Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating, follicular disease of the skin. Despite a high prevalence in the general population, the physiopathology of HS remains poorly understood. The use of antibiotics and immunosuppressive agents for therapy suggests a deregulated immune response to microflora. Using cellular and gene expression analyses, we found an increased number of infiltrating CD4(+) T cells secreting IL-17 and IFN-γ in perilesional and lesional skin of patients with HS. By contrast, IL-22-secreting CD4(+) T cells are not enriched in HS lesions contrasting with increased number of those cells in the blood of patients with HS. We showed that keratinocytes isolated from hair follicles of patients with HS secreted significantly more IL-1β, IP-10, and chemokine (C-C motif) ligand 5 (RANTES) either constitutively or on pattern recognition receptor stimulations. In addition, they displayed a distinct pattern of antimicrobial peptide production. These findings point out a functional defect of keratinocytes in HS leading to a balance prone to inflammatory responses. This is likely to favor a permissive environment for bacterial infections and chronic inflammation characterizing clinical outcomes in patients with HS.

Interleukin (IL)-10 and glucocorticoids (GCs) inhibit the ability of antigen-presenting dendritic cells (DCs) to stimulate T lymphocytes. We show that induction of GILZ (GC-induced leucine zipper) is involved in this phenomenon. IL-10, dexamethasone (DEX), and transforming growth factor (TGF)beta stimulate GILZ production in human immature DCs derived from monocytes and from CD34+ cells. GILZ is necessary and sufficient for DEX, IL-10, and TGFbeta modulation of CD80, CD83, CD86, immunoglobulin-like transcript (ILT)-3, and B7-H1 expression by DCs, and alteration of DC functions. GILZ stimulates the production of IL-10 by immature DCs and prevents the production of inflammatory chemokines by CD40L-activated DCs. In contrast, GILZ does not prevent CD40 ligand-mediated inhibition of phagocytosis, indicating that it affects some but not all aspects of DC maturation. GILZ prevents DCs from activating antigen-specific T lymphocyte responses. Administration of GCs to patients stimulates GILZ expression in their circulating antigen-presenting cells, and this contributes to the weak lymphocyte responses of GC-treated patients. Thus, regulation of GILZ expression is an important factor determining the decision of DCs whether or not to stimulate T lymphocytes, and IL-10, GCs, and TGFbeta share this mechanism for influencing DC functions and the balance between immune response and tolerance.

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IntroductionRegulatory T lymphocytes (Tregs) play a key role in controlling immune responses. Initially, 2 types of Tregs were identified. Natural (or constitutive) Tregs are generated in the thymus and they spontaneously express the transcription factor FOXP3 and high levels of CD25. Inducible (or adaptive) Tregs are generated by peripheral activation, particularly in the presence of IL-10 or TGF␤. However, the relationship between these 2 subpopulations has not been completely elucidated. Tregs inhibit immune responses by a combination of effects requiring direct contact with their targets and the production of inhibitory cytokines, including IL-10 and TGF␤. In addition to the coexpression of CD25 hi and FOXP3 and the production of IL-10 and TGF␤, several markers potentially characteristic of Tregs have been identified, but none of them has been unequivocally associated with the suppressive function of Tregs or with their classification into natural or inducible Tregs. [1][2][3][4] Antigen presentation by dendritic cells (DCs) leads to either immune stimulation or tolerance. The mechanisms underlying the decision of DCs to orientate the immune response toward one of these 2 opposite outcomes are not fully understood. Toleranceinducing DCs are also called regulatory DCs. One method used by regulatory DCs to prevent immune activation is to trigger T-lymphocyte anergy or apoptosis during antigen presentation. This involves production of the enzyme indoleamine 2,3-dioxygenase (IDO) and of nitric oxide by DCs. 5,6 The other method is to generate regulatory cells, including Tregs. Although IDO production by DCs may play a role in the induction of Tregs, 7 additional mechanisms are presumably involved. The state of maturation and activation of DCs is critical to Treg development: DCs activated and maturing in response to inflammatory stimuli trigger immune responses, but immature or "semimature" DCs, in contrast, induce tolerance, [8][9][10][11] and this is in part mediated by the generation of Tregs. [12][13][14][15] Phenotypically mature DCs can also be tolerogenic, and certain environmental signals can induce maturation of DCs in a tolerogenic mode. 10 IL-10, TGF␤, glucocorticoids (GCs), vasoactive intestinal peptide, vitamin D3, and antioxidative vitamins, used alone or in combination, orientate DC maturation to induce tolerance, [16][17][18][19][20][21][22][23][24] and Treg development has been demonstrated for several of these agents. 18,19,22,24 The molecular mechanisms involved in this switch of DC maturation toward regulatory DCs are largely unknown. Several tolerogenic agents down-regulate the NF-kB and p38 MAPK transduction pathways in DCs, which contrasts with the potency of inflammatory agents to activate them. 24,25 In addition, DCs from RelB-deficient mice induce immune tolerance and antigen-specific Tregs. 26 This suggests that modulation of NF-kB and p38 MAPK function contributes to the decision of DCs to differentiate into regulatory DCs.An intracellular factor called glucocorticoid-induced leucine ...

