Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment.

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients.

Single-cell profiling reveals preferential reduction of memory B cell subsets in cladribine patients that correlates with treatment response.

Background: Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect.

Objectives: Our aim was to provide a more profound understanding of the detailed effects of cladribine, also with regard to the patients' therapy response.

Attenuation of immune activation in patients with multiple sclerosis on a wheat-reduced diet: a pilot crossover trial.

Background: Western lifestyle has been associated with an increase in relapsing-remitting multiple sclerosis (RRMS). In mice, dietary wheat amylase-trypsin inhibitors (ATIs) activate intestinal myeloid cells and augment T cell-mediated systemic inflammation.

Objective: The aim of this study was to assess whether a wheat- and thus ATI-reduced diet might exert beneficial effects in RRMS patients with modest disease activity.

Immunoadsorption versus double-dose methylprednisolone in refractory multiple sclerosis relapses.

Objective: Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing.

Methods: In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed.

Intracavity Raman scattering couples soliton molecules with terahertz phonons.

Ultrafast atomic vibrations mediate heat transport, serve as fingerprints for chemical bonds and drive phase transitions in condensed matter systems. Light pulses shorter than the atomic oscillation period can not only probe, but even stimulate and control collective excitations. In general, such interactions are performed with free-propagating pulses.

Impact of disease-modifying therapies on humoral and cellular immune-responses following SARS-CoV-2 vaccination in MS patients.

The impact of distinct disease-modifying therapies (DMTs) on severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination efficacy in patients with multiple sclerosis (MS) is still enigmatic. In this prospective comparative study, we investigated humoral and cellular immune-responses in patients with MS receiving interferon beta, natalizumab, and ocrelizumab pre-vaccination and 6 weeks post second SARS-CoV-2 vaccination. Healthy individuals and interferon beta-treated patients generated robust humoral and cellular immune-responses.

Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis.

Background And Objectives: In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation.

Methods: To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85).

Results: Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS.

Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity.

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells.

The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice.

The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in a number of processes and disorders. While it is known that RAGE-signaling can contribute to toxic liver damage and fibrosis, its role in acute inflammatory liver injury and septic multiorgan failure is yet undefined. We examined RAGE in lipopolysaccharide (LPS) induced acute liver injury of D-galN sensitized mice as a classical model for tumor necrosis factor alpha (TNF-α) dependent inflammatory organ damage.

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS).

[Patient involvement in clinical practice guidelines is poor after 12 years of German guideline standards: A review of guideline methodologies].

Background: As early as 1997, the German Guideline for Guidelines laid down patient participation in guideline development as the cornerstone of good, trustworthy medical guidelines. The German Guideline Assessment Tool (DELBI) published in 2005 requires patients or relatives to be involved in the development of medical guidelines. Ideally, this should be effected through membership in the author group.

Immune Cell Profiling During Switching from Natalizumab to Fingolimod Reveals Differential Effects on Systemic Immune-Regulatory Networks and on Trafficking of Non-T Cell Populations into the Cerebrospinal Fluid-Results from the ToFingo Successor Study.

Leukocyte sequestration is an established therapeutic concept in multiple sclerosis (MS) as represented by the trafficking drugs natalizumab (NAT) and fingolimod (FTY). However, the precise consequences of targeting immune cell trafficking for immunoregulatory network functions are only incompletely understood. In the present study, we performed an in-depth longitudinal characterization of functional and phenotypic immune signatures in peripheral blood (PB) and cerebrospinal fluid (CSF) of 15 MS patients during switching from long-term NAT to FTY treatment after a defined 8-week washout period within a clinical trial (ToFingo successor study; ClinicalTrials.

Activation-dependent cell death of human monocytes is a novel mechanism of fine-tuning inflammation and autoimmunity.

In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ.

Memory-updating abrogates extinction of learned immunosuppression.

