Original articleExpression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa
Introduction
Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory disease of the apocrine gland–bearing skin. In early stages, HS is characterized by tender subcutaneous nodules primarily localized in the axillary, inguinal, and anogenital regions. During the chronic and recurrent course, the initial lesions progress into deep dermal abscesses, causing pronounced tenderness and pain. Formation of draining sinuses and fistula can lead to the exudation of a purulent and malodorous drainage. Ultimately, these deep-seated inflammatory lesions heal, leaving fibrotic scars, dermal contractures, and induration of the skin. For the patient, HS is disabling and has a detrimental impact on the quality of life.1, 2
The pathogenesis of this recalcitrant disease is still poorly understood. Because of its typical distribution pattern, it was long thought to be a primary disorder of the apocrine gland. Later histological studies showed a lack of focal inflammation within the apocrine gland but found follicular involvement as the predominant feature of HS. Therefore HS is now believed to begin with follicular keratinization leading to occlusion, dilation, and subsequent rupture of the pilosebaceous unit, followed by a profound inflammatory response. Still, the nature and cause of such a marked inflammation remain concealed. Several pathogenetic factors have been suggested, including genetic, infectious, hormonal, behavioral, and, more recently, host defense factors.2
This increased focus on the role of the immune system in the pathogenesis of HS is based on both clinical and experimental observations. On the one hand, a growing number of studies report therapeutic success in HS with anti–tumor necrosis factor alpha agents such as infliximab and adalimumab, thereby indirectly pointing toward a substantial involvement of the immune system.3, 4 On the other hand, investigative studies described alterations of the innate immune system in HS, such as an enhanced expression of toll-like receptors (TLRs) and an altered expression of antimicrobial peptides in lesional skin.5, 6 Other investigations postulated functional defects of neutrophils and monocytes in patients with HS.7, 8 Finally, there is a common clinical association between HS and immunologically mediated diseases, such as pyoderma gangrenosum and Crohn's disease.2, 9 Taken together, both clinical and experimental data suggest an involvement of the immune system in the pathogenesis of HS.
Interestingly, various autoinflammatory diseases share with HS the feature of excessive and protracted inflammation which may be the cause, consequence, or both of dysregulated effector T-cell responses. Until recently, the IL-12/Th1 pathway was thought to be responsible for the pathogenesis of these inflammatory diseases. However, with the discovery of IL-23, this concept had to be revised. IL-23 was found to be critically involved in the establishment of chronic inflammation and the development of a novel T helper cell subset producing IL-17 (also referred to as IL17A), therefore designated Th17.10 Th17-derived cytokines are capable of inducing massive tissue inflammation and autoimmunity.11 Indeed, the IL-23/Th17 axis is of crucial importance in the pathogenesis of various human autoinflammatory diseases, such as psoriasis12 and Crohn's disease.13
Based on the important role of IL-12 and IL-23 in promoting excessive tissue inflammation, we thought to investigate the expression and cellular source of IL-12, IL-23, and consequently IL-17 in lesional skin of HS by semiquantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Furthermore, since activated macrophages contribute substantially to the mononuclear infiltrate in HS and are an important source of innate proinflammatory cytokines,6, 11 we further sought to phenotypically characterize these innate immune cells and analyze their production of IL-12 and IL-23 by double immunofluorescence.
Section snippets
Samples from patients
The study was approved by the Medical Ethics Committee of the Canton of Berne, Switzerland. Written informed consent was obtained from all patients enrolled in this study and the Declaration of Helsinki protocols were followed. Tissue samples were obtained from 10 patients with HS (5 women and 5 men) with median age of 42 years (range, 21-49 years). Patients had a history of HS of at least 6 months and suffered from Hurley stage II axillary or inguinal HS. Study subjects had no history of
Expression of IL-12 and IL-23 mRNA in lesions of HS
The expression of IL-12(p35), IL-12/-23(p40), and IL-23(p19) was determined in lesional and healthy skin by semiquantitative RT-PCR. Relative changes in gene expression between healthy and lesional skin are shown in Fig 1, A. Whereas the IL-12-specific subunit p35 was increased 2.6 fold, the IL-12/IL-23 common p40 subunit and the IL-23p19 subunit were comparably increased by a factor of 4.7 and 5.2, respectively, suggesting that gene expression of IL-23 is more pronouncedly induced in HS than
Discussion
The pathogenesis of chronic inflammatory diseases is increasingly linked to abnormal production of inflammatory mediators. In particular, the IL-12/Th1 pathway was believed to be crucially involved because of its ability to produce IFN-γ and induce macrophage activation.10 This concept was challenged by the discovery of IL-23, a cytokine structurally related to IL-12. Both IL-12 and IL-23 are heterodimeric cytokines. They share a common subunit (p40) but have a distinct subunit, p35 (IL-12p35)
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Cited by (0)
Funding sources: Supported by a grant from the Swiss National Foundation (No. 3200B0-100232).
Conflicts of interest: None declared.