Advances in the Understanding of the Pathogenesis of Inflammatory Acne

Acne vulgaris (AV) is a chronic inflammatory disease of the pilosebaceous unit, and it is the most pervasive skin disorder regardless of gender, skin color, or ethnicity.^1-3 For decades it was thought that AV lesions initially developed after abnormal desquamation of the keratinocytes that line the sebaceous follicle, creating hyperkeratinization and microcomedone formation.^4-6 The pathological process in AV was then facilitated by an increase in circulating androgens at the onset of puberty, which stimulated the production of sebum in the pilosebaceous unit.^4-6 The combination of hyperkeratinization and the increase in circulating androgens then created a milieu that was conducive for the colonization of Propionibacterium acnes, resulting in various inflammatory molecules and chemotactic factors that initiate and perpetuate inflammatory cascades.^4-6

However, a paradigm shift has occurred with regard to understanding the pathogenesis of AV. A seminal study demonstrating subclinical inflammatory cascades in AV was conducted by Norris and Cunliffe in 1988, and they observed lymphocytes and polymorphonuclear leukocytes prior to and concurrently with hyperkeratinization and microcomedone formation.⁷ Moreover, in 1998, Layton et al found that CD4+ lymphocytes and macrophages (CD68+) were the earliest immune cells to infiltrate sites of nascent, subclinical inflammatory AV lesions.⁸

In 2003, Jeremy et al published a landmark study regarding the pathogenesis of AV that produced a paradigm shift.⁹ The investigators biopsied clinically normal follicles from the uninvolved skin of AV patients, the nascent lesions from AV patients, and the skin of healthy controls. After the biopsies were performed, cellular, vascular, and proliferative markers for inflammation were evaluated from the 3 groups.

Jeremy et al found that although CD3+ and CD4+ T cells were elevated in the uninvolved skin of AV patients, the elevation of these cells was not equivalent to the elevation in the papules of AV patients. The number of macrophages in the uninvolved skin of AV patients was also significantly increased and comparable to those in the papules of AV patients. E-selectin, vascular adhesion molecule 1, and interleukin-1 (IL-1) levels were also upregulated in the uninvolved skin of AV patients. The investigators concluded that vascular endothelial cell activation and the involvement of inflammatory responses are integral to the earliest stages of AV lesion development, and occur during hyperkeratinization.

The study conducted by Jeremy et al played a crucial role in deconstructing the dogma that the pathogenesis of AV commences with hyperkeratinization and comedogenesis. A subsequent study conducted by Do et al provided additional evidence that AV is an inflammatory skin disorder instead of an hyperproliferative disorder of the sebaceous follicle.¹⁰ Using digital photographs and spatial alignment software, Do et al photographed 25 subjects with untreated facial AV every 2 weeks for 12 weeks. The investigators discovered that although 54% of inflammatory lesions were preceded by comedones, 28% of inflammatory lesions were preceded by normal-appearing skin. Consequently, Do et al further demonstrated that cellular inflammatory events occur at every stage of AV, from subclinical manifestations to the clinical presentation of active lesions.