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.
A properly functioning T cell compartment is crucial to protect the host from infections, tumors, and environmental substances. In recent years, it has become increasingly clear that the processes ...underlying proper T cell activation, proliferation, and differentiation require well-tuned and dynamic changes in T cell metabolism. Thus, proper metabolic reprogramming in T cells is crucial to ensure proper immunity in the context of infection and anti-tumor immunity. Conversely, aberrant regulation of T cell metabolism can impair T cell function and thereby contribute to T cell-mediated disease. In this review, the relevance of recent insights into T cell metabolism for prototypical T cell-mediated skin diseases will be discussed and their therapeutic potential will be outlined. First, the major modules of T cell metabolism are summarized. Then, the importance of T cell metabolism for T cell-mediated skin diseases such as psoriasis and allergic contact dermatitis is discussed, based on the current state of our understanding thereof. Finally, novel therapeutic opportunities for inflammatory skin disease that might emerge from investigations in T cell metabolism are outlined.
T helper type 9 (TH9) cells can mediate tumor immunity and participate in autoimmune and allergic inflammation in mice, but little is known about the TH9 cells that develop in vivo in humans. We ...isolated T cells from human blood and tissues and found that most memory TH9 cells were skin-tropic or skin-resident. Human TH9 cells coexpressed tumor necrosis factor-α and granzyme B and lacked coproduction of TH1/TH2/TH17 cytokines, and many were specific for Candida albicans. Interleukin-9 (IL-9) production was transient and preceded the up-regulation of other inflammatory cytokines. Blocking studies demonstrated that IL-9 was required for maximal production of interferon-γ, IL-9, IL-13, and IL-17 by skin-tropic T cells. IL-9-producing T cells were increased in the skin lesions of psoriasis, suggesting that these cells may contribute to human inflammatory skin disease. Our results indicate that human TH9 cells are a discrete T cell subset, many are tropic for the skin, and although they may function normally to protect against extracellular pathogens, aberrant activation of these cells may contribute to inflammatory diseases of the skin.
Bullous pemphigoid (BP) is a blistering autoimmune skin disease. Omalizumab, a monoclonal antibody directed to IgE, showed a beneficial effect in treatment of recalcitrant BP in case series. More ...recently, dupilumab, an interleukin (IL)-4-receptor alpha antagonist, also showed promising preliminary results. We describe a patient with refractory BP who showed a complete response to a combination therapy with omalizumab and dupilumab.
Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most frequent subepidermal blistering ...disease of the skin Use of IgE targeted therapies, such as omalizumab, has been shown promising in recent studies. The aim of this study was to assess the effect of omalizumab on FcεRI and IgE expression on circulating basophils and on lesional intradermal cells in BP to generate insight into the immunological effects of omalizumab in BP. We report two cases of BP patients treated with omalizumab. Efficacy of treatment was assessed clinically 4 months after initiation of the therapy. Lesional and non-lesional skin biopsies where taken before and 4 weeks after initiation of omalizumab therapy. In addition, FcεRI expression on circulating cells and IgE levels in serum and in the skin samples, as well as anti-BP180 and anti-BP230 in serum and eosinophils and basophils counts in blood were assessed before and during treatment. Both patients showed a marked improvement after 4 months, with no adverse effects. Down-regulation of FcεRI, IgE in lesional skin and on circulating basophils were observed in parallel with clinical improvement. The current case study supports the role of omalizumab in the treatment of a subset of BP patients. Our observations suggest that omalizumab represents a valuable therapeutic option in the management of BP patients. Its efficacy might be related to reduction in FcεRI+ and IgE+ basophils and intradermal cells.
Psoriasis is a chronic relapsing, remitting interleukin (IL)-23/IL-17-driven skin disease mediated by the interplay of T cells and polymorphonuclear granulocytes. Although preclinical studies have ...provided insights into the mechanisms of disease initiation, the underpinnings of natural disease remission remain largely unknown. Here, we addressed the contribution of regulatory Foxp3+ T cells (Treg cells) in psoriasiform skin inflammation and remission using the Aldara-skin inflammation model in combination with the inducible depletion of Foxp3+ Treg cells. Loss of Treg cells exacerbated skin inflammation, but this did not involve increased γδ T cell expansion or the local production of the psoriasis-associated cytokines IL-17A, IL-17F, and IL-22, which are the main driving forces of disease development. Instead, Treg cells suppressed the infiltration of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells into the lesioned skin, and neutralizing GM-CSF in Treg cell-deficient mice reversed hyper-inflammation, resulting in disease regression. Therefore, we identified a non-redundant role of Treg cells restraining skin inflammation and mediating skin homeostasis.
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•Treg cells infiltrate into psoriasiform skin lesions•Treg cells limit the exacerbation of skin inflammation and initiate disease remission•GM-CSF+CD4+ T cells emerge in Treg-cell-depleted skin•Neutralization of GM-CSF reverses exacerbated skin inflammation to wild-type levels
The contribution of Treg cells to psoriasis is poorly understood. By combining inducible depletion of Treg cells with the Aldara model of psoriasiform inflammation, Hartwig et al. reveal a non-redundant role of Treg cells in promoting the remission of skin inflammation by limiting invasion of CD4+ GM-CSF-producing T cells into psoriatic skin.
•The majority of PNP patients develop autoantibodies against A2ML1.•The biological function of A2ML1 in the epidermis remains incompletely understood.•Current diagnostic methods in PNP are inadequate ...to detect anti-A2ML1 antibodies.•Here we developed sensitive and quantitative assays to detect anti-A2ML1 antibodies.•Our approach can be applied for the characterization of antibodies against various antigens.
Paraneoplastic pemphigus (PNP) is a devastating autoimmune multiorgan syndrome associated with autoantibodies against several autoantigens, including the alpha-2-macroglobulin-like-1 (A2ML1). A2ML1 is recognized by up to 70 % of PNP sera. The currently recommended techniques for serological diagnosis of PNP are inadequate to detect anti-A2ML1 antibodies.
To develop novel assays which allow to easily and reliably detect anti-A2ML1 autoantibodies in PNP sera.
We produced full-length A2ML1 in fusion with enhanced green fluorescent protein (EGFP-A2ML1) in transfected human embryonic kidney 293 T cells. The recombinant protein was used as fluorescent ligand for immunoprecipitation studies. We further developed an enzyme-linked immunosorbent assay (ELISA) by immobilizing EGFP-A2ML1 on 96-well plates.
A2ML1-positive PNP sera were able to immunoprecipitate EGFP-A2ML1. Direct measurement of fluorescence in immunoprecipitates correlates with the relative levels of anti-A2ML1 antibodies in the PNP sera. By the novel ELISA, based on the determined best cut-off value, 61 % of the tested 36 PNP sera were A2ML1 positive with a specificity of 88.9 % and a sensitivity of 95 %. The 20 tested normal sera (NHS) were negative, while 2 (10 %) of 20 pemphigus vulgaris and 3 (15 %) of 20 bullous pemphigoid sera showed borderline values.
Our novel immunoassays enable rapid stratification of PNP patients. The novel green fluorescent protein-based ELISA utilizing an active eukaryotic A2ML1 is highly sensitive and reliable and, hence, is useful for a better understanding of the immunological background of PNP. This approach may be easily applied for the rapid detection of antibodies to various other antigens.
T helper 9 (T
9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in ...human T
9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in T
9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in T
cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human T
9 cells.
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