Innate lymphoid cell (ILC) subsets are enriched in the skin of patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis.

Anti-inflammatory Trained Immunity Mediated by Helminth Products Attenuates the Induction of T Cell-Mediated Autoimmune Disease.

Recent studies have suggested that the innate immune system can display characteristics of immunological memory and this has been called "innate immune memory" or "trained immunity." Certain fungal products have been shown to induce epigenetic imprinting on monocytes/macrophages that results in heightened inflammatory responses to subsequent stimuli. Here we report that innate immune cells can be trained to be more anti-inflammatory following exposure to products of a helminth pathogen. Macrophages trained in vitro with Fasciola hepatica total extract (FHTE) had enhanced IL-10 and IL-1RA, but reduced TNF production upon re-stimulation with FHTE or TLR ligands and this was reversed by inhibitors of DNA methylation. In contrast, macrophages trained with ß-glucan or Bacillus Calmette-Guérin had enhanced TNF production upon re-stimulation with Pam3cys or LPS. Furthermore, FHTE-trained macrophages had enhanced expression of markers of alternative activated macrophages (AAM). Macrophages from mice treated with FHTE expressed markers of AAM and had heightened IL-10 and IL-1RA production in response to FHTE or TLR ligands and had suppressed TNF and IL-12p40 production. Macrophages from mice treated with FHTE had reduced APC function and inhibited IL-17 production and the encephalitogenic activity of T cells in the experimental autoimmune encephalomyelitis (EAE) model. In addition, mice pre-treated with FHTE were resistant to induction of EAE and this was associated with a significant reduction in IL-17-producing γδ and CD4 T cells infiltrating the CNS. Our findings reveal that cells of the innate immune system can be trained in vitro or in vivo to be more anti-inflammatory by exposure to helminth products and this protects mice against the induction of a T cell-mediated autoimmune disease.

Naturally derived Heme-Oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells and T cells: relevance for psoriasis treatment.

Psoriasis is a chronic autoimmune disease mediated by dysregulated immune responses in dendritic cells (DC) and T cells. The stress-response enzyme heme oxygenase-1 (HO-1) has been described as protective in animal models of psoriasis, however, implementation of HO-1-based therapies is hindered by the lack of clinically-suitable HO-1 inducers. The plant-derived polyphenols, carnosol and curcumin, have been identified as candidate HO-1 inducers however there has been little investigation into their effects on human immune cells. We demonstrate that treatment of human DC with these polyphenols limits DC maturation, reduces pro-inflammatory cytokine production, and prevents induction of allospecific T cell responses, in a manner partially dependent on carbon monoxide (CO). We also characterised their effects in ex-vivo psoriasis PBMC and report that curcumin, but not carnosol, strongly reduces T cell proliferation and cytokine poly-functionality, with reduced expression of psoriatic cytokines IFNγ, IL-17, GM-CSF and IL-22. This study therefore supports reports highlighting the therapeutic potential of curcumin in psoriasis by providing insight into its immunological effects on healthy human DC and psoriasis PBMC. We also demonstrate, for the first time, the anti-inflammatory effects of carnosol in human immune cells.

Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating disease of hair follicles with 1-4% prevalence and high morbidity. There is a dearth of information on the pathogenesis and immune dysregulation underlying HS; therefore, we carried out a detailed analysis of skin-infiltrating T cells. Cells isolated from skin biopsy samples and blood from HS patients and healthy control subjects were analyzed by 16-parameter flow cytometry to provide detailed profiles of CD4 T-cell subsets. We observed substantial infiltration of inflammatory T cells with a striking T helper (Th) type 17-skewed cytokine profile in HS skin; these cells expressed the Th17 lineage marker CD161 and IL-17, as well as proinflammatory cytokines GM-CSF, IL-22, IFN-γ, and tumor necrosis factor. Regulatory T cells were also enriched in HS lesional skin; however, the ratio of Th17 to regulatory T cells was nonetheless highly dysregulated in favor of Th17 cells. In contrast, lesional skin from anti-tumor necrosis factor-treated HS patients who showed substantial clinical improvement exhibited a significant reduction in the frequency of Th17 cells and normalization of the Th17 to regulatory T cell ratio. These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease.