In vivo and in vitro studies of Th17 response to specific immunotherapy in house dust mite-induced allergic rhinitis patients

10.1371/journal.pone.0091950PLoS ONE93-POLN

Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel

Identification of Baicalin as an Immunoregulatory Compound by Controlling TH17 Cell Differentiation

TH17 cells have been implicated in a growing list of inflammatory disorders. Antagonism of TH17 cells can be used for the treatment of inflammatory injury. Currently, very little is known about the natural compound controlling the differentiation of TH17 cells. Here, we showed that Baicalin, a compound isolated from a Chinese herb, inhibited TH17 cell differentiation both in vitro and in vivo. Baicalin might inhibit newly generated TH17 cells via reducing RORγt expression, and together with up-regulating Foxp3 expression to suppress RORγt-mediated IL-17 expression in established TH17 cells. In vivo treatment with Baicalin could inhibit TH17 cell differentiation, restrain TH17 cells infiltration into kidney, and protect MRL/lpr mice against nephritis. Our findings not only demonstrate that Baicalin could control TH17 cell differentiation but also suggest that Baicalin might be a promising therapeutic agent for the treatment of TH17 cells-mediated inflammatory diseases

Interleukin-17 regulation: an attractive therapeutic approach for asthma

Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma

Early Production of IL-22 but Not IL-17 by Peripheral Blood Mononuclear Cells Exposed to live Borrelia burgdorferi: The Role of Monocytes and Interleukin-1

If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

International audienceABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology

The therapeutic effect of anti-CD52 treatment in murine experimental autoimmune encephalomyelitis is associated with altered IL-33 and ST2 expression levels

Experimental autoimmune encephalomyelitis (EAE) mice were administered with murine anti-CD52 antibody to investigate its therapeutic effect and whether the treatment modulates IL-33 and ST2 expression. EAE severity and central nervous system (CNS) inflammation were reduced following the treatment, which was accompanied by peripheral T and B lymphocyte depletion and reduced production of various cytokines including IL-33, while sST2 was increased. In spinal cords of EAE mice, while the number of IL-33+ cells remained unchanged, the extracellular level of IL-33 protein was significantly reduced in anti-CD52 antibody treated mice compared with controls. Furthermore the number of ST2+ cells in the spinal cord of treated EAE mice was downregulated due to decreased inflammation and immune cell infiltration in the CNS. These results suggest that treatment with anti-CD52 antibody differentially alters expression of IL-33 and ST2, both systemically and within the CNS, which may indicateIL-33/ST2 axis is involved in the action of the antibody in inhibiting EAE

The electron transfers associated with the cytochrome c peroxidase of Paracoccus denitrificans

A study of the electron transfers associated with the cytochrome c peroxidase of Paracoccus denitrificans has been made.The peroxidase is similar to the well-studied enzyme from Pseudomonas aeruginosa, although significant differences do exist. Like the Pseudomonas enzyme, the Paracoccus peroxidase contains two haem c groups, one high potential (Em= +226mV) and one low potential (Em ≈ -lOOmV). The high potential haem acts as a source of the second electron for hydrogen peroxide reduction and the low potential haem acts as a peroxidatic centre.The fully oxidised form of the Paracoccus enzyme is inactive and does not bind added ligands. Reduction of the high potential haem (by ascorbate treatment) results in a switch of the low potential haem to a high spin state, as shown by visible and n.m.r. spectroscopy. This high spin haem of the mixed-valence enzyme is accessible to ligands and binds CN⁻ with a KD of 5μM.The Paracoccus enzyme is significantly different from that from Pseudomonas in the time course of high spin formation after reduction of the high potential haem, and in the requirement for divalent cations. Reduction with ImM ascorbate at pH 6 is complete within 2 min and this is followed by a slow appearance of the high spin state with a half time of 10 min. This separation is also evident in e.p.r. spectra although the slow change involves an alteration in the low spin ligation at this low temperature rather than a change in spin state. The appearance of the high spin state after ascorbate-reduction is correlated with an increase in enzyme activity, suggesting that the mixed-valence, high-spin state of the enzyme is the active form.At pH 7.5 the separation between ascorbate-reduction and spin-state change in the low potential haem is even more striking, no high spin form being obtained until 1 mM Ca⁺⁺ is added to the mixed valence enzyme. This spectroscopic observation is also reflected in the kinetics where no enzyme activity is seen until lmM Ca⁺⁺ is added. The same result can be obtained at pH6 by pretreating the enzyme with EGTA prior to ascorbate-reduction. The spin state switch of the low potential haem shifts the midpoint redox potential of the high potential haem by 50mV, a further indication of haem-haem interaction.A comparison of the molecular weight of the enzyme under native and denaturing conditions suggests that the enzyme exists in a monomer/ dimer equilibrium. Dilution of the enzyme results in loss of some of the enzyme activity, suggesting that only the dimer is active. Reconcentration of the enzyme recovers the activity lost upon dilution. From the kinetic data, the KD for the monomer/ dimer equilibrium is estimated at 0.6μMThe peroxidase can receive electrons both from the acidic Paracoccus cytochrome c-550 and from the basic mitochondrial cytochrome c. Under conditions where the reaction is rapid, the enzyme exhibits first order kinetics with respect to mitochondrial cytochrome c, even at very high substrate concentrations. Deviation from first order is observed at slow rates with mitochondrial cytochrome c and under all conditions tested with Paracoccus cytochrome c550. The apparent maximal turnover of the enzyme is 62000 min⁻¹ with mitochondrial cytochrome c and 85000 min⁻¹ with Paracoccus c-550. The concentrations required for half-maximal activity are 3.25μM mitochondrial cytochrome c and 13μM Paracoccus c-550.Although the mitochondrial and Paracoccus cytochrome donors are very different in overall charge, an examination of their crystal structures show that they both contain a high concentration of positive charge around their front face. The positive front surface in combination with a negatively charged back hemisphere gives the c550 a large dipole moment which has been calculated as 935 Debye (compared to 342 Debye for tuna cytochrome c). This dipole moment may be important for preorientation of the cytochrome prior to its interaction with the peroxidase. Such a preorientation would allow for an increased number of fruitful collisions