Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T H 2)-type allergic inflammation is not known.We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c + dendritic cells (DCs) and induced production of the T H 2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22).TSLP-activated DCs primed naïve T H cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-α, while downregulating IL-10 and interferon-γ. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis.TSLP expression was associated with Langerhans cell migration and activation in situ.These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLPAbout 20% of the population in Western countries suffers from allergic diseases, which include asthma, allergic rhinitis, atopic dermatitis and food allergy 1 . Allergic inflammation is the result of a complex immunological cascade that leads to dysregulated production of T helper type 2 (TH2)-derived cytokines such as interleukin 4 (IL-4), IL-5 and IL-13 2-4 , which trigger immunoglobulin E (IgE) production, eosinophilia and mucus production [5][6][7] . Dendritic cells (DCs), which are professional antigen-presenting cells 8 , play an important role in the pathogenesis of allergic diseases 9-11 . However, the initial signal that primes DCs to induce T cells to produce proallergic TH2 cytokines is unknown. Epithelial cells are located at the sites of allergen entry into the body and interact closely with DCs in situ. However, it is not known whether DCs play a role in triggering the allergic immune cascade. Although skin keratinocytes and mucosal epithelial cells produce proinflammatory cytokines such as IL-1, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) after activation 12 , none of these cytokines explain the mechanism that underlies the induction of allergic inflammation. Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, cloned from a murine thymic stromal cell line 13 . The TLSP receptor is a heterodimer that consists of the IL-7 receptor α chain (IL-7Rα) and a common γ-like receptor chain called TSLP receptor (TSLPR) [14][15][16][17] . Mouse TSLP supports murine early B and T cell developments 18,19 and does not appear to have any biological effects on murine DCs (unpublished data). In contrast, human TSLP activates CD11c + DCs, but does not appear to have any direct biological effects on B cells, T cells, NK cells, neutrophils or mast cells 17 . This is in accordance with the coexpression of IL-7Rα chain and TSLPR mRNA in CD11c + DCs, but not in other cell types. We show here that human TSLP potently activated ...

T(H)-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the T(H)-17 lineage is dependent on transforming growth factor-beta and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1beta induced the development of human T(H)-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-gamma, the chemokine CCL20 and transcription factor RORgammat. In situ, T(H)-17 cells were identified by expression of the IL-23 receptor and the memory T cell marker CD45RO. Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human T(H)-17 cells that promote the production of antimicrobial peptides in human keratinocytes. Our data collectively indicate that human and mouse T(H)-17 cells require distinct factors during differentiation and that human T(H)-17 cells may regulate innate immunity in epithelial cells.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

Tissue factor (TF)-producing cells were identified in normal human vessels and atherosclerotic plaques by in situ hybridization and immunohistochemistry using a specific riboprobe for TF mRNA and a polyclonal antibody directed against human TF protein. TF mRNA and protein were absent from endothelial cells lining normal internal mammary artery and saphenous vein samples. In normal vessels TF was found to be synthesized in scattered cells present in the tunica media as well as fibroblast-like adventitial cells surrounding vessels. Atherosclerotic plaques contained many cells synthesizing TF mRNA and protein. Macrophages present as foam cells and monocytes adjacent to the cholesterol clefts contained TF mRNA and protein, as did mesenchymalappearing intimal cells. Significant TF protein staining was found deposited in the extracellular matrix surrounding mRNA-positive cells adjacent to the cholesterol clefts and within the necrotic cores. These results suggest that deposition of TF protein in the matrix of the necrotic core of the atherosclerotic plaque may contribute to the hyperthrombotic state of human atherosclerotic vessels.