Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa.
TL;DR: The findings suggest that the IL-23/Th17 pathway is expressed in hidradenitis suppurativa and further support involvement of the immune system.
Abstract: Background Hidradenitis suppurativa is a debilitating chronic disease primarily affecting intertriginous skin of the axillae, perineum, and inframammary regions. The pathogenesis of this inflammatory disease is still poorly understood. Recently, increased attention has been paid to the role of the immune system. Objective Since the interleukin 12 (IL-12)/T helper 1 (Th1) and the IL-23/Th17 pathways are believed to be crucially involved in the pathogenesis of multiple chronic inflammatory diseases, we investigated the expression and cellular source of IL-12, IL-23, and IL-17 in hidradenitis suppurativa. Methods Ten patients with hidradenitis suppurativa were included in the study. Tissue samples were obtained from lesional skin and compared with healthy skin as a control. Expression of IL-12, IL-23, and IL-17 was analyzed by semiquantitative real-time polymerase chain reaction and immunohistochemistry, and the cellular source of these cytokines was determined by double immunofluorescence. Results IL-12 and IL-23 were found to be abundantly expressed by macrophages infiltrating papillary and reticular dermis of lesional skin. In accordance with the high expression of IL-23 and its important role in the development of T helper 17 (Th17) cells, IL-17-producing T helper cells were found to distinctly infiltrate lesional dermis. Limitations The sample size was small. Conclusions Our findings suggest that the IL-23/Th17 pathway is expressed in hidradenitis suppurativa and further support involvement of the immune system. Moreover, targeting the IL-12/IL-23-common subunit p40 with novel monoclonal antibodies may represent a new option for the treatment of this recalcitrant disease.
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TL;DR: Hidradenitis suppurativa/acne inversa is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep‐seated, inflamed lesions in the apocrine gland‐bearing areas of the body.
Abstract: Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 person-years and an average prevalence of 1% has been reported in Europe. HS has the highest impact on patients' quality of life among all assessed dermatological diseases. HS is associated with a variety of concomitant and secondary diseases, such as obesity, metabolic syndrome, inflammatory bowel disease, e.g. Crohn's disease, spondyloarthropathy, follicular occlusion syndrome and other hyperergic diseases. The central pathogenic event in HS is believed to be the occlusion of the upper part of the hair follicle leading to a perifollicular lympho-histiocytic inflammation. A highly significant association between the prevalence of HS and current smoking (Odds ratio 12.55) and overweight (Odds ratio 1.1 for each body mass index unit) has been documented. The European S1 HS guideline suggests that the disease should be treated based on its individual subjective impact and objective severity. Locally recurring lesions can be treated by classical surgery or LASER techniques, whereas medical treatment either as monotherapy or in combination with radical surgery is more appropriate for widely spread lesions. Medical therapy may include antibiotics (clindamycin plus rifampicine, tetracyclines), acitretin and biologics (adalimumab, infliximab). A Hurley severity grade-relevant treatment of HS is recommended by the expert group following a treatment algorithm. Adjuvant measurements, such as pain management, treatment of superinfections, weight loss and tobacco abstinence have to be considered.
769 citations
TL;DR: A 36-year-old woman has recurrent boils under both arms and in the groin, causing pain, suppuration, and an offensive odor and has become socially isolated because of embarrassment about her condition.
Abstract: Copyright © 2012 Massachusetts Medical Society. A 36-year-old woman has recurrent boils under both arms and in the groin. They flare premenstrually, causing pain, suppuration, and an offensive odor. Scarring has developed in the groin area, and chronically draining sinus tracts are interspersed with normal skin. Treatment with short courses of antibiotics or with incision and drainage has had no apparent effect, and she has become socially isolated because of embarrassment about her condition. How would you manage this case?
656 citations
TL;DR: This retrospective case-control study chart-validated all patients within a hospital database who received at least 1 billing code for HS between 1980 and 2013 and highlights the high comorbidity burden of patients with HS compared with matched control subjects.
