Journal of the American Academy of Dermatology
Pathophysiology of hidradenitis suppurativa: An update
Introduction
Follicular occlusion is thought to be the primary event in hidradenitis suppurativa (HS; also known as acne inversa).1, 2, 3 The occlusion is caused by infundibular keratosis and hyperplasia of the follicular epithelium and results in accumulation of cellular debris, leading to cyst formation.4, 5 Eventually the hair follicle will rupture, followed by a massive local immune response, resulting in painful inflammation, abscess formation, and in later stages, sinus tract formation and scarring.4, 5
Although HS originates in the follicular infundibulum and is characterized by suppuration, it is generally not triggered by infection and does not originate in the apocrine sweat glands.1 Careful examination of histologic skin specimens from early and advanced HS lesions have shown that the sweat glands are not primarily or selectively inflamed. In many ways, the term HS is a misnomer.
The contribution of the immune system in HS has become apparent by the favorable response of HS to tumor necrosis factor-alpha (TNF-α) inhibitors.6, 7 Current views on the pathophysiology of HS abound and range from deficient innate immunity to an aberrant, exaggerated immune response. Immune mechanisms are also considered to contribute to the primary abnormality in HS, that being follicular occlusion. Considerable progress has been made in HS research, but many aspects of the pathogenesis of the condition and involved inflammatory mediators are still being explored.8
Section snippets
Immunogenetics of hidradenitis suppurativa
Genetic investigations of HS have demonstrated loss of function in mutations in 3 out of 4 subunits of gamma-secretase, namely presenilin-1, presenilin enhancer-2, and nicastrin.9 Potential target proteins are type I integral membrane proteins like Notch, E-cadherin, or CD44.10 Notch plays a significant role in normal hair follicle development.9 Defective Notch signaling is associated with the formation of follicular keratin-enriched epidermal cysts. In addition, Notch is also an important
Follicular occlusion
Occlusion of the follicular infundibulum in HS pathogenesis is a certainty. Regardless of disease duration, follicular occlusion is an early feature in the pathogenesis of the disease.3, 5 von Laffert et al5 described a variable hyperkeratosis and hyperplasia of the epithelial lining of terminal follicles in a majority of examined HS specimens. Pronounced perifolliculitis and ruptured follicles were also frequently observed. Follicular occlusion leads to dilatation of the hair follicle followed
Smoking
HS is epidemiologically associated with smoking. Tobacco smoke is composed of thousands of chemicals, of which nicotine, polyaromatic hydrocarbons, and dioxin-like compounds are the most well-known.12 These components activate keratinocytes, fibroblasts, and immunocytes via at least 2 types of receptors: nicotinic acetylcholine receptors and aryl hydrocarbon receptors.13, 14 In keratinocytes, this leads to acanthosis, infundibular epithelial hyperplasia, and excessive cornification.14 Tobacco
Hormones
Hormones may induce follicular occlusion via increased proliferation of follicular keratinocytes, leading to intrafollicular acanthosis, keratosis, and plugging of the follicle.22 An important counterargument to the role of sex hormones in HS is the normal androgen profile of most HS patients.23, 24 Nevertheless, variable improvements with antiandrogen therapies have been reported.25, 26, 27
Obesity and mechanical forces
Obesity may aggravate HS via increased skin–skin and skin–clothing friction.26 Mechanical stress is associated with worsening of HS by increasing follicular occlusion and follicular rupture.28 Mechanical compression, friction, or shear forces are sensed by several mechanotransducers in human skin.29 Several membrane-bound mechanosensory complexes have been described, including stretch-activated ion channels, integrins, growth factor receptors, and G protein–coupled receptors.30 In fibroblasts
Antimicrobial peptides
Schlapbach et al20 noted significant upregulation of the antimicrobial peptide (AMP) hβD-1 and psoriasin mRNA, but a relative deficiency of hβD-2 in HS lesional skin. Wolk et al19 reported a relative deficiency of all AMP mRNA (ie, hβD-1, hβD-2, hβD-3, S100A7 [psoriasin], S100A8 [calgranulin A], and S100A9 [calgranulin B]) in HS lesions, which was related to a relative deficiency of IL-22 and IL-20 in HS. Suppressed levels of RNase-7 were also observed. Relative deficiencies of AMPs—namely
The inflammatory response and involved cytokines
The cytokines and immune pathways that drive inflammation in HS continue to be investigated. TNF-α, a proinflammatory cytokine produced by innate and adaptive immune cells, has a critical role in several autoinflammatory diseases.34 A few studies have noted the presence of TNF-α at the mRNA and protein levels in HS skin.19, 31, 33, 35 This is consistent with the clinical improvement that is usually observed with infliximab6 and adalimumab therapy.7 Some investigators reported that TNF-α protein
Conclusion
In conclusion, there is a subclinical inflammatory state in noninvolved HS skin that starts with an aberrant keratinocyte response to commensal follicular bacteria, resulting in abnormal cytokine and AMP production. Attracted immunocytes start secreting proinflammatory cytokines and chemokines. The follicular epithelium reacts and becomes hyperplastic, showing keratosis of the infundibulum, follicular occlusion, and cyst formation. Smoking and defective Notch signaling contribute to this
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This publication was supported through funding provided by AbbVie Corporation.
Conflicts of interest: None declared.