Pulmonary hypertension is characterised by a progressive increase in pulmonary arterial resistance due to endothelial and smooth muscle cell proliferation resulting in chronic obstruction of small pulmonary arteries. There is evidence that inflammatory mechanisms may contribute to the pathogenesis of human and experimental pulmonary hypertension.The aim of the study was to address the role of fractalkine (CX3CL1) in the inflammatory responses and pulmonary vascular remodelling of a monocrotaline-induced pulmonary hypertension model.The expression of CX3CL1 and its receptor CX3CR1 was studied in monocrotaline-induced pulmonary hypertension by means of immunohistochemistry and quantitative reverse-transcription PCR on laser-captured microdissected pulmonary arteries.It was demonstrated that CX3CL1 was expressed by inflammatory cells surrounding pulmonary arterial lesions and that smooth muscle cells from these vessels had increased CX3CR1 expression. It was then shown that cultured rat pulmonary artery smooth muscle cells expressed CX3CR1 and that CX3CL1 induced proliferation but not migration of these cells.In conclusion, the current authors proposed that fractalkine may act as a growth factor for pulmonary artery smooth muscle cells. Chemokines may thus play a role in pulmonary artery remodelling.

SUMMARYTo clarify the role of Th1-and Th2-type cytokines in the various outcomes of human alveolar echinococcosis (AE), the cytokine immune response of self-cured patients was studied and compared with those of progressive AE patients and healthy subjects. Self-cured patients were divided into two groups according to the following clinical features: subjects who had positive Echinococcus multilocularis serologies and hepatic calcifications typical of AE were classified as`abortive AE' patients, and those who had positive E. multilocularis serologies but no hepatic lesions or calcifications detectable by ultrasonography were classified as`positive serology' subjects. Secretions of IL-5, IL-10 and interferon-gamma, and expression of IL-5 mRNA were evaluated in peripheral blood mononuclear cells (PBMC) stimulated in vitro with the mitogen phytohaemagglutinin-C or specific E. multilocularis antigenic preparations. The cytokine profile of abortive AE patients was the opposite of that observed in progressive AE patients. An intermediate profile was observed in positive serology subjects. PBMC from abortive AE patients, whether non-stimulated or stimulated with PHA and antigenic preparations, secreted significantly lower levels of IL-10 than those isolated from progressive AE patients. Our observations seem to confirm the regulatory role of IL-10 in the immunopathology of human AE.

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Chemerin is a potent chemotactic factor that was identified recently as the ligand of ChemR23, a G protein-coupled receptor expressed by mononuclear phagocytes, dendritic cells (DCs), and NK cells. Chemerin is synthesized as a secreted precursor, prochemerin, which is poorly active on ChemR23. However, prochemerin can be converted rapidly into a full ChemR23 agonist by proteolytic removal of a carboxy-terminal peptide. This maturation step is mediated by the neutrophil-derived serine proteases elastase and cathepsin G. In the present work, we have investigated proteolytic events that negatively control chemerin activity. We demonstrate here that neutrophil-derived proteinase 3 (PR3) and mast cell (MC) chymase are involved in the generation of specific chemerin variants, which are inactive, as they do not induce calcium release or DC chemotaxis. Mass spectrometry analysis showed that PR3 specifically converts prochemerin into a chemerin form, lacking the last eight carboxy-terminal amino acids, and is inactive on ChemR23. Whereas PR3 had no effect on bioactive chemerin, MC chymase was shown to abolish chemerin activity by the removal of additional amino acids from its C-terminus. This effect was shown to be specific to bioactive chemerin (chemerin-157 and to a lesser extent, chemerin-156), as MC chymase does not use prochemerin as a substrate. These mechanisms, leading to the production of inactive variants of chemerin, starting from the precursor or the active variants, highlight the complex interplay of proteases regulating the bioactivity of this novel mediator during early innate immune responses.