Abstract: Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving intertriginous skin. Previous epidemiologic studies have been limited by small sample size. Objective We sought to describe the prevalence and comorbidities of HS in a large patient care database. Methods In this retrospective case-control study, we chart-validated all patients within a hospital database who received at least 1 billing code for HS between 1980 and 2013. Verified cases were matched with controls based on age, gender, and race. Prevalences of a priori selected comorbidities were compared between HS and control groups. Results A total of 2292 patients at Massachusetts General Hospital received at least 1 code for HS. A total of 1776 cases had a validated diagnosis of HS, yielding a prevalence of 0.08%. In unadjusted analysis, all comorbidities were diagnosed significantly more in HS compared with control including (in rank order of likelihood): smoking, arthropathies, dyslipidemia, polycystic ovarian syndrome, psychiatric disorders, obesity, drug dependence, hypertension, diabetes, thyroid disease, alcohol dependence, and lymphoma (all P Limitations Control subjects were not validated for absence of HS and comorbidity validation was not performed for either group. Conclusions Our results highlights the high comorbidity burden of patients with HS compared with matched control subjects.
237 citations
Cites background from "Expression of the IL-23/Th17 pathwa..."
...proinflammatory states of metabolic syndrome and skin disease may be related, and certainly, there appear to be biologic similarities in the T-helper 17 and tumor necrosis factor-alfa pathways.(26-32) Lastly, recent randomized control trials for systemic immunosuppressive agents such as infliximab and adalimumab, both tumor necrosis factor-alfa inhibitors, have showed therapeutic efficacy that improves the extent and severity of the disease....
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TL;DR: There is a dearth of information on the precise pathogenesis of hidradenitis suppurativa, but immune dysregulation is implicated and its role in infectious disease is implicated.
Abstract: SummaryBackground
There is a dearth of information on the precise pathogenesis of hidradenitis suppurativa (HS), but immune dysregulation is implicated.
Objectives
To determine the nature of the immune response in HS.
Methods
Skin biopsies – lesional, perilesional (2 cm away) and uninvolved (10 cm away) – were obtained from patients with HS and healthy controls. The expression of various cytokines was determined by enzyme-linked immunosorbent assay, flow cytometry and real-time polymerase chain reaction.
Results
The expression of the inflammatory cytokines interleukin (IL)-17, IL-1β and tumour necrosis factor-α was enhanced in lesional skin of patients with HS. In addition, IL17A and IL1B mRNA were enhanced in clinically normal perilesional skin. CD4+ T cells produced IL-17 in HS, while CD11c+ CD1a− CD14+ cells were sources of IL-1β. Activated caspase-1 was detected in HS skin and was associated with enhanced expression of NLRP3 and IL18. Inhibition of caspase-1 decreased IL-1β and IL-18 production, suggesting that the caspase-1 pathway participates in IL-1β and IL-18 expression in HS. Abnormal cytokine expression was detected in perilesional and uninvolved skin, which may suggest that subclinical inflammation is present in HS skin prior to the formation of an active lesion.
Conclusions
This study demonstrates that CD4+ T cells produce IL-17 in HS and that the IL-17 pathway may be important in HS pathogenesis. CD11c+ CD1a− CD14+ cells are a source of IL-1β in HS, the production of which was shown to be mediated, in part, via a caspase-1-dependent pathway. These results suggest that IL-17 and the caspase-1-associated cytokines IL-1β and IL-18 may play a role in the pathogenesis of HS.
191 citations
TL;DR: Anakinra has the potential to be an effective and well-tolerated treatment for HS and inhibition of interleukin 1 is a promising treatment strategy.
Abstract: Importance Hidradenitis suppurativa (HS) is a common skin disorder in which excessive inflammation is believed to have an important role. There is no specific therapy for HS. Objective To investigate the safety and efficacy of the anti-inflammatory biological therapy anakinra in HS. Design, Setting, and Participants Double-blind, randomized, placebo-controlled clinical trial with a 12-week treatment phase and a 12-week follow-up phase. The setting was Attikon University General Hospital, a tertiary care institution in Athens, Greece. Participants were 20 patients with Hurley stage II or III HS. The study and the analysis were conducted between March 1, 2012, and February 28, 2014. Interventions Patients were randomized to receive injections from identical syringes containing placebo or anakinra subcutaneously once daily for 12 weeks. Peripheral blood mononuclear cells were isolated and stimulated for cytokine production before the beginning of treatment and at week 12 (the end of treatment) and week 24. Main Outcomes and Measures The primary end point was the effect of anakinra on HS disease severity. Secondary end points were the time to a new exacerbation and the production of cytokines. Results Among the 20 trial participants, 10 each were randomized to the group to receive anakinra or the placebo group. The mean (SD) ages were 42.8 (13.8) and 36 (11.3) years in the anakinra and placebo groups, respectively. The disease activity score was decreased at the end of treatment in 20% (2 of 10) of the placebo arm compared with 78% (7 of 9) of the anakinra arm ( P = .02). Hidradenitis suppurativa clinical response at 12 weeks was achieved in 30% (3 of 10) of the placebo arm and in 78% (7 of 9) of the anakinra arm ( P = .04). The production of interferon-γ by peripheral blood mononuclear cells in the anakinra arm was decreased, and the production of interleukin 22 was increased. The time to a new HS exacerbation was prolonged in the anakinra arm by log-rank test (log rank, 6.137; P = .01). No serious adverse events were reported. Conclusions and Relevance Anakinra has the potential to be an effective and well-tolerated treatment for HS. Inhibition of interleukin 1 is a promising treatment strategy. Trial Registration clinicaltrials.gov Identifier:NCT01558375
186 citations
Cites background from "Expression of the IL-23/Th17 pathwa..."
