, P. acnes induces a3, a6 and aVB6 integrin expression and fillaggrin expression on differentiated keratinocytes. P. acnes extracts increase fillaggrin expression in the suprabasal layer of the epidermis. P. acnes are directly able to modulate the differentiation of keratinocytes suggesting that this bacteria plays a role not only in the development of inflammatory acne lesions but also in the formation of the microcomedo.
  6. 6. Follicular keratinocytes fail to differentiate by apoptosis and produce hypergranulosis similar to the impermeable skin outer layer, resulting in the formation of microcomedones. Further inflammatory responses lead to the development of increasing degrees of severity in inflammatory forms of acne. p.Acnes and ROS P. acnes can lead to the formation of reactive oxygen species, especially superoxide anions, by keratinocytes. These may be other potential mechanisms explaining the involvement of P. acnes in inflammatory acne. Last but not least, P. acnes can also exaggerate inflammation in acne by the induction and activation of toll like receptors 2 and 4. P. acnes secretes lipases, chemotactic factors, metalloproteases and porphyrins. All interact with molecular oxygen generating toxic, reduced oxygen species and free radicals causing keratinocyte damage. P. acnes interacts with markers of the innate immunity, such as toll-like receptors (TLR), antimicrobial peptides (AMP), protease- activated receptors, inflammatory, protease-activated receptors (PAR) and the matrix metalloproteinase (MMP). TLRs are transmembrane receptors of the innate immunity system, detecting the invasion by exogenous pathogens. In patients with acne, TLR-2 and TLR4 are overexpressed in the superficial layers of the epidermis. P. acnes stimulate the expression of TLR-2 and TLR-4 by keratinocytes as well as of TLR-2 by macrophages. Inhibition of the expression of TLR-2 is associated with a reduced ability of the microorganism to stimulate keratinocyte synthesis of IL-8 and human monocytes production of IL-8 and IL-12. TLR2 may provide a novel target for the treatment of this common skin disease. P. acnes upregulates the secretion of different proinflammatory cytokines (IL1a, IL-1b, IL-6, IL-8, IL-12, IL-17, TNF-a or granulocyte macrophage colony stimulating factor) by human keratinocytes, sebocytes or macrophages and strongly activates the inflammasome of human peripheral neutrophils. p.Acnes and MMP’s P. acnes induces MMP-9 expression in human keratinocytes. P. acnes stimulates MMP-2 expression through tumour necrosis factor alpha in dermal fibroblasts whereas doxycycline inhibits the expression of MMP-2 induced by P. acnes. The proliferation of P. acnes in acne lesions induces an increase in MMP secretion enhancing the rupture of the follicle and the spread of the inflammation in the dermis. p.Acnes and Inflammation
  7. 7. In particular, IL-8 along with other P. acnes -induced chemotactic factors may play an important role in attracting neutrophils to the pilosebaceous unit. In addition, P. acnes releases lipases, proteases and hyaluronidases which contribute to tissue injury. P. acnes triggers inflammatory cytokine responses in acne by activation of TLR2. As such, New Research in 2014 has shown P. acnes contributes to the inflammatory response seen in acne by triggering the activation of the NLRP3- inflammasome in antigen presenting cells (APCs), subsequently leading to enhanced IL-1b secretion. The inflammasome is a cytoplasmic molecular complex that can rapidly initiate inflammation upon sensing pathogen- and danger-associated molecular patterns (PAMPs/DAMPs) by regulating the secretion of caspase-1 activationdependent cytokines including IL-1b. Inflammasome deficiency or IL-1b blockade prevents P. acnes-induced inflammatory responses. Several human diseases are associated with the activation of inflammasomes. Such findings suggest that molecules targeting IL-1b and/or the NLRP3 inflammasome may constitute new treatment possibilities for acne vulgaris. References: Propionibacterium acnes Activates the IGF-1/IGF-1R System in the Epidermis and Induces Keratinocyte Proliferation Isard, Knol, Arie`s, Nguyen, Khammari, Castex-Rizzi and Dre´ Journal of Investigative Dermatology (2011) 131, 59–66; Investigation on mouse model for acne vulgaris-like lesions: The role of inflammation induced by P. acnes Lee, Kim, Lee, Sub Lee, Hyuk Choi, Son, Jung, Sohn, Jang, Lee, Kim Department of Dermatology, Kyungpook National University School of Medicine, Daegu, Republic of Korea Propionibacterium acnes and Sebaceous Lipogenesis: A Love–Hate Relationship? Zouboulis. Journal of Investigative Dermatology (2009), Volume 129 pp2093-2095. ‘‘Acne biofilms,’’ temperature, and microenvironments” J AM ACAD DERMATOLogy JANUARY 2005 pp 182. Acne sans P. acnes B. Shaheen,* M. Gonzalez
  8. 8. Journal of the European Academy of Dermatology and Venereology 2013, 27, 1–10 Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors. Coenye, Peeters, and Nelis. Research in Microbiology 158 (2007) 386-392. Microbiology’s principle of biofilms as a major factor in the pathogenesis of acne vulgaris Burkhart and Burkhart International Journal of Dermatology 2003, 42, 925–927 An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case–control study. Jahns, Lundskog, Ganceviciene, Palmer, Golovleva, Zouboulis, McDowell, Patrick and Alexeyev BJD _ 2012 British Association of Dermatologists 2012 167, pp50–58 Propionibacterium acnes: an update on its role in the pathogenesis of acne Beylot, Auffret, Poli, Claudel, Leccia, Del Giudice, Dreno. July 2013 European Academy of Dermatology and Venereology Review of the Innate Immune Response in Acne vulgaris: Activation of Toll-Like Receptor 2 in Acne Triggers Infl ammatory Cytokine Responses. Kim. Dermatology 2005;211:193–198 Propionibacterium acnes Resistance: A Worldwide Problem Eady, E A;Gloor, M;Leyden, J J Dermatology; 2003; 206, 1; New Insights into Acne Pathogenesis: Propionibacterium Acnes Activates the Inflammasome. Contassot and French. Journal of Investigative Dermatology (2014) 134, 310–313. Natural compounds as inflammation inhibitors Schumacher, Junckerm, Schnekenburger, Gaascht and Diederich. Genes Nutr (2011) 6:89–92 Modulation of integrins and Fillaggrin expression by Propionibacterium acnes extracts on keratinocytes. Jarrousse, Castex-Rizzi, Khammari, Charveron and Dréno. Arch Dermatol Res (2007) 299:441–447 Current Concepts of the Pathogenesis of Acne Implications for Drug Treatment Harald Gollnick
  9. 9. Drugs 2003; 63 (15): 1579-1596