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

Main and alternative pathways of the renin-angiotensin system in autoimmune inflammation of the central nervous system

In der Arbeit wurde die Rolle des Renin-Angiotensin Systems (RAS) bei experimenteller autoimmuner Enzephalomyelitis (EAE) untersucht. Die EAE bei Mäusen ähnelt bezüglich Pathogenese und Gewebeschädigung der Multiplen Sklerose - einer neurologischen Erkrankung des Menschen ohne verfügbares Heilmittel. Das RAS reguliert den Blutdruck. Seine Effektorhormone, die Angiotensine (ATs), können jedoch auch entzündliche Prozesse fördern. Blockierte man Wirkungen von AT II, verbesserte dies die EAE durch Immunmodulation. Ein weiteres Angiotensin, AT IV, spielte keine Rolle. Da das RAS auch den Salzhaushalt beeinflusst, wurden Auswirkungen erhöhter Salzaufnahme bei EAE getestet. Diese verlief unter Hochsalzdiät schwerer, begleitet von verstärkten T-Zell Antworten. Die Ergebnisse sprechen für eine krankheitsfördernde Rolle des RAS sowie salzreicher Ernährung - als möglicher Umweltfaktor - in entzündlichen Autoimmunerkrankungen und liefern Zielstrukturen für die pharmakologische Intervention.The renin-angiotensin system (RAS) was studied in murine experimental autoimmune encephalomyelitis (EAE). EAE partly resembles the autoimmune pathogenesis and histopathology of Multiple Sclerosis (MS), a neurological disease in humans lacking an effective cure. The RAS regulates blood pressure but its effector hormones, the angiotensins, can drive cardiovascular and inflammatory diseases. Antagonizing angiotensin II modulated the immune response, ameliorating EAE while the alternative RAS hormone angiotensin IV did not affect EAE. Since the RAS also influences sodium homeostasis, the role of dietary sodium intake in autoimmune responses was investigated as well. A high salt diet aggravated EAE and drove T cell responses. These results delineate the RAS and excess dietary sodium intake as drivers of autoimmune neuroinflammation and identify targets for pharmacological intervention. They suggest nutritional sodium as an environmental factor in MS and diseases with related pathology

Vascular pathology in multiple sclerosis: mind boosting or myth busting?

The investigation of central nervous system vascular changes in the pathophysiology of multiple sclerosis (MS) is a time-honored concept. Yet, recent reports on changes in venous cerebrospinal outflow, the advent of new magnetic resonance imaging techniques and the investigation of immunomodulatory properties of several vascular mediators on the molecular level have added new excitement to hypotheses centering around vascular pathology as determining factor in the pathophysiology of MS. Here we critically review the concept of chronic cerebrospinal venous insufficiency in MS patients and describe new imaging techniques including perfusion weighted imaging, susceptibility weighted imaging and diffusion weighted imaging which reveal central nervous system hypoperfusion, perivascular iron deposition and diffuse structural changes in the MS brain. On a molecular basis, vascular mediators represent interesting targets connecting vascular pathology with immunomodulation. In summary, the relation of venous changes to the pathophysiology of MS may not be as simple as initially described and it certainly seems awkward to think of the complex disease MS solely as result of a simple venous outflow obstruction. Yet, the investigation of new vascular concepts as one variable in the pathophysiology of the autoimmune attack seems very worthwhile and may add to a better understanding of this devastating disorder

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis

Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded. Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden

Additional file 1: Figure S1. of Role of glial 14-3-3 gamma protein in autoimmune demyelination

14-3-3 γ deficiency does not influence numbers of NogoA positive OL in naive mice. A, B Representative sections of the spinal cord lesions from naive mice. Bar represents 200 μm for both sections. Labelling for NogoA positive OL does not reveal any difference between 14-3-3 γ knockout mice and controls (see arrows). C Blinded quantification of NogoA positive OL on the spinal cord cross sections reveals no difference between both groups (n = 3 mice per group, p = n.s.)

Pivotal role of choline metabolites in remyelination

Neuroprotective approaches for central nervous system regeneration have not been successful in clinical practice so far and compounds that enhance remyelination are still not available for patients with multiple sclerosis. The objective of this study was to determine potential regenerative effects of the substance cytidine-5′-diphospho (CDP)-choline in two different murine animal models of multiple sclerosis. The effects of exogenously applied CDP-choline were tested in murine myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. In addition, the cuprizone-induced mouse model of de- and remyelination was used to specifically test the hypothesis that CDP-choline directly increases remyelination. We found that CDP-choline ameliorated the disease course of experimental autoimmune encephalomyelitis and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, CDP-choline effectively enhanced myelin regeneration and reversed motor coordination deficits. The increased remyelination arose from an increase in the numbers of proliferating oligodendrocyte precursor cells and oligodendrocytes. Further in vitro studies suggest that this process is regulated by protein kinase C. We thus identified a new mechanism to enhance central nervous system remyelination via the choline pathway. Due to its regenerative action combined with an excellent safety profile, CDP-choline could become a promising substance for patients with multiple sclerosis as an add-on therapy