Mirentxu Iruretagoyena

Inhibition of Nuclear Factor-κB Enhances the Capacity of Immature Dendritic Cells to Induce Antigen-Specific Tolerance in Experimental Autoimmune Encephalomyelitis

Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Because dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance, we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize self-peptide-major histocompatibility complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor nuclear factor (NF)-κB. We evaluated the capacity of drugs that inhibit NF-κB to enhance the tolerogenic properties of immature DCs in the experimental autoimmune encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, were able to interfere with NF-κB activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-κB-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-κB blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.

Modulation of nuclear factor‐κB activity can influence the susceptibility to systemic lupus erythematosus

Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self‐antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor FcγRIIb leads to the production of anti‐nuclear antibodies and glomerulonephritis. Splenic DCs from FcγRIIb‐deficient mice suffering from SLE showed increased expression of co‐stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor‐κB (NF‐κB) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule IκB‐α was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF‐κB activity in FcγRIIb‐deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti‐nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF‐κB function, which can be considered as a new therapeutic target for this disease.

Opposing roles of interferon-gamma on cells of the central nervous system in autoimmune neuroinflammation

Multiple sclerosis (MS) is the principal cause of autoimmune neuroinflammation in humans, and its animal model, experimental autoimmune encephalomyelitis (EAE), is widely used to gain insight about their immunopathological mechanisms for and the development of novel therapies for MS. Most studies on the role of interferon (IFN)-γ in the pathogenesis and progression of EAE have focused on peripheral immune cells, while its action on central nervous system (CNS)-resident cells has been less explored. In addition to the well-known proinflammatory and damaging effects of IFN-γ in the CNS, evidence has also endowed this cytokine both a protective and regulatory role in autoimmune neuroinflammation. Recent investigations performed in this research field have exposed the complex role of IFN-γ in the CNS uncovering unexpected mechanisms of action that underlie these opposing activities on different CNS-resident cell types. The mechanisms behind these two-faced effects of IFN-γ depend on dose, disease phase, and cell development stage. Here, we will review and discuss the dual role of IFN-γ on CNS-resident cells in EAE highlighting its protective functions and the mechanisms proposed.

Activating and inhibitory Fcγ receptors can differentially modulate T cell-mediated autoimmunity

The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FcγR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FcγRIII) and inhibitory (FcγRIIb) FcγR can modulate myelin‐specific T cell response, as well as the susceptibility to develop EAE in mice. While FcγRIIb–/– mice showed a significant increase in EAE severity, an FcγRIII deficiency protected mice from disease. In addition, FcγRIIb–/– mice showed enhanced activation of myelin‐specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild‐type mice. In contrast, FcγRIII–/– mice showed a significantly reduced activation of myelin‐specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FcγRIII–/– mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FcγR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.

The Dendritic Cell-T Cell Synapse as a Determinant of Autoimmune Pathogenesis

Autoimmune diseases occur when the immune response is targeted to self-antigens, leading to destruction or altered function of specific cells and tissues. Although the aetiology of these diseases has not yet been fully elucidated, it is believed that genetically determined susceptibility and environmental triggers are both implicated in the detrimental immune response against the bodys own tissues. Dendritic cells (DCs) are professional antigen presenting cells that play an important role in maintaining peripheral tolerance by preventing self-reactive T cells from causing autoimmune damage. Thus, alterations in the physiology of DCs are likely to be responsible for defective immune regulatory mechanisms and incomplete tolerance to self. Here, we will focus specifically on the ways in which the immunological synapse occurring at the DC-T cell interface can fine-tune the balance between tolerance and immunity and how alterations of this synapse can determine induction or perpetuation of autoimmune responses. Activating/inhibitory receptors expressed on the surface of DCs and T cells modulate the function of these cells and influence the course of the immune response. Pharmacological approaches that can modulate DC function will be also addressed as a potential antigen-specific strategy in the design of new, noninvasive therapies to prevent or to treat chronic inflammatory autoimmune disorders.

Inhibition of angiogenesis by platelets in systemic sclerosis patients

IntroductionSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angiogenesis of human dermal microvascular endothelial cells (DMVECs) in a tubule formation assay and to characterize the secretion of profibrotic and proinflammatory cytokines in these platelets.MethodsWe analyzed platelets obtained from 30 patients with SSc and 12 healthy control subjects. Angiogenesis was evaluated in vitro with a DMVEC tubule formation assay on Matrigel and platelet-derived angiogenic factors such as vascular endothelial growth factor (VEGF), 165b isoform (VEGF165b), and cytokine secretion was evaluated. Platelet serotonin content was also determined.ResultsWhen DMVECs were incubated with SSc platelet releasates, tubule formation was significantly inhibited (p < 0.01, t test), and higher expression of endothelin-1 in these cells was observed compared with control subjects (p < 0.05, Mann–Whitney U test). In SSc platelet releasates, VEGF165b was significantly higher (p < 0.05, t test), and the VEGF165b/VEGF ratio was increased compared with that of control subjects. Higher secretion of transforming growth factor β (p < 0.01, t test) and CD40L (p < 0.01, t test) was observed compared with control subjects. Also, intraplatelet serotonin levels were lower in platelets obtained from patients with diffuse SSc compared with patients with limited SSc and control subjects (p < 0.05, t test).ConclusionsOur findings suggest that antiangiogenic factors such as VEGF165b, together with proinflammatory and profibrotic factors secreted by platelets, can contribute to the progression of peripheral microvascular damage, defective vascular repair, and fibrosis in patients with SSc.

Immune Response Modulation by Vitamin D: Role in Systemic Lupus Erythematosus.

Vitamin D plays key roles as a natural immune modulator and has been implicated in the pathophysiology of autoimmune diseases, including systemic lupus erythematosus (SLE). This review presents a summary and analysis of the recent literature regarding immunoregulatory effects of vitamin D as well as its importance in SLE development, clinical severity, and possible effects of supplementation in disease treatment.

Interactions at the Dendritic Cell / T-Cell Interface Define the Balance between Immunity and Tolerance

Autoimmunity develops when the adaptive immune system reacts against self-antigens, causing destruction or altered function of the host’s own healthy tissues. Although the mechanisms responsible for the loss of tolerance to self have not yet been fully elucidated, it is thought that both genetic predisposition and environmental triggers may be involved. Considering that dendritic cells (DCs) are the antigen- presenting cells (APCs) determining the primary activation of naïve T cells, they play a pivotal role in the regulation of adaptive immunity and the maintenance of immune tolerance to self-antigens. It is thought that T cells recognizing self-constituents in the periphery are kept under control by immature DCs, through the presentation of self-antigens in the absence of costimulation. Thus, alterations in the physiology of DCs could be responsible for incomplete tolerance to self. The main focus of this review will be the capacity of the immunological synapse occurring at the DC/T-cell interface to fine-tune the balance between tolerance and immunity and how alterations on some of the constituents that participate in the synapse can determine induction or perpetuation of undesired immune responses. Factors modulating DC function and thus influencing the course of the adaptive immunity, such as activating/inhibitory receptors expressed on the surface of DCs, and pharmacological approaches will be also discussed.

Tobacco promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

BACKGROUND The dual potential to promote tolerance or inflammation when facing self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. There is an association between smoking and DCs maturation in patients with rheumatoid arthritis (RA). However, ethnicity is a key factor in autoimmune disorders. AIM To evaluate phenotypic and functional alterations of DCs obtained from Chilean patients with RA as compared to healthy controls (HC). In second term, to compare the inflammatory behaviour of DCs between smoker and non-smoker patients. MATERIAL AND METHODS Monocyte-derived DCs and T-cells were obtained from blood samples isolated from 30 HC and 32 RA-patients, 14 of which were currently smokers and 18 non-smokers. Several maturation surface markers were evaluated in DCs, including HLA-DR, CD40, CD80, CD83 and CD86. Furthermore, autologous co-cultures of DCs and T-cells were carried out and then T-cell proliferation, and expansion of Th1, Th17 and Tregs were analysed. RESULTS Compared with HC, RA-patients displayed increased HLA-DR expression in DCs, which was manifested mainly in patients with moderate-to- high disease activity scores (DAS28). Furthermore, RA-patients presented a stronger Th17-expansion and a correlation between DAS28 and Th1-expansion. Both effects were mainly observed in patients in remission or with a low DAS28. Moreover, smoker RA-patients displayed enhanced HLA-DR and CD83 expression in DCs as well as an exacerbated Th17-expansion and a correlation between DAS28 and Th1-expansion. CONCLUSIONS These findings suggest that smoking enhances the inflammatory behaviour of DCs and the consequent Th1 and Th17-mediated response in patients with RA.

Role of dendritic cells in peanut allergy

ABSTRACT Introduction: The prevalence of peanut allergy (PA) has increased, affecting approximately 1.1% of children in Western countries. PA causes life-threatening anaphylaxis and frequently persists for life. There are no standardized curative therapies for PA, and avoidance of peanuts remains the main therapeutic option. A better understanding of the pathogenesis of PA is essential to identify new treatment strategies. Intestinal dendritic cells (DCs) are essential in the induction and maintenance of food tolerance because they present dietary allergens to T cells, thereby directing subsequent immune responses. Areas covered: In this review, we discuss the factors related to the acquisition of oral tolerance to peanut proteins. We focus on intestinal DC-related aspects, including the latest advances in the biology of intestinal DC subtypes, effect of tolerance-inducing factors on DCs, effect of dietary components on oral tolerance, and role of DCs in peanut sensitization. Expert commentary: Given the increasing prevalence of PA, difficulty of avoiding peanut products, and the potentially serious accidental reactions, the development of novel therapies for PA is needed. The ability of DCs to trigger tolerance or immunity makes them an interesting target for new treatment strategies against PA.