Background Allergic contact dermatitis is a typical delayed-type hypersensitivity to sensitizing haptens mediated by T cells. Th1/Tc1 cells are currently considered to be the primary effectors in allergic contact dermatitis. There is little information concerning the role played in allergic contact dermatitis in humans by Th-17/Tc-17 cells, a recently defined subpopulation of effector T cells. Objectives In the present report we attempted to characterize Th-17/Tc-17 cells in the infiltrates of the skin in elicitation phase of allergic contact dermatitis. Patients/Methods Th-17 as well as Th1/Th2 cytokine gene expression was examined by semi-quantitative real-time polymerase chain reaction in paired samples of positive patch test biopsies and normal skins from 11 patients allergic to 9 different allergens. The in situ characterization of IL-17-producing cells was carried out using anti-RORC and anti-T cell subset antibodies by double immunofluorescence. Results Compared to normal paired skins, gene expression of transcription factor for human Th-17 cells, RORC, and Th-17-related cytokines IL-17A, IL-17F and IL-23, was significantly increased in positive patch test biopsies. The mRNA for IFN-γ and IL-4 was also increased. In the dermal infiltrates, about 20 % of the infiltrating cells were IL-17-producing cells as they expressed RORC, and such RORC expressing cells were detected in both CD4+ (~30%) and CD8+ (~20%) subsets. Conclusions This is the first demonstration of Th-17/Tc-17 cells in the elicitation phase of human allergic contact dermatitis, showing that they are a regular participant in the immunopathology of this common allergic reaction regardless of the nature of the triggering allergens.

The purpose of this study is to identify invariant natural killer T cells (NKT cells) in cellular infiltrate of human allergic contact dermatitis (ACD) skin challenge sites. Skin biopsy specimens were taken from positive patch test reactions from 10 different patients (9 different allergens) and studied by immunochemistry, real-time PCR, nested PCR, and in situ hybridization to identify NKT cells and the cytokines associated with this cell type. Invariant NKT cells were identified in all the 10 skin biopsy specimens studied, ranging from 1.72 to 33% of the cellular infiltrate. These NKT cells were activated in all cases, as they expressed cytokine transcripts for IFN-gamma and IL-4. Invariant NKT cells are present in ACD, regardless of the allergen that triggers the reaction, and are in an activated state. We conclude that innate immunity plays a role in late phases of type IV hypersensitivity reactions and may be responding to self-lipids released during allergic inflammation. These data complement the previous work by other investigators that suggest that NKT cells are important in the early cellular response during primary immune responses to allergens. Herein, it is demonstrated that NKT cells are constantly present during the late elicitation phase of human type IV hypersensitivity reactions.

Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

The cytokine IL-9, derived primarily from T-helper (Th)-9 lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also plays a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch test sites from non-atopic patients were assayed using qPCR and immunohistochemistry. Along with Th2 associated cytokines, IFN-γ, IL-4, and IL-17A, expression of IL-9, and PU.1, a Th9-associated transcription factor, were elevated when compared to paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+CD3+, and PU.1+CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. PBMC from nickel-allergic patients, but not non-allergic controls, show significant IL-9 production in response to nickel. Blocking studies with monoclonal antibodies to HLA-DR (but not HLA-A, B, C) or chloroquine significantly reduced this nickel-specific IL-9 production. Additionally, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-γ production. A contact hypersensitivity model using IL-9−/− mice, shows enhanced Th1 lymphocyte immune responses, when compared to WT mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD.

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