Regulatory T cell proliferative potential as novel marker to investigate immune tolerance and clinical progression in Multiple Sclerosis

In autoimmune disorders such as Multiple Sclerosis (MS) one of the determining alteration is the breakdown of self-antigen immune-tolerance. Peripheral immune tolerance is maintained, at least in part, by Regulatory T cells (Treg). Several studies have shown that either defects in the frequency or the suppressive capacity of Treg cells can contribute to the development of break of self-tolerance, and that in animal models of autoimmunity, adoptive transfer of Treg cells was able to stop disease process. Treg cells are known to be anergic in vitro to T cell receptor-induced (TCR) stimulation and this state correlates with their in vitro suppressive capacity. It has been reported that there are differences in the number of Treg cells in MS patients when compared with healthy controls. However there is also extensive evidence indicating a defect in the suppressive function of Treg cells from MS patients. In previous studies we showed that Treg cells produce an higher amount of leptin when compared with effector T cells and that leptin acts as a negative signal for the proliferation of Treg cells. In vitro leptin neutralization results in Treg cells proliferation. Although in last few years several studies have been performed to understand the molecular mechanism leading to autoimmune disorders development, there are no surrogate markers to predict the clinical progression of autoimmune diseases and the clinical response to the classical therapeutic regimes

The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements

Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells

BACE1 influences clinical manifestations and central inflammation in relapsing remitting multiple sclerosis

Neurodegenerative and inflammatory processes influence the clinical course of multiple sclerosis (MS). The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been associated with cognitive dysfunction, amyloid deposition and neuroinflammation in Alzheimer's disease.We explored in a group of 50 patients with relapsing-remitting MS the association between the cerebrospinal fluid (CSF) levels of BACE1, clinical characteristics at the time of diagnosis and prospective disability after three-years follow-up. In addition, we assessed the correlations between the CSF levels of BACE 1, amyloid beta (A beta) 1-40 and 1-42, phosphorylated tau (pTau), lactate, and a set of inflammatory and anti-inflammatory molecules.BACE1 CSF levels were correlated positively with depression as measured with Beck Depression Inventory-Second Edition scale, and negatively with visuospatial memory performance evaluated by the Brief Visuospatial Memory Test-Revised. In addition, BACE CSF levels were positively correlated with Bayesian Risk Estimate for MS at onset, and with Expanded Disability Status Scale score assessed three years after diagnosis. Furthermore, a positive correlation was found between BACE1, amyloid beta 42/40 ratio (Spearman's r = 0.334, p = 0.018, n = 50), pTau (Spearman's r = 0.304, p = 0.032, n = 50) and lactate concentrations (Spearman's r = 0.361, p = 0.01, n = 50). Finally, an association emerged between BACE1 CSF levels and a group of pro and anti-inflammatory molecules, including interleukin (IL)-4, IL-17, IL-13, IL-9 and interferon-gamma.BACE1 may have a role in different key mechanisms such as neurodegeneration, oxidative stress and inflammation, influencing mood, cognitive disorders and disability progression in MS

The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus

Establishment and maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens and tolerate paternal alloantigens expressed in fetal tissues. Regulatory T (Treg) cells, a subset of suppressor CD4(+) T cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. Although localized mechanisms contribute to fetal evasion from immune attack, in the last few years it has been observed that Treg cells are essential in promoting fetal survival avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system. Several functional studies have shown that unexplained infertility, miscarriage and pre-clampsia are often associated with deficit in Treg cell number and function while normal pregnancy selectively stimulates the accumulation of maternal forkhead-box-P3(+) (FoxP3(+)) CD4(+) Treg cells with fetal specificity. Some papers have been reported that the number of Treg cells persists at elevated levels long after delivery developing an immune regulatory memory against father's antigens, moreover these memory Treg cells rapidly proliferate during subsequent pregnancies, however, on the other hand, there are several evidence suggesting a clear decline of Treg cells number after delivery. Different factors such as cytokines, adipokines, pregnancy hormones and seminal fluid have immunoregulatory activity and influence the success of pregnancy by increasing Treg cell number and activity. The development of strategies capable of modulating immune responses toward fetal antigens through Treg cell manipulation, could have an impact on the induction of tolerance against fetal antigens during immune-mediated recurrent abortion

Leptin as immune mediator: Interaction between neuroendocrine and immune system

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates

Role of Adipokines Signaling in the Modulation of T Cells Function

The field that links immunity and metabolism is rapidly expanding. Apparently non-immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation, suggesting that metabolic alterations can be induced by or be consequence of an altered self-immune tolerance. In this context, adipose tissue produces and releases a variety of pro-inflammatory and anti-inflammatory factors, termed “adipokines,” which can be considered as the bridge between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events leading to metabolic syndrome, inflammatory, and/or autoimmune conditions. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, modulation of immune responses, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism, and so on. This report aims to discuss some of the recent topics of adipocytokine research and their related signaling pathways, that may be of particular importance as could lead to effective therapeutic strategies for obesity-associated diseases

Gluten consumption and inflammation affect the development of celiac disease in at-risk children

: Gene expression, lipidomic and growth impairment findings suggest that the natural history of celiac disease (CD) starts before the gluten-induced immune response. Gluten intake in the first years of life is a controversial risk factor. We aimed to estimate the risk of developing CD associated with the amount of gluten intake and the serum inflammatory profile in genetically predisposed infants. From an Italian cohort of children at risk for CD, we enrolled 27 children who developed CD (cases) and 56 controls matched by sex and age. A dietary interview at 9, 12, 18, 24 and 36 months was performed. Serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10 IL12p70, IL17, and TNFα) were analysed at 4 and 36 months. Infants who developed CD by 6 years showed an increase in serum cytokines (INFγ, IL1β, IL2, IL6, IL10, IL12p70 and TNFα) at 4 months of age before gluten introduction. CD cases ate significantly more gluten in the second year of life than controls, and gluten intake in the second year of life was strongly correlated with serum cytokines (INFγ, IL2, IL4, IL12p70, IL17) at 36 months only in CD cases. The dietary pattern of infants who developed CD was characterized by high consumption of biscuits and fruit juices and low intake of milk products, legumes, vegetables and fruits. Genetically predisposed infants who developed CD showed a unique serum cytokine profile at 4 months before gluten consumption. The amount of gluten was strongly correlated with an inflammatory profile in serum cytokines at 36 months only in infants who developed CD

Metabolic control of immune tolerance in health and autoimmunity

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

Cutting edge: Increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T Cells and an impaired regulatory T Cell function

Glycogen storage disease type 1b (GSD-1b) is an autosomal-recessive disease caused by mutation of glucose-6-phosphate transporter and characterized by altered glycogen/glucose homeostasis. A higher frequency of autoimmune diseases has been observed in GSD-1b patients, but the molecular determinants leading to this phenomenon remain unknown. To address this question, we investigated the effect of glucose-6-phosphate transporter mutation on immune cell homeostasis and CD4(+) T cell functions. In GSD-1b subjects, we found lymphopenia and a reduced capacity of T cells to engage glycolysis upon TCR stimulation. These phenomena associated with reduced expression of the FOXP3 transcription factor, lower suppressive function in peripheral CD4(+) CD25(+) FOXP3(+) regulatory T cells, and an impaired capacity of CD4(+) CD25-conventional T cells to induce expression of FOXP3 after suboptimal TCR stimulation. These data unveil the metabolic determinant leading to an increased autoimmunity risk in GSD-1b patients