Acne Vulgaris: Pathophysiology

Pilosebaceous Unit - Acne's Ground Zero

• PSU: Skin unit where acne originates.
• Comprises:
  • Hair Follicle: Infundibulum (upper part) is key.
    • Lined by keratinocytes; site of acne's hyperkeratinization.
  • Sebaceous Gland: Attached to follicle.
    • Produces sebum (lipids: triglycerides, wax esters, squalene).
    • Holocrine secretion; activity androgen-influenced.
• Distribution: Face, chest, upper back (high PSU density).

⭐ All primary pathological events of acne (follicular hyperkeratinization, sebum overproduction, C. acnes proliferation, inflammation) occur within the pilosebaceous unit.

Sebum Hypersecretion - Oily Overload

• Key pathogenic factor: ↑ sebum output from hypertrophied sebaceous glands.
• Primary Hormonal Drivers:
  • Androgens (esp. Dihydrotestosterone - DHT): Major stimulants, ↑ gland size & activity. Active during puberty.
  • Insulin-like Growth Factor-1 (IGF-1): Synergizes with androgens.
  • Other factors: CRH, neuropeptides (e.g., Substance P).
• Sebum Alterations:
  • ↑ Quantity (oily skin/seborrhea).
  • ↓ Linoleic acid: May promote comedogenesis & inflammation.
• Creates lipid-rich anaerobic environment favouring Cutibacterium acnes proliferation.

⭐ Androgens, particularly dihydrotestosterone (DHT), are the primary stimulants of sebum production. They bind to receptors in sebocytes, increasing gland size and sebum output.

Follicular Hyperkeratinization - Pore Plug Panic

• Core Problem: Dysregulation of keratinocyte proliferation and differentiation in the follicular infundibulum. This leads to an overproduction and inadequate shedding of keratinocytes.
• Mechanism of Obstruction:
  • Keratinocytes become more cohesive (sticky).
  • Shed corneocytes accumulate instead of being expelled.
  • This forms a dense plug, obstructing the pilosebaceous duct.
• Result: The Microcomedone
  • This initial plug is the microcomedone.

  ⭐ The microcomedone is the primary, non-inflammatory, and clinically invisible precursor to all acne lesions.

• Contributing Factors:
  • Androgenic stimulation.
  • Local cytokines (e.g., IL-1α).

Cutibacterium acnes - Bug's Life, Acne Style

• Gram-positive, anaerobic/microaerophilic rod; normal skin commensal.
• Colonizes pilosebaceous follicles; proliferates in lipid-rich sebum.
• Key pathogenic roles:
  • Hydrolyzes sebum triglycerides via lipases → pro-inflammatory free fatty acids (FFAs) & comedogenic byproducts.
  • Releases chemotactic factors & enzymes, attracting neutrophils & promoting follicular rupture.
  • Forms biofilms, potentially increasing persistence & treatment resistance.

⭐ Cutibacterium acnes (formerly Propionibacterium acnes) stimulates inflammation by activating Toll-like receptor 2 (TLR-2) on immune cells and keratinocytes.

Inflammation & Immune Response - Red Alert Rampage

• C. acnes surface proteins & metabolic byproducts (e.g., porphyrins, lipases) act as potent chemoattractants and antigens.
• Activation of innate immunity: Toll-like receptors (TLR-2 on keratinocytes, macrophages) recognize C. acnes.
• Release of pro-inflammatory cytokines (IL-1α, IL-8, TNF-α, IL-12) & chemokines, attracting neutrophils.
• Neutrophils phagocytose C. acnes, releasing lysosomal enzymes & ROS, causing follicular wall rupture and dermal inflammation.
• Adaptive immune response: T-cells (Th1, Th17) and B-cells contribute to chronic inflammation and lesion persistence.

⭐ C. acnes activates the NLRP3 inflammasome, boosting IL-1β production and inflammation significantly.

High-Yield Points - ⚡ Biggest Takeaways

• Follicular hyperkeratinization (abnormal desquamation) forms microcomedones, the precursor lesion.
• Increased sebum production, stimulated by androgens, creates a lipid-rich follicular milieu.
• Cutibacterium acnes (P. acnes), an anaerobe, proliferates within these blocked follicles.
• C. acnes metabolizes sebum, releasing pro-inflammatory mediators and chemotactic factors.
• Host immune response (innate & adaptive) causes inflammation (papules, pustules, nodules).
• Genetic predisposition strongly influences acne susceptibility and severity.
• High glycemic load diets may exacerbate acne in some individuals.