When memories are recalled, they enter a transient labile phase in which they can be impaired or enhanced followed by a new stabilization process termed reconsolidation. It is unknown, however, whether reconsolidation is restricted to neurocognitive processes such as fear memories or can be extended to peripheral physiological functions as well. Here, we show in a paradigm of behaviorally conditioned taste aversion in rats memory-updating in learned immunosuppression.

Granulocyte Macrophage Colony-Stimulating Factor-Activated CD39/CD73 Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells.

Background & Aims: Granulocyte macrophage colony-stimulating factor (GM-CSF) treatment induces clinical response in patients with active Crohn's disease. To explore whether monocytes mediate GM-CSF effects in vivo, we used a mouse model of chronic colitis induced by dextran sulfate sodium (DSS).

Methods: Murine bone marrow-derived monocytes were activated with GM-CSF in vitro, and gene expression, phenotype, and function of GM-CSF-activated monocytes (GMaM) were analyzed.

Reprogramming of monocytes by GM-CSF contributes to regulatory immune functions during intestinal inflammation.

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo.

The sympathetic nervous system modulates CD4(+)Foxp3(+) regulatory T cells via noradrenaline-dependent apoptosis in a murine model of lymphoproliferative disease.

The sympathetic nervous system (SNS) plays a crucial role in the course and development of autoimmune disease in Fas-deficient lpr/lpr mice. As regulatory T cells (Tregs) are considered important modulators of autoimmune processes, we analyzed the interaction between the SNS and Tregs in this murine model of lymphoproliferative disease. We found that the percentage of Tregs among CD4(+) T cells is increased in the spleen, lymph nodes, and thymus of lpr/lpr mice as compared to age-matched C57Bl/6J (B6) mice.

Proinflammatory S100A12 can activate human monocytes via Toll-like receptor 4.

Rationale: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far.

Amygdaloid signature of peripheral immune activation by bacterial lipopolysaccharide or staphylococcal enterotoxin B.

Activated immune cells produce soluble mediators that not only coordinate local and systemic immune responses but also act on the brain to initiate behavioral, neuroendocrine and metabolic adaptations. Earlier studies have shown that the amygdala, a group of nuclei located in the medial temporal lobe, is engaged in the central processing of afferent signals from the peripheral immune system. Here, we compared amygdaloid responses to lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB), two prototypic bacterial products that elicit distinct immune responses.

Neurobehavioural activation during peripheral immunosuppression.

Like other physiological responses, immune functions are the subject of behavioural conditioning. Conditioned immunosuppression can be induced by contingently pairing a novel taste with an injection of the immunosuppressant cyclosporine A (CsA) in an associative learning paradigm. This learned immunosuppression is centrally mediated by the insular cortex and the amygdala.

Repeated recall of learned immunosuppression: evidence from rats and men.

Akin to other physiological responses, the immune system can be modified, via Pavlovian or behavioral conditioning. It is unknown, however, whether and to what extent learned immune responses can be repeatedly recalled over time. Here we demonstrate in both rats and humans that repeated contingent pairing of a novel taste (conditioned stimulus, CS) together with the immunosuppressive drug cyclosporine A as unconditioned stimulus (US) leads to the acquisition of a learned immunosuppression.

Electrical activity in rat cortico-limbic structures after single or repeated administration of lipopolysaccharide or staphylococcal enterotoxin B.

Immune-to-brain communication is essential for an individual to aptly respond to challenging internal and external environments. However, the specificity by which the central nervous system detects or 'senses' peripheral immune challenges is still poorly understood. In contrast to post-mortem c-Fos mapping, we recorded neural activity in vivo in two specific cortico-limbic regions relevant for processing visceral inputs and associating it with other sensory signalling, the amygdala (Am) and the insular cortex (IC).

Stimulation of β₂-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction.

The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of β₂-adrenergic receptors (AR) on CD4(+) T lymphocytes has been shown to inhibit Th1-cytokine production and cell proliferation. Here, we investigated the role of the calcium/calmodulin-dependent protein phosphatase calcineurin (CaN), a key element of the T cell receptor (TCR)-signaling pathway, in β₂-AR-mediated suppression of T cell function.