Have you ever had a pimple and wondered what your immune system was doing beneath your skin? Most of us have had some degree of acne during our lives, be it the occasional pimple or a full-blown “break out”. Indeed, acne is a globally occurring phenomenon; the Global Burden of Disease project estimates that 9 percent of the global population has clinically-defined acne, with the North American prevalence ranging from 23 to 37 percent. Moreover, if these measures were to include the occurrence of common acne, the numbers would skyrocket. Given the widespread prevalence of acne and the equally widespread desire to avoid it, it seems prudent to delve further into its pathogenesis and treatment.

So what is the immunology of acne? To answer this question, a basic understanding of dermatology is required (Fig. 1). Our so called “pores” are more properly termed hair follicles, tissue structures in the skin involved in the production and maintenance of hair. A major function of the hair follicle is to produce sebum — a lipid composed of triglycerides, wax, and free fatty acids — that coats the skin. The sebum layer not only traps moisture, maintaining skin elasticity, but also forms a protective coating that impedes bacterial penetration. Unfortunately, this protection does not extend to bacteria that have already colonized the skin such as Propionibacterium acnes (P. acnes), commensal, anaerobic gram-positive bacteria that reside deep within the hair follicle and utilize sebum as a food source. In individuals with acne, elevated sebum production drives the proliferation of this bacteria, inducing an inflammatory immune response that produces the morphological pimple. A key player in this excessive sebum production is the insulin-like growth factor 1 (IGF-1), which binds to cognate receptors on sebocytes to promote their proliferation and lipid production. IGF-1 serum levels are elevated during puberty (acne and puberty onset are highly correlated) and as a result of western diet (high glycemic load). It has been hypothesized that acne is less common in children and older adults due to lower levels of serum IGF-1. In support of this, people with Laron syndrome who completely lack IGF-1 and do not have acne may develop it only after receiving exogenous IGF-1 therapy, underscoring the importance of IGF-1 in acne pathogenesis.

ROLE OF THE IMMUNE RESPONSE IN ACNE

The major morphological changes associated with acne, such as the formation of a whitehead filled with pus, are caused by the immune response against P. acnes. The innate immune toll-like receptor 2 (TLR2) expressed on cells near the surface of the skin has been shown to activate in response to P. acnes, inducing the secretion of pro-inflammatory cytokines such as tumour necrosis factor alpha and interleukin 8 (IL-8). These cytokines act as chemoattractants for neutrophils and macrophages, which migrate to and kill the growing bacteria. Biopsies of inflammatory acne lesions demonstrate high levels of TLR2-expressing immune cells relative to normal skin biopsies, as well as TLR2-dependent increases in the expression of matrix metalloproteases (MMPs) involved in inflammation and neutrophil function. The adaptive arm of the immune system also plays a role in the immune response to acne. Recent studies have demonstrated that P. acnes promotes a joint Th1 and Th17 response by inducing the secretion of IL-17 and interferon gamma. Acne patients have significantly higher levels of these T cell subsets in both their peripheral blood and in the acne lesions themselves; however, the importance of these subsets in acne pathogenesis is not yet well characterized.

If P. acnes is a commensal bacterium that is typically well-tolerated by the immune system, what causes it to become pathogenic? Recent studies have suggested that at high bacterial densities, P. acnes uses quorum sensing (QS) to upregulate lipases that generate free fatty acid ligands for TLR2 and TLR4. Moreover, QS is involved in the formation of P. acnes biofilms, extracellular matrices of polysaccharides, proteins, and DNA that can rupture the sebaceous gland and increase immunogenicity. In acne lesions, the P. acnes count can be up to 100-fold greater than in healthy controls, and the bacteria are more likely to be found in biofilms.

THERAPIES & PREVENTION

Current acne therapeutics are reasonably effective. Daily application of 5% benzoyl peroxide foam can decrease P. acnes density by half, and topical clindamycin, a protein synthesis-inhibiting antibiotic, is able to greatly reduce inflammatory lesions. Both therapies improve overall acne symptoms as measured by a global acne severity score, and a combination of the two is currently one of the first-line therapies for clinical acne. However, both treatments have their limitations (BOX 1); benzoyl peroxide is known to cause skin dryness and discomfort, while clindamycin induces antibiotic resistance. Given the role of TLR2 in acne pathogenesis, immunomodulatory therapies could represent a more effective and targeted approach. All trans retinoic acids such as isotretinoin (Accutane) have been shown to generate long-term remission by inducing sebocyte apoptosis, decreasing the expression of TLR2 and pro-inflammatory cytokines in monocytes and suppressing MMP production. Through similar mechanisms, topical retinoids (e.g. Retin-A) have also shown efficacy as acne therapeutics. Unfortunately, these therapies exhibit similar adverse effects including depleting healthy microbiota and inducing drug resistance, or extreme dryness and discomfort. It is clear that a greater understanding of P. acnes biology and host interaction is required to develop more targeted therapies.

Therapeutic acne vaccination has also been investigated as a potential treatment based on IgG deposition and IgG-bound bacteria in acne lesions. Mouse models of acne exist wherein intradermal injection of P. acnes into the ear induces an inflammation similar to clinical acne lesions in humans. Using this model, intranasal immunization with heat-inactivated P. acnes followed by intradermal challenge generated antibodies against two components of P. acnes, reduced ear swelling and erythema, and suppressed P. acnes-induced IL-8 secretion relative to PBS-immunized mice. Passive immunization against P. acnes virulence factors such as the hemolytic Christie-Atkins-Munch-Peterson (CAMP) factor have also been studied in mice. Intranasal administration of plant-derived CAMP-specific antibodies was able to suppress ear inflammation with similar potency as immunization with heat-killed P. acnes without affecting commensal P. acnes. These results suggest that passive or inactivated P. acnes vaccines could be used to suppress acne symptoms in humans. However, it is important to note that acne can often progress in patients despite the presence of P. acnes-specific antibodies. It remains to be determined whether this progression occurs because the antibodies do not target key virulence factors or because vaccination against P. acnes in humans is ineffective.

CONCLUSION

While the mechanisms driving the initial overgrowth of P. acnes are well characterized, the role of the immune response in supporting or exacerbating acne is unclear. TLR2 has been suggested to play an important role in acne pathogenesis by mediating inflammatory processes and accordingly, TLR2 antagonists such as isotretinoin have shown clinical efficacy. Immunotherapy involving immunization with heatkilled P. acnes or virulence factor-specific antibodies has also shown efficacy in mouse models, underscoring the importance of understanding the mechanisms by which P. acnes survives and subverts the immune response. To this end, genome sequencing of P. acnes has revealed several virulence factors (lipases, pore-forming factors, etc.) that might serve as candidate antibody targets for systematic investigation.

However, given that P. acnes can exist in a commensal manner, these targeted immune therapies could have their own adverse effects. Furthermore, it remains to be determined whether the immune response in acne is productive since multiple post-acne conditions such as post-inflammatory hyperpigmentation and scarring are linked to immune-driven dysfunction. Perhaps a different change in treatment paradigm is necessary: one that focuses on dietary interventions to reduce IGF-1 levels and attenuate excess sebum production. Such an approach is supported by the complete absence of acne seen in non-westernized tribal populations, presumably due to their low glycemic, neolithic diets. Thus, acne may be among the many other conditions that reflect our physiological inertia to the rapidly changing nutritional environment around us.

References:

. Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. J. Invest. Dermatol. 132, 2198–2205 (2012). 2. Dispenza, MC et al2198–2205 (2012).