Clinical Implications
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Acne vaccination would possibly circumvent the adverse effects of antibiotics and retinoids.
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Christie-Atkins-Munch-Peterson factor 2, a secreted virulence factor from Propionibacterium acnes, can induce inflammatory responses.
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The targeting of Christie-Atkins-Munch-Peterson factor 2 in a vaccination approach could inhibit P. acnes pathogenicity as evidenced by the anti-inflammatory properties of antibodies to this virulence factor.
Acne vulgaris is a disease of the pilosebaceous unit featuring increased sebum production, altered follicular keratinization, inflammation, and colonization of the pilosebaceous unit by the skin commensal
Propionibacterium acnes. This multifactorial cutaneous inflammatory condition affects more than 85% of adolescents and 73% of adults to varying degrees. It is estimated to be moderate to severe in around 20% of adolescents. Acne develops in sebum-rich regions, and the face is particularly affected. It is therefore difficult to dissimulate and frequently impairs the self-esteem of affected individuals especially during adolescence—a period of important physical, emotional, and social development. Acne lesions and/or scars may persist in adults. Even though acne is not a life-threatening disease, the psychological burden of acne is potentially high and underestimated. A recent study revealed that acne negatively impacts the quality of life of 90% of patients (
Lukaviciute et al., 2017xLukaviciute et al., 2017Lukaviciute, L., Navickas, P., Navickas, A., Grigaitiene, J., Ganceviciene, R., and Zouboulis, C.C. Quality of life, anxiety prevalence, depression symptomatology and suicidal ideation among acne patients in Lithuania. J Eur Acad Dermatol Venereol. 2017;
31: 1900–1906
Crossref | PubMed | Scopus (2) | Google ScholarSee all ReferencesLukaviciute et al., 2017). Of note, more than a half of patients suffering from acne show severe emotional disorders including anxiety, the most prevalent sign (
Lukaviciute et al., 2017xLukaviciute et al., 2017Lukaviciute, L., Navickas, P., Navickas, A., Grigaitiene, J., Ganceviciene, R., and Zouboulis, C.C. Quality of life, anxiety prevalence, depression symptomatology and suicidal ideation among acne patients in Lithuania. J Eur Acad Dermatol Venereol. 2017;
31: 1900–1906
Crossref | PubMed | Scopus (2) | Google ScholarSee all ReferencesLukaviciute et al., 2017), depression, and marked emotional distress that can be accompanied by suicidal ideation. Acne patients, especially those with the most severe forms, are in need of effective and safe treatments.
Current therapeutic options for acne include topical or systemic retinoids and antibiotics. Unfortunately, side effects associated with the use of these medications are numerous and range from skin dryness and irritation to depression and suicidal thoughts. Wang et al. (2018)xWang et al., 2018Wang, Y., Hata, T.R., Tong, Y.L., Kao, M.S., Zouboulis, C.C., Gallo, R.L. et al. The anti-inflammatory activities of Propionibacterium acnes CAMP factor-targeted acne vaccines. J Invest Dermatol. 2018;
138 ()
Google ScholarSee all References)Wang et al. (2018) describe a vaccine aimed at diminishing P. acnes colonization and inflammatory properties by targeting Christie-Atkins-Munch-Peterson (CAMP) factor. The authors show that antibodies to CAMP factor decrease the inflammatory response to P. acnes in mice and ex vivo in human acne explants. The resulting reduction in inflammation is accompanied by decreased MIP-2 (a murine neutrophil chemoattractant) levels in mice, and decreased IL-8 and IL-1β in a human explant model. These findings support P. acnes CAMP factor as a promising target for acne immunotherapy. P. acnes is a skin flora bacterium that colonizes sebum-rich regions of the human skin and preferentially accumulates in pilosebaceous units in both acne sufferers and healthy individuals. This commensal has been shown to comprise several evolutionary lineages, designated as IA1, IA2, IB, IC, II, and III. P. acnes strains are suspected to have opposing pathogenic/protective properties (Fitz-Gibbon et al., 2013xFitz-Gibbon et al., 2013Fitz-Gibbon, S., Tomida, S., Chiu, B.H., Nguyen, L., Du, C., Liu, M. et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol. 2013;
133: 2152–2160
Abstract | Full Text | Full Text PDF | PubMed | Scopus (177) | Google ScholarSee all ReferencesFitz-Gibbon et al., 2013). P. acnes phylotypes IA-2, IB-1, and IC are strongly associated with acne, whereas phylotypes IB-3, II, and III are associated with other tissue infections.
P. acnes phylotypes are also characterized by variations in the expression of pathogenic factors such as neuraminidase, lipase, and CAMP factor (McDowell et al., 2013xMcDowell et al., 2013McDowell, A., Nagy, I., Magyari, M., Barnard, E., and Patrick, S. The opportunistic pathogen Propionibacterium acnes: insights into typing, human disease, clonal diversification and CAMP factor evolution. PLoS One. 2013;
8: e70897
Crossref | PubMed | Scopus (42) | Google ScholarSee all ReferencesMcDowell et al., 2013), possibly reflecting the pathogenic potential of the different phylotypes identified to date. CAMP is a secreted virulence factor considered to be crucial for P. acnes survival and pathogenicity. The genome of P. acnes contains five genes encoding five CAMP homologs including CAMP factor 2, a major active co-hemolytic factor of P. acnes. CAMP acts as a pore-forming toxin working in combination with factors derived from other bacteria such as sphingomyelinase derived from Staphylococcus aureus (Nakatsuji et al., 2011xNakatsuji et al., 2011Nakatsuji, T., Tang, D.C., Zhang, L., Gallo, R.L., and Huang, C.M. Propionibacterium acnes CAMP factor and host acid sphingomyelinase contribute to bacterial virulence: potential targets for inflammatory acne treatment. PLoS One. 2011;
6: e14797
Crossref | PubMed | Scopus (50) | Google ScholarSee all ReferencesNakatsuji et al., 2011). Of note, the high conserved nature of camp genes favors the possibility of important roles for CAMPs in the life of P. acnes.
Although P. acnes is suspected to be pathogenic in acne and other diseases such as medical device-related infections or prostate cancer, this commensal is also crucial for skin homeostasis. Given the variety of P. acnes groups with proposed opposing effects (protective vs. pathogenic), it is important to develop specific therapies to rebalance the skin flora and not cause further dysbiosis. Indeed, equilibrium and dialog between organisms that comprise the microbiome, and the microbiome and host, are essential for maintenance of healthy skin. In healthy skin, Staphylococcus epidermidis limits P. acnes-induced inflammation through the release of succinic acid. In turn, P. acnes plays an essential role in skin homeostasis by preventing invasion from other pathogens, notably by limiting the proliferation of S. aureus and Streptococcus pyogenes by hydrolyzing lipids present in the sebum and maintaining a low pH in the environment (Shu et al., 2013xShu et al., 2013Shu, M., Wang, Y., Yu, J., Kuo, S., Coda, A., Jiang, Y. et al. Fermentation of Propionibacterium acnes, a commensal bacterium in the human skin microbiome, as skin probiotics against methicillin-resistant Staphylococcus aureus. PLoS One. 2013;
8: e55380
Crossref | PubMed | Scopus (59) | Google ScholarSee all ReferencesShu et al., 2013). Moreover, a recent report showed that specific P. acnes phylotypes might exert some protective effect, notably by shaping skin T helper type 17 cell responses and immunomodulatory IL-10 (Agak et al., 2018xAgak et al., 2018Agak, G.W., Kao, S., Ouyang, K., Qin, M., Moon, D., Butt, A. et al. Phenotype and antimicrobial activity of Th17 cells induced by Propionibacterium acnes strains associated with healthy and acne skin. J Invest Dermatol. 2018;
138: 316–324
Abstract | Full Text | Full Text PDF | PubMed | Scopus (3) | Google ScholarSee all ReferencesAgak et al., 2018). It is also thought that, in contrast to what was previously believed, acne might result from the preferential proliferation of one or few phylotypes as a result of sebum overproduction rather than from the proliferation of all acne strains, because P. acnes is not more abundant in acne sufferers than healthy individuals.
The strong inflammatory properties of P. acnes, mediated by Pattern Recognition Receptors, are now well documented and are further supported by the demonstration by Wang et al. (2018)xWang et al., 2018Wang, Y., Hata, T.R., Tong, Y.L., Kao, M.S., Zouboulis, C.C., Gallo, R.L. et al. The anti-inflammatory activities of Propionibacterium acnes CAMP factor-targeted acne vaccines. J Invest Dermatol. 2018;
138 ()
Google ScholarSee all References)Wang et al. (2018), using a vaccine-based approach, that shows that CAMP factor 2 is essential for P. acnes-induced inflammation. This is an important observation because CAMP factor had not been previously implicated in the pathogenesis of acne vulgaris.
Acne vaccination targeting virulence factors such as CAMP from pathogenic P. acnes strains would circumvent the lack of specificity, generation of resistant bacterial strains, and possible associated side effects of antibiotics. The choice of the antigen to be targeted is obviously critical not only as a determinant of the efficacy of the vaccine, but also to minimize possible off-target effects or cross-reactivity impairing the microbiota equilibrium and subsequent skin barrier homeostasis. In addition, immunotherapy candidate targets should not be subject to positive selection. Indeed, selection-driven generation of variable epitopes might impair the efficacy of the therapeutic approach. It has been demonstrated that the gene encoding CAMP factor 2 (camp2) evolved like housekeeping genes with camp2 sequences displaying no evidence of selection and very low rates of recombination (McDowell et al., 2013xMcDowell et al., 2013McDowell, A., Nagy, I., Magyari, M., Barnard, E., and Patrick, S. The opportunistic pathogen Propionibacterium acnes: insights into typing, human disease, clonal diversification and CAMP factor evolution. PLoS One. 2013;
8: e70897
Crossref | PubMed | Scopus (42) | Google ScholarSee all ReferencesMcDowell et al., 2013). These observations support the limited risk of positive selection by targeting CAMP factor 2 in acne immunotherapy. To date, the relationships of CAMP expression levels to the pathogenicities of individual P. acnes phylotypes remain incompletely characterized. However, CAMP factor 1 has been shown to be more abundantly expressed by phylotype II P. acnes than phylotype IA (Valanne et al., 2005xValanne et al., 2005Valanne, S., McDowell, A., Ramage, G., Tunney, M.M., Einarsson, G.G., O'Hagan, S. et al. CAMP factor homologues in Propionibacterium acnes: a new protein family differentially expressed by types I and II. Microbiology. 2005;
151: 1369–1379
Crossref | PubMed | Scopus (78) | Google ScholarSee all ReferencesValanne et al., 2005), and, although the expression levels were dramatically lower than CAMP factor 1, higher expression of CAMP 2 was detected in phylotype IA, suspected to be associated with severe acne, as compared with phylotype II.
It has been suggested that, because camp2 is expressed by all strains including strains associated with healthy skin, camp2 might be important not only for bacteria pathogenicity but also for the normal existence of the commensal. Whether CAMP factors including CAMP 2 are crucial to the survival of P. acnes on human skin remains to be demonstrated, but if this is the case, targeting CAMP 2 via vaccination may also affect P. acnes groups involved in the preservation of skin homeostasis by favoring colonization by more pathogens. Also, ideal immunotherapy targets should be highly specific to avoid unwanted side effects due to the elimination of important bacteria. Of note, P. acnes comprises several phylotypes with different phenotype and pathological properties. Recent developments in microbiota composition analyses led to a classification of bacteria phylotypes of increasing complexity, and the respective representation of the different phylotypes/ribotypes in acne of variable severity appears sometimes to be contradictory. It is currently thought that P. acnes phylotype IA is strongly associated with acne, whereas the phylotype II is associated with healthy skin (Fitz-Gibbon et al., 2013xFitz-Gibbon et al., 2013Fitz-Gibbon, S., Tomida, S., Chiu, B.H., Nguyen, L., Du, C., Liu, M. et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol. 2013;
133: 2152–2160
Abstract | Full Text | Full Text PDF | PubMed | Scopus (177) | Google ScholarSee all References, McDowell et al., 2013xMcDowell et al., 2013McDowell, A., Nagy, I., Magyari, M., Barnard, E., and Patrick, S. The opportunistic pathogen Propionibacterium acnes: insights into typing, human disease, clonal diversification and CAMP factor evolution. PLoS One. 2013;
8: e70897
Crossref | PubMed | Scopus (42) | Google ScholarSee all References). However, a recent study was not able to demonstrate a clear link between P. acnes phylotypes and acne severity (Paugam et al., 2017xPaugam et al., 2017Paugam, C., Corvec, S., Saint-Jean, M., Le Moigne, M., Khammari, A., Boisrobert, A. et al. Propionibacterium acnes phylotypes and acne severity: an observational prospective study. J Eur Acad Dermatol Venereol. 2017;
31 ()
Crossref | PubMed | Scopus (6) | Google ScholarSee all ReferencesPaugam et al., 2017), which would be rather dependent on the basal level of active innate immunity in patients prone to severe acne (Saint-Jean et al., 2016xSaint-Jean et al., 2016Saint-Jean, M., Khammari, A., Jasson, F., Nguyen, J.M., and Dreno, B. Different cutaneous innate immunity profiles in acne patients with and without atrophic scars. Eur J Dermatol. 2016;
26: 68–74
PubMed | Google ScholarSee all ReferencesSaint-Jean et al., 2016). If the hypothesis that acne severity is driven by the patient’s basal innate immune condition rather than by the P. acne virulence level is true, it might have consequences on the design of immunotherapy protocols, especially on the choice of the target antigen. The specific inhibition of secreted virulence factors should limit the risk of unwanted targeting of nonpathogenic bacteria and overcome a possible selection of resistant bacteria. Therefore, the approach involving inhibition of secreted CAMP proposed by Wang et al. (2018)xWang et al., 2018Wang, Y., Hata, T.R., Tong, Y.L., Kao, M.S., Zouboulis, C.C., Gallo, R.L. et al. The anti-inflammatory activities of Propionibacterium acnes CAMP factor-targeted acne vaccines. J Invest Dermatol. 2018;
138 ()
Google ScholarSee all References)Wang et al. (2018) should circumvent such pitfalls and might be safer than the use of killed P. acnes or the targeting of a surface antigen as previously reported by this same group.
In conclusion, while addressing an unmet medical need and providing an appealing approach, acne immunotherapies that target P. acnes-derived factors have to be cautiously designed to avoid unwanted disturbance of the microbiome that guarantees skin homeostasis. Whether or not CAMP-factor-targeted vaccines will impact multiple P. acnes subtypes and other commensals has to be determined, but acne immunotherapy presents an interesting avenue to explore nonetheless.
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