Role of “Western Diet” in Inflammatory Autoimmune Diseases

Developed societies, although having successfully reduced the burden of infectious disease, constitute an environment where metabolic, cardiovascular, and autoimmune diseases thrive. Living in westernized countries has not fundamentally changed the genetic basis on which these diseases emerge, but has strong impact on lifestyle and pathogen exposure. In particular, nutritional patterns collectively termed the “Western diet”, including high-fat and cholesterol, high-protein, high-sugar, and excess salt intake, as well as frequent consumption of processed and ‘fast foods’, promote obesity, metabolic syndrome, and cardiovascular disease. These factors have also gained high interest as possible promoters of autoimmune diseases. Underlying metabolic and immunologic mechanisms are currently being intensively explored. This review discusses the current knowledge relative to the association of “Western diet” with autoimmunity, and highlights the role of T cells as central players linking dietary influences to autoimmune pathology.National Institutes of Health (U.S.) (NIH grant P30-ES002109

Metabolic, mental and immunological effects of normoxic and hypoxic training in multiple sclerosis patients: a pilot study

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells. Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed. Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39(+) and CD31(+) Tregs, respectively, and decreased IL-17A-producing CD4(+) cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group. Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin

Rapamycin rescues loss of function in blood-brain barrier- interacting Tregs

In autoimmunity, FOXP3+ Tregs skew toward a proinflammatory, nonsuppressive phenotype and are, therefore, unable to control the exaggerated autoimmune response. This largely affects the success of autologous Treg therapy, which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the CNS during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss of function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential and a proinflammatory Th1/17 signature, and they upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less-suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In summary, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive proinflammatory phenotype switch. These insights help improve the efficacy o

Pyridoxamine Limits Cardiac Dysfunction in a Rat Model of Doxorubicin-Induced Cardiotoxicity.

peer reviewedThe use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-β1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy

Metabolic, Mental and Immunological Effects of Normoxic and Hypoxic Training in Multiple Sclerosis Patients: A Pilot Study

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells.Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed.Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P &lt; 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39+ and CD31+ Tregs, respectively, and decreased IL-17A-producing CD4+ cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group.Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin.Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.go

Microbial Reprogramming Inhibits Western Diet-Associated Obesity

A recent epidemiological study showed that eating ‘fast food’ items such as potato chips increased likelihood of obesity, whereas eating yogurt prevented age-associated weight gain in humans. It was demonstrated previously in animal models of obesity that the immune system plays a critical role in this process. Here we examined human subjects and mouse models consuming Westernized ‘fast food’ diet, and found CD4[superscript +] T helper (Th)17-biased immunity and changes in microbial communities and abdominal fat with obesity after eating the Western chow. In striking contrast, eating probiotic yogurt together with Western chow inhibited age-associated weight gain. We went on to test whether a bacteria found in yogurt may serve to lessen fat pathology by using purified Lactobacillus reuteri ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone was sufficient to change the pro-inflammatory immune cell profile and prevent abdominal fat pathology and age-associated weight gain in mice regardless of their baseline diet. These beneficial microbe effects were transferable into naïve recipient animals by purified CD4[superscript +] T cells alone. Specifically, bacterial effects depended upon active immune tolerance by induction of Foxp3[superscript +] regulatory T cells (Treg) and interleukin (Il)-10, without significantly changing the gut microbial ecology or reducing ad libitum caloric intake. Our finding that microbial targeting restored CD4[superscript +] T cell balance and yielded significantly leaner animals regardless of their dietary ‘fast food’ indiscretions suggests population-based approaches for weight management and enhancing public health in industrialized societies.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant RO1CA108854)National Institutes of Health (U.S.) (Grant P01 AI045757)National Institutes of Health (U.S.) (Grant U19 AI046130)National Institutes of Health (U.S.) (Grant U19 AI070352)National Institutes of Health (U.S.) (Grant P01 AI039671)National Institute of Neurological Disorders and Stroke (U.S.) (Jacob Javits Merit Award NS2427)The Penates FoundationNancy Taylor Foundation for Chronic Diseases, Inc

Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants

Summary Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models

Characterization of CD25+ regulatory T cells

Titelblatt und Inhaltsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Literaturverzeichnis Zusammenfassung Summary Abkürzungen Danksagung und ErklärungRegulatorische T Zellen sind ein zentrales Element bei der Kontrolle der peripheren immunologischen Selbst-Toleranz in Säugetieren. Aufgrund ihrer speziellen Eigenschaften überwachen sie im Zusammenspiel mit weiteren Zellen des Immunsystems wie z.B. dendritischen Zellen (DC) und natürlichen killer T Zellen (NKT) zahlreiche Immunreaktion und sind in der Lage CD4+ und CD8+ T Zellen als auch B Zellen spezifisch zu regulieren. Im Thymus entstandene natürliche CD25+ CD4+ regulatorische T Zellen (Treg) scheinen bei diesem Prozess eine Hauptrolle einzunehmen. Mit dieser Analyse wurde gezeigt, dass Treg Zellen entgegen früheren Vorstellungen eine heterogene Population darstellen. Anhand der Expression vom Chemokinrezeptor CCR6 kann eine neue Subpopulationen von Effektor-Gedächtniszell ähnlichen Treg (TREM) definiert werden. Diese Treg Subpopulation zeigt einen charakteristischen Gedächtniszell-Phänotyp und weitere typische Eigenschaften, die sie von CCR6 negativen Treg, welche einen vorwiegend naiven Phänotyp zeigen, unterscheidet. TREM entstehen nach Antigenkontakt im Beisein weiterer Faktoren aus CCR6 negativen Treg und scheinen eine wichtige Rolle bei der Kontrolle von peripheren Inflammationen im entzündeten Gewebe einzunehmen. Hier scheinen sie die direkten Gegenspieler von konventionellen Effektor-Gedächtniszellen (TEM) zu sein. Neben dem typischen Gedächtniszell Phänotyp unterscheidet sich diese Population auch funktionell von CCR6 negativen Treg. Im Gegensatz zu CCR6- CD25+ T Zellen exprimieren TREM nach wiederholten Antigenkontakt hohe Mengen an IL10 und haben die Fähigkeit eine IDO (indoleamine 2,3-dioxygenase) Expression nach Ko-Kultivierung in CD11c+ DC zu induzieren. Eine zur Maus analoge Population von CCR6+ TREM kann auch im Menschen gefunden werden. Humane Effektor-Gedächtniszell ähnliche Treg können zusätzlich über eine hohe CLA (cutaneous lymphocyte antigen) und niedrige α4 Integrin (CD49d) Expression definiert werden. Sie zeigen die höchste Foxp3 Proteinexpression unter CD25high regulatorischen CD4+ T Zellen und scheinen daher möglicherweise die effektivste Treg Population im Menschen zu sein. Die differentielle Adhäsionsmolekül Ausprägung ermöglicht eine selektive Kontrolle der Treg oder effektor T Zell- (Teff) Rekrutierung zum Entzündungsherd und scheint somit ein entscheidender Faktor zur Steuerung der Balance zwischen Treg und Teff zu sein. Auch im Thymus kann eine CCR6 Expression auf CD25+ ausprägenden T Zellen nachgewiesen werden. Die Chemokinrezeptor Expression scheint im Gegensatz zur peripheren CCR6 Ausprägung jedoch transient zu sein und eine besondere Stufe während der Reifung von Treg Vorläuferzellen zu markieren. CCR6+ Thymozyten exsprimieren noch intermediäre Mengen von CD8 und zeigen einen aktivierten, unreifen Phänotyp, während sie schon voll funktionsfähig sind und hohe Mengen an Foxp3 ausprägen. Interessanterweise kann mit zunehmenden Alter der Tiere eine höhere Anzahl an CCR6+ Treg Vorläuferzellen im Thymus detektiert werden. CCR6+ CD25+ Thymozyten stellen daher wahrscheinlich eine Vorstufe von reifen Treg Vorläuferzellen dar, die möglicherweise im Zusammenhang mit einem speziellem Selektionsmechanismus im Thymus steht.Regulatory T cells are a central element for the control of the peripheral immunological self-tolerance in mammals. Based on their special characteristics they are able to control numerous immune reactions. By the interplay with other cells of the immune system like e.g. dendritic cells (DC) and natural killer T cells (NKT) they are able to specifically regulate CD4+ T cells, CD8+ T cells and B cells. CD25+ natural regulatory T cells (Treg) emerge in the thymus and seem to take a leading role in this process. With this analysis it was shown that Treg cells represent a heterogeneous cell population contrary to past studies. Based on the expression of the chemokinereceptor CCR6, a new subpopulation can be defined as effector/memory- like Treg (TREM). This Treg subpopulation shows characteristic effector/memory phenotype as well as further typical traits, that distinguishes it from CCR6 negative Treg, which show a predominantly naive phenotype. TREM develop after antigen contact, most likely in the presence of additional factors from CCR6 negative Treg and seem to take an important role in the control of peripheral inflammations directly within inflamed tissues. Here they seem to be the direct counterparts of conventional effector/memory cells (TEM). In addition to the typical memory phenotype, this population also differs functionally from CCR6 negative Treg. In contrast to CCR6- CD25+ T cells, TREM express, after repeated antigen contact, high quantities of IL10 and are able to induce IDO (indoleamine 2,3-dioxygenase) expression of CD11c+ DC after co-cultivation with these cells. An analogous population to the mouse CCR6+ TREM can also be found in humans. Human effector/memory-like Treg can be defined additionally by a high expression of CLA (cutaneous lymphocyte antigen) and a low alpha4 Integrin (CD49d) expression. They show the highest Foxp3 protein expression of CD25high regulatory CD4+ T cells and therefore seem to be the most effective Treg population in humans. The differential adhesionmolecule expression enables a selective control of the Treg or effector T cell (Teff) recruitment to the inflamed tissue and seems to be therefore a decisive factor for the control of the balance between Treg and Teff. Also in the Thymus, CCR6 can be found on CD25+ expressing T cells. The chemokinereceptor expression however seems to be transient in contrast to the peripheral CCR6 expression and marks a special step during the maturation of Treg precurser cells. CCR6+ thymocytes still express intermediate levels of CD8 and they show an activated, premature phenotype, although they express high quantities of Foxp3 and are fully functional. Interestingly, a higher amount of CCR6+ Treg in the Thymus can be detected with increasing age. CCR6+ CD25+ thymocytes appear therefore to represent an initial stage of Treg precursers, that stands most likely in connection with a special selection mechanism of these cells in the thymus

Interrelation of Diet, Gut Microbiome, and Autoantibody Production

B cells possess a predominant role in adaptive immune responses via antibody-dependent and -independent functions. The microbiome of the gastrointestinal tract is currently being intensively investigated due to its profound impact on various immune responses, including B cell maturation, activation, and IgA antibody responses. Recent findings have demonstrated the interplay between dietary components, gut microbiome, and autoantibody production. “Western” dietary patterns, such as high fat and high salt diets, can induce alterations in the gut microbiome that in turn affects IgA responses and the production of autoantibodies. This could contribute to multiple pathologies including autoimmune and inflammatory diseases. Here, we summarize current knowledge on the influence of various dietary components on B cell function and (auto)antibody production in relation to the gut microbiota, with a particular focus on the gut–brain axis in the pathogenesis of multiple sclerosis