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Background and ObjectivesObesity aggravates disease severity in multiple sclerosis (MS). Altered neural processing of food motivation and cognitive control, and the sensitivity of these processes to stress have been recognized as key obesity mechanisms but never been investigated in MS.MethodsIn this cross-sectional observational study, we evaluated the link between body mass and neural, endocrine and immunological stress parameters in persons with MS (PwMS). We conducted an Arterial-Spin-Labeling MRI task comprising a rest and stress stage (mental arithmetic plus evaluative feedback) in 57 PwMS (37 female, 46.4 ± 10.6 years) covering the full spectrum of the Body Mass Index (BMI [kg/m2]; 6 obese, 19 over-, 28 normal-, 4 underweight). We tested whether BMI in MS links to (i) functional connectivity (FC) between stress-reactive brain regions (showing activity differences for stress vs. rest) computed separately for the task’s rest and stress stage, (ii) T cell glucocorticoid sensitivity and (iii) salivary cortisol secretion.ResultsBMI correlated positively with MS relapse rate (t = 3.23, p = 0.003 = pFamily-Wise-Error [FWE]-corrected= 0.012, and f2= 0.22) and rest stage FC between right anterior insula and supramarginal gyrus (t = 4.02, p = 2.5 · 10−4= pFWE= 0.034, f2= 0.51) and negatively with stress stage FC between right superior parietal lobule and cerebellum exterior (t = -3.67, p = 3.3 · 10−4= pFWE= 0.045, f2= 0.30). Further, BMI was negatively associated with the expression of the co-chaperone FKBP4 on CD8+T cells (t = -2.96, p = 0.003 = pFWE= 0.024, f2= 0.13) and positively with that of FKBP5 (t = 1.83, p = 0.003 = pFWE= 0.024, f2= 0.38).ConclusionOur study shows that higher BMI in MS is linked to increased FC between key food motivation and stimulus salience regions and to reduced FC between regions critically involved in cognitive control and generation of stressful states. We further report on correlations between BMI and co-chaperones modulating immune system stress responsivity. Taken together, these results demonstrate that BMI in MS is tied to stress processing across different biological systems.

Epidemiological, clinical and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T-cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T-cell glucocorticoid signalling in patients versus healthy persons as a potential indicator of disease-specific CNS–immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T-cell glucocorticoid signalