Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate ne... more Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and n...
IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). ... more IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using tr...
doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and di... more doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and disease
Clinical and experimental immunology, Jan 12, 2016
Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. A... more Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR) and interleukin 6 (IL-6) and SAA serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimes. Serum concentrations of sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6...
The past 20 years of research on leptin have provided crucial information on the link between met... more The past 20 years of research on leptin have provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. We discuss here the role of leptin in the regulation the immune response, innate and adaptive response, both in normal and pathological conditions and the influence of this cytokine/hormone in the physiopathology of inflammation.
TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mu... more TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4(+)CD25(-) and regulatory CD4(+)CD25(+) T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4(+) conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (C... more Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells. Animal modeling has been critical for addressing MS pathogenesis. The three most characterized animal models of MS are (1) the experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally-induced chronic demyelinating disease, known as Theiler׳s murine encephalomyelitis virus (TMEV) infection and (3) the toxin-induced demyelination. All these models, in a complementary way, have allowed to reach a good knowledge of the pathogenesis of MS. Specifically, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely useful to study potential experimental treatments. Furthermore, both TMEV and toxin-induced demyelination models are suitable for characterizing the role of the axonal injury/repair and the remyelination process in MS. In conclusion, animal models, despite their limitations, remain the most useful instrument for implementing the study of MS.
Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and or... more Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggest...
Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited aut... more Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited auto-inflammatory disorder caused by mutations in TNFRSF1A, the gene encoding for tumour necrosis factor receptor superfamily 1A. The mechanism of inflammation in TRAPS is still unknown. In particular the involvement of adaptive immunity in autoinflammatory disorders hasn’t been investigated yet. In this project we investigated how TNFa/TNRSF1A signalling network regulates T cell responses. In particular, we focused on conventional CD4+CD25- (Tconv) and regulatory CD4+CD25+ (Treg) T cell functions in TRAPS patients carrying either high or low penetrance mutation in TNFRSF1A gene (HP-TRAPS and LP-TRAPS, respectively). HP-TRAPS showed an upregulation of several inflammation-related molecular signalling pathways in Tconv cells. In addition, these patients had a lower frequency of peripheral Treg cells which also displayed a defective suppressive phenotype. These alterations were partially foun...
Background Behçet's disease (BD) is a rare and poorly understood condition characterised by s... more Background Behçet's disease (BD) is a rare and poorly understood condition characterised by systemic inflammation. Current biomarkers are still largely insensitive and unable to predict disease progression and response to treatment in BD patients. Objectives The specific aims of this study were i) to explore serum levels of soluble CD40L (sCD40L), soluble intracellular-adhesion-molecule (sICAM-1), monocyte-chemoattractant-protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble-type 1 tumour-necrosis-factor-receptor (sTNFR), interleukin-6 (IL-6) and serum-amyloid-A (SAA); ii) to evaluate potential correlations between the putative circulating biomarkers with the demographic profile, disease activity, organ involvement, genetical background, and different therapeutic regimes. Methods 57 serum samples were collected from 27 BD patients and 35 healthy controls (HC) after written consent. Demographic and clinical data are summarized in Table 1. Adipocytokines were analyzed using the bead-based-analyte-detection-system. Data were acquired by flow-cytometry. SAA serum concentration was determined with a enzyme linked-immunosorbent assay (ELISA). We used ANOVA test to identify statistical differences. P<0.05 was considered statistically significant. Results BD patients showed higher levels of circulating sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6 (p=0.0154) than HC while no difference was found in MCP-1, MPO, sICAM, and resistin serum levels. Patients HLA-B51- had higher sTNFR and sICAM-1 serum levels than HC (p=0.0034, p=0.0037, respectively), while sICAM levels were significantly higher in patients HLA-B51- than in patients HLAB51+ (p=0.0010) as well as leptin was significantly higher in both HLA-B51+ and HLA-B51- BD patients than in HC (p=0.0183, p=0.0303, respectively). Patients treated with biologic-agents showed significantly higher sTNFR and leptin serum levels when compared to DMARDs-treated-patients (p=0.0246,p=0.0023, respectively). Moreover, sTNFR was found higher in patients with inactive disease and in patients over 40 years than HC (p=0.0104, p=0.0329, respectively).Table 1. Demographic and clinical data of BD patients BD patients BD serum samples Males/females 12/15 27/30 Age (mean ± SD), years 45.7±13.54 51.19±30.26 Disease onset (mean ± SD), years 32.55±14.35 34.15±13.48 Disease duration (mean ± SD), years 13.59±12.67 13.85±12.34 HLA-B51 positivity. n (%) 17 (62.96) 40 (70.17) Oral/genital aphtosis 23 (85.18) 39 (68.42) Skin manifestations 10 (37.03) 12 (21.05) Uveitis 11 (40.74) 20 (35.08) SNC involvement 18 (66.66) 26 (45.61) Vascular involvement 2 (7.40) 4 (07.01) Gastrointestinal manifestations 4 (14.81) 4 (07.01) Musculoskeletal involvement 20 (74.07) 27 (47.36) Conclusions The identification of a specific meta-immunological profile associated with disease status and response to therapy may contribute to our understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach. Disclosure of Interest None declared
In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)... more In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells. In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy. The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays. Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the m... more The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate ne... more Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and n...
IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). ... more IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using tr...
doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and di... more doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and disease
Clinical and experimental immunology, Jan 12, 2016
Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. A... more Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR) and interleukin 6 (IL-6) and SAA serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimes. Serum concentrations of sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6...
The past 20 years of research on leptin have provided crucial information on the link between met... more The past 20 years of research on leptin have provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. We discuss here the role of leptin in the regulation the immune response, innate and adaptive response, both in normal and pathological conditions and the influence of this cytokine/hormone in the physiopathology of inflammation.
TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mu... more TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4(+)CD25(-) and regulatory CD4(+)CD25(+) T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4(+) conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (C... more Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells. Animal modeling has been critical for addressing MS pathogenesis. The three most characterized animal models of MS are (1) the experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally-induced chronic demyelinating disease, known as Theiler׳s murine encephalomyelitis virus (TMEV) infection and (3) the toxin-induced demyelination. All these models, in a complementary way, have allowed to reach a good knowledge of the pathogenesis of MS. Specifically, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely useful to study potential experimental treatments. Furthermore, both TMEV and toxin-induced demyelination models are suitable for characterizing the role of the axonal injury/repair and the remyelination process in MS. In conclusion, animal models, despite their limitations, remain the most useful instrument for implementing the study of MS.
Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and or... more Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggest...
Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited aut... more Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited auto-inflammatory disorder caused by mutations in TNFRSF1A, the gene encoding for tumour necrosis factor receptor superfamily 1A. The mechanism of inflammation in TRAPS is still unknown. In particular the involvement of adaptive immunity in autoinflammatory disorders hasn’t been investigated yet. In this project we investigated how TNFa/TNRSF1A signalling network regulates T cell responses. In particular, we focused on conventional CD4+CD25- (Tconv) and regulatory CD4+CD25+ (Treg) T cell functions in TRAPS patients carrying either high or low penetrance mutation in TNFRSF1A gene (HP-TRAPS and LP-TRAPS, respectively). HP-TRAPS showed an upregulation of several inflammation-related molecular signalling pathways in Tconv cells. In addition, these patients had a lower frequency of peripheral Treg cells which also displayed a defective suppressive phenotype. These alterations were partially foun...
Background Behçet's disease (BD) is a rare and poorly understood condition characterised by s... more Background Behçet's disease (BD) is a rare and poorly understood condition characterised by systemic inflammation. Current biomarkers are still largely insensitive and unable to predict disease progression and response to treatment in BD patients. Objectives The specific aims of this study were i) to explore serum levels of soluble CD40L (sCD40L), soluble intracellular-adhesion-molecule (sICAM-1), monocyte-chemoattractant-protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble-type 1 tumour-necrosis-factor-receptor (sTNFR), interleukin-6 (IL-6) and serum-amyloid-A (SAA); ii) to evaluate potential correlations between the putative circulating biomarkers with the demographic profile, disease activity, organ involvement, genetical background, and different therapeutic regimes. Methods 57 serum samples were collected from 27 BD patients and 35 healthy controls (HC) after written consent. Demographic and clinical data are summarized in Table 1. Adipocytokines were analyzed using the bead-based-analyte-detection-system. Data were acquired by flow-cytometry. SAA serum concentration was determined with a enzyme linked-immunosorbent assay (ELISA). We used ANOVA test to identify statistical differences. P<0.05 was considered statistically significant. Results BD patients showed higher levels of circulating sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6 (p=0.0154) than HC while no difference was found in MCP-1, MPO, sICAM, and resistin serum levels. Patients HLA-B51- had higher sTNFR and sICAM-1 serum levels than HC (p=0.0034, p=0.0037, respectively), while sICAM levels were significantly higher in patients HLA-B51- than in patients HLAB51+ (p=0.0010) as well as leptin was significantly higher in both HLA-B51+ and HLA-B51- BD patients than in HC (p=0.0183, p=0.0303, respectively). Patients treated with biologic-agents showed significantly higher sTNFR and leptin serum levels when compared to DMARDs-treated-patients (p=0.0246,p=0.0023, respectively). Moreover, sTNFR was found higher in patients with inactive disease and in patients over 40 years than HC (p=0.0104, p=0.0329, respectively).Table 1. Demographic and clinical data of BD patients BD patients BD serum samples Males/females 12/15 27/30 Age (mean ± SD), years 45.7±13.54 51.19±30.26 Disease onset (mean ± SD), years 32.55±14.35 34.15±13.48 Disease duration (mean ± SD), years 13.59±12.67 13.85±12.34 HLA-B51 positivity. n (%) 17 (62.96) 40 (70.17) Oral/genital aphtosis 23 (85.18) 39 (68.42) Skin manifestations 10 (37.03) 12 (21.05) Uveitis 11 (40.74) 20 (35.08) SNC involvement 18 (66.66) 26 (45.61) Vascular involvement 2 (7.40) 4 (07.01) Gastrointestinal manifestations 4 (14.81) 4 (07.01) Musculoskeletal involvement 20 (74.07) 27 (47.36) Conclusions The identification of a specific meta-immunological profile associated with disease status and response to therapy may contribute to our understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach. Disclosure of Interest None declared
In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)... more In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells. In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy. The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays. Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the m... more The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
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