Advances in the Understanding of the Pathogenesis of Inflammatory Acne

For example, TNF-α and IL-1β have been shown to up-regulate adhesion molecules ICAM-1 and VCAM-1 on endothelial cells.^19,20 Consequently, Kang et al hypothesized that ICAM-1, VCAM-1, and E-selectin expression levels on the luminal surface of endothelial cells are increased in inflammatory acne papules due to TNF-α and IL-1β induction.

In the wake of mounting evidence that AV is initially driven by abnormal, subclinical inflammatory responses and also after various biomarkers in the disease progression of AV have been identified, Trivedi et al performed gene expression profiling of acne patients.²¹ Skin biopsies were obtained from an inflammatory papule and from the normal skin of 6 patients with AV, as well as from the normal skin of 6 subjects without AV. The biopsies demonstrated that 211 genes were upregulated in the lesional skin of AV subjects compared with the non-lesional skin of AV subjects and healthy controls.

Trivedi et al found that a significant proportion of upregulated genes are involved in pathways that regulate inflammation and initiate inflammatory cascades. The upregulated genes included MMP-1, MMP-3, IL-8, human beta-defensin 4, and granzyme B. The investigators concluded that matrix metalloproteinases, inflammatory cytokines, and antimicrobial peptides play a salient role in AV lesions.

Although the Trivedi et al gene expression profiling of acne patients established that multiple inflammatory cascades were involved in the pathogenesis of AV, the investigators observed that the normal skin of AV patients did not elicit the plethora of up-regulated genes as biopsied lesional skin. In fact, there were no gene expression differences between the normal skin of subjects with AV patients and without AV in the array analysis. These results were most likely due to the nominal inflammation involved in the small, 5 mm biopsies that were taken from the AV patients.

In addition to cellular inflammatory mechanisms playing a role from subclinical comedogenesis to the clinical presentation of active lesions, research has shown that cellular inflammatory mechanisms are involved in AV resolution and scarring. Lee et al conducted a histopathological analysis of atrophic acne scars from AV patients, and found cellular infiltrates from transforming growth factor-β, (MMP-1), MMP-2, MMP-9, and MMP-13 in 77% of the scars.²²

In an effort to differentiate the cell-mediated immune responses in patients who were prone to AV scarring vs AV patients who were not prone to AV scarring, Holland et al investigated various cellular and vascular biomarkers from the biopsies of inflamed lesions on the backs of AV patients.²³ The lesions were 6 hours to 7 days in duration.

Holland et al observed that patients who did not have AV scarring had an effuse influx of CD4+ T cells, macrophages, and Langerhans cells early in the lesions’ development, and a significant number of these cells expressed HLA-DR. In the patients without AV scarring, the investigators also noted significant angiogenesis and vascular adhesion molecule expression in the early phase of their lesion development.

Conversely, the patients with scarring had significantly less CD4+ T cells, Langerhans cells, and a lower cellular HLA-DR expression in the early development of their lesions. Moreover, patients with scarring had higher angiogenesis molecule expression after 48 hours, and they experienced a later influx of macrophages, and increased cellular HLA-DR expression. Holland et al concluded that patients with scarring had an initial cellular response to AV that was weaker and less effective, but that it was more protracted throughout the resolution of AV lesions.

As the understanding of the pathogenesis of AV has expanded, so has the understanding of multiple facets of P. acnes, including its various genotypes. P. acnes has been subdivided into type I, type II, and type III. Within type I, there are 2 subtypes, IA and IB, whose distinction was initially based on serologic differentiation of cell wall carbohydrates and phage typing and later confirmed by analysis of recA, tly, and CAMP gene sequences.^24,25 P. acnes type III was identified in a 2008 article in which the investigators found isolates belonging to a novel recA cluster of P. acnes that was distinct from types I and II.²⁶

P. acnes type IA has an extremely high association with acne, and it has been shown to be phenotypically resistant to multiple antibiotics, including tetracycline, clindamycin, and erythromycin, because of resistance conferring mutations in the 16S ribosomal RNA gene and the 23S rRNA gene.²⁷ In contrast, P. acnes type 1B is not specifically associated with AV, which challenges the traditional concept that all P. acnes contributes to AV pathogenesis. When comparing the different P. acnes types for pro-inflammatory expression, Jasson et al found that P. acnes type III had the highest pro-inflammatory potential due to its up-regulation of PAR-2, TNF-α, MMP-13, and tissue inhibitor of metalloproteinases-2.²⁸

P. acnes resistance to antibiotics is a major concern for clinicians. A growing body of evidence indicates that antibiotic resistance and AV pathogenesis are associated with particular types or subtypes of P. acnes. For example, resistance to erythromycin was described as early as 1972 and, since then, widespread resistance among P. acnes to macrolides, lincosamines, and tetracyclines has been reported in several countries.^29,30 Acne vulgaris patients who do not respond to antibiotics may carry a strain of P. acnes with diverse virulence potential and antibiotic resistance patterns. These findings provide an explanation for the difficulties in predicting the clinical effects of antibiotic treatment for AV.