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Background: Dominantly gain-of-function mutations in the NLRP3 gene lead to Cryopyrin associated periodic syndromes (CAPS) characterized by constitutive activation of the inflammasome, increased secretion of interleukin (IL)-1beta and IL-18, and systemic inflammation. IL-1beta and active caspase-1 subunits are released in the serum together with the oligomeric particles of the adaptor ASC (apoptosis-associated Speck-like protein with a caspase-recruitment domain) after activation of the inflammosome complex and, as a consequence, patients with CAPS show an increased serum concentration of ASC+ particles. Objectives: Patients suffering from CAPS are characterized by clinical manifestation similar to other autoinflammatory diseases. This phenomenon together with the lack of specific laboratory tests makes difficult the diagnosis of CAPS. In this context the development of a test for the evaluation of serum ASC levels could provide novel biomarkers facilitating early disease diagnosis and able to monitor treatment responses. Methods: We analysed, with a novel ELISA assay, the levels of ASC particles in serum and plasma of normal subjects, CAPS patients and patients with autoimmune disorders (Multiple Sclerosis (MS), Type 1 Diabetes (T1D) and juvenile idiopathic arthritis), to confirm that ASC presence in the serum is not due to other chronic inflammatory processes characterizing autoimmunity. To evaluate the specificity of this biomarker in CAPS patients and not in individuals suffering from others inflammatory disorders, we also analysed sera from TNF receptor–associated periodic syndrome (TRAPS) patients. Results: ASC particles were higher in untreated CAPS patients with respect to healthy controls and patients suffering from MS and T1D. This tendency was also evident in patients with arthritis and TRAPS even if the difference was not statistically significant due to the small number of samples. In addition after pharmacological treatment there is a tendency to be confirmed through a reduction of ASC levels in CAPS patients. Conclusion: These data suggest that ELISA quantitation of ASC protein could represent a novel and additional strategy for the diagnosis and monitoring of CAPS.

Dimethyl fumarate (DMF) is a first line oral treatment for relapsing-remitting multiple sclerosis (RR-MS) patients. Although it is known that DMF have protective antioxidant properties against brain and spinal cord damage during MS, its precise mechanism of action remains still elusive. Here, we evaluated the immunological effects of DMF treatment in RR-MS patients and we investigated the impact of DMF on metabolic profile of T cells. We observed that DMF treatment results in reduction of number of total lymphocytes and of CD19+ B cells, CD4+ and CD8+ T cells. In addition, DMF treatment is associated with a specific reduction of the memory T cells. Furthermore, we found that DMF treatment was able to increase the proliferative capacity of Treg cells over time and to restore the altered metabolic profile of T cells in RR-MS patients. Taken together, these data suggest a novel mechanism of action for DMF by modulation of the metabolic pathways of T cells that could lead to an improvement of immune tolerance during autoimmunity.

Supplemental material, Supplemental_PDF for Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-β1a-treated multiple sclerosis by Marcello Moccia, Antonio Capacchione, Roberta Lanzillo, Fortunata Carbone, Teresa Micillo, Francesco Perna, Anna De Rosa, Antonio Carotenuto, Roberto Albero, Giuseppe Matarese, Raffaele Palladino and Vincenzo Brescia Morra in Therapeutic Advances in Neurological Disorders

Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluatedthe effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress andinflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (inan open-label crossover design). At baseline and at the 3 and 6-month visits, we measuredmarkers of scavenging activity, oxidative damage and inflammation in the peripheral blood,and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity(as mediated by uric acid), reduced intracellular reactive oxygen species production, reducedoxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheralblood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colonystimulatingfactor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R,IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cellexpressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growthfactor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability StatusScale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidativedamage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral bloodof relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effectwas noted but deserves to be confirmed over longer follow ups. Progetto giovani ricercatori[GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colonystimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups. Progetto giovani ricercatori [GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen(RCR) is one of the e ective therapy for this condition. Aim of the study was to evaluate the effectof lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver onRCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized crossover clinical trial was performed. Participants were assigned to RCR alone or with a supplement oflycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternativeregimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size,and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groupswhereas adiponectin raised only after tomato supplementation. RCR is associated with the impairedengagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolyticmetabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obesechildren, improve oxidative and inflammatory state and modulates the mitochondrial metabolismof T-cells contributing to a maintenance of a proper immune surveillance in children, impaired byRCR. The addition of tomato to RCR could be considered a protective and preventive support toobese child. Progetto giovani ricercatori[GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Studying multiple sclerosis (MS) and its treatments requires the use of biomarkers forunderlying pathological mechanisms. We aim to estimate the required sample size for detectingvariations of biomarkers of inflammation and oxidative stress. This is a post-hoc analysis on60 relapsing-remitting MS patients treated with Interferon-1a and Coenzyme Q10 for 3 monthsin an open-label crossover design over 6 months. At baseline and at the 3 and 6-month visits, wemeasured markers of scavenging activity, oxidative damage, and inflammation in the peripheralblood (180 measurements). Variations of laboratory measures (treatment eect) were estimated usingmixed-eect linear regression models (including age, gender, disease duration, baseline expandeddisability status scale (EDSS), and the duration of Interferon-1a treatment as covariates; creatininewas also included for uric acid analyses), and were used for sample size calculations. Hypothesizinga clinical trial aiming to detect a 70% eect in 3 months (power = 80% alpha-error = 5%), the samplesize per treatment arm would be 1 for interleukin (IL)-3 and IL-5, 4 for IL-7 and IL-2R, 6 for IL-13,14 for IL-6, 22 for IL-8, 23 for IL-4, 25 for activation-normal T cell expressed and secreted (RANTES),26 for tumor necrosis factor (TNF)-, 27 for IL-1, and 29 for uric acid. Peripheral biomarkers ofoxidative stress and inflammation could be used in proof-of-concept studies to quickly screen themechanisms of action of MS treatments. Progetto giovani ricercatori[GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the e ective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child. Progetto giovani ricercatori [GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Studying multiple sclerosis (MS) and its treatments requires the use of biomarkers for underlying pathological mechanisms. We aim to estimate the required sample size for detecting variations of biomarkers of inflammation and oxidative stress. This is a post-hoc analysis on 60 relapsing-remitting MS patients treated with Interferon-1a and Coenzyme Q10 for 3 months in an open-label crossover design over 6 months. At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage, and inflammation in the peripheral blood (180 measurements). Variations of laboratory measures (treatment eect) were estimated using mixed-eect linear regression models (including age, gender, disease duration, baseline expanded disability status scale (EDSS), and the duration of Interferon-1a treatment as covariates; creatinine was also included for uric acid analyses), and were used for sample size calculations. Hypothesizing a clinical trial aiming to detect a 70% eect in 3 months (power = 80% alpha-error = 5%), the sample size per treatment arm would be 1 for interleukin (IL)-3 and IL-5, 4 for IL-7 and IL-2R, 6 for IL-13, 14 for IL-6, 22 for IL-8, 23 for IL-4, 25 for activation-normal T cell expressed and secreted (RANTES), 26 for tumor necrosis factor (TNF)-, 27 for IL-1, and 29 for uric acid. Peripheral biomarkers of oxidative stress and inflammation could be used in proof-of-concept studies to quickly screen the mechanisms of action of MS treatments. Progetto giovani ricercatori [GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Significance Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by limitation of expiratory airflow. Cellular and molecular pathways involved in disease pathogenesis are not completely defined. Our study reveals that metabolism and immune response cooperate in COPD pathogenesis and progression. COPD subjects with different disease stages showed progressive increase of systemic leptin, an adipose tissue-derived proinflammatory molecule, that, at high concentrations, impaired the capacity of T cells to engage in glycolysis and to generate regulatory T cells. Thus, the loss of these immunoregulatory circuits during COPD determined the hyperactivation of effector T cells that amplified inflammation, leading to progressive decline of lung function. Understanding these immunometabolic mechanisms can have important implications for monitoring COPD progression and for disease treatment., Chronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with abnormal immune responses, leading to airflow obstruction. Lungs of COPD subjects show accumulation of proinflammatory T helper (Th) 1 and Th17 cells resembling that of autoreactive immune responses. As regulatory T (Treg) cells play a central role in the control of autoimmune responses and their generation and function are controlled by the adipocytokine leptin, we herein investigated the association among systemic leptin overproduction, reduced engagement of glycolysis in T cells, and reduced peripheral frequency of Treg cells in different COPD stages. These phenomena were also associated with an impaired capacity to generate inducible Treg (iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited the expression of forkhead-boxP3 (FoxP3) and its splicing variants containing the exon 2 (FoxP3-E2) that correlated inversely with inflammation and weakened lung function during COPD progression. Our data reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a decline in the expression of FoxP3 splicing forms, and an impairment in Treg cell generation and function. These results have potential implications for better understanding the autoimmune-like nature of COPD and the pathogenic events leading to lung damage.

Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups.

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days, subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child.

Reliable immunologic biomarkers able to monitor disease course during multiple sclerosis (MS) are still missing. We aimed at identifying possible immunometabolic biomarkers able to predict the clinical outcome in MS patients during treatment with interferon (IFN)-beta-1a. We measured in 45 relapsing-remitting (RR) MS patients, blood circulating levels of several immunometabolic markers, at enrolment, and correlated their levels to disease activity and progression over time. Higher levels of interleukin (IL)-6, soluble-CD40-ligand (sCD40L) and leptin at baseline associated with a higher relapse rate and a greater risk of experiencing at least one relapse in the following year. Higher values of soluble tumor necrosis factor receptor (sTNF-R) and leptin at baseline were predictive of a higher number of lesions in the following one-year of follow up. In conclusion, our data suggest that an immunometabolic profiling measuring IL-6, sCD40L, leptin and sTNF-R at baseline, could represent a useful tool to predict disease course in RRMS patients during treatment with IFN-beta-1a.

The filed that links immunity and metabolism is rapidly expanding. The adipose tissue, by secreting a series of immune regulators called adipokines, represents the common mediator linking metabolic processes and immune system functions. The dysregulation of adipokine secretion, occurring in obese individuals or in conditions of malnutrition or dietary restriction, affects the activity of immune cells resulting in inflammatory autoimmune responses or increased susceptibility to infectious diseases. Alterations of cell metabolism that characterize several autoimmune diseases strongly support the idea that the immune tolerance is also regulated by metabolic pathways. The comprehension of the molecular mechanisms underlying these alterations may lead to the development of novel therapeutic strategies to control immune cell differentiation and function in conditions of autoimmunity.