...70 Exacerbations per month, median (range) 2 (1-16) 2 (1-10) ....
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...Theseincluded (1) history of systemic lupus erythematosus, rheumatoid arthritis, or seronegative inflammatory arthritis; (2) prior administration of any type of TNF-blocking therapy over the last 6 months; (3) administration of any live (attenuated) vaccine over the last 4 weeks; (4) history of recurrent vein thrombosis or embolism compatible with antiphospholipid syndrome; (5) any present or smoldering infection; (6) hepatic dysfunction, defined as any value of transaminases, γ-glutamyl transpeptidase, or bilirubin greater than 2 times the upper normal limit; (7) history of hematological or solid tumor malignancy, arterial hypertension, liver cirrhosis, human immunodeficiency virus infection, or hepatitis virus B or C infection; (8) history of episodes mimicking demyelinating disorders or a definite diagnosis of multiple sclerosis; (9) any serum creatinine level above 1....
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References
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TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...
4,548 citations
"Expression of the IL-23/Th17 pathwa..." refers background in this paper
...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 psoriasis(12) and Crohn’s disease....
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...First, IL-17 is known to mobilize neutrophils to peripheral tissues and increase their local survival.(11,23) Hence Th17 cells may be partly responsible for the excessive neutrophilic inflammation and purulent drainage seen in primary and secondary lesions of HS....
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...These classically activated macrophages are known to secrete IL12p70 and IL-23 after activation of TLRs by microbial agents.(11,19) Therefore it might be possible that in HS chronic inflammation, regardless of its cause, fosters colonization of lesional skin by bacteria, which on their part trigger production of these cytokines by stimulating TLRs, thereby closing a positive feedback loop....
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TL;DR: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation as mentioned in this paper, which have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis.
Abstract: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.
3,831 citations
"Expression of the IL-23/Th17 pathwa..." refers background in this paper
...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....
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TL;DR: It is shown that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL- 12, is the critical factor in this response.
Abstract: Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
2,915 citations
TL;DR: Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer, which places IL- 17 family members and their receptors as potential targets for future pharmacotherapy.
2,382 citations
"Expression of the IL-23/Th17 pathwa..." refers background in this paper
...First, IL-17 is known to mobilize neutrophils to peripheral tissues and increase their local survival.(11,23) Hence Th17 cells may be partly responsible for the excessive neutrophilic inflammation and purulent drainage seen in primary and secondary lesions of HS....
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TL;DR: The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.
Abstract: Interleukin (IL) 23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 affects memory T cell and inflammatory macrophage function through engagement of a novel receptor (IL-23R) on these cells. Recent analysis of the contribution of IL-12 and IL-23 to central nervous system autoimmune inflammation demonstrated that IL-23 rather than IL-12 was the essential cytokine. Using gene-targeted mice lacking only IL-12 (p35−/−) or IL-23 (p19−/−), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis. IL-23 gene-targeted mice did not develop clinical signs of disease and were completely resistant to the development of joint and bone pathology. Resistance correlated with an absence of IL-17–producing CD4+ T cells despite normal induction of collagen-specific, interferon-γ–producing T helper 1 cells. In contrast, IL-12–deficient p35−/− mice developed more IL-17–producing CD4+ T cells, as well as elevated mRNA expression of proinflammatory tumor necrosis factor, IL-1β, IL-6, and IL-17 in affected tissues of diseased mice. The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.
1,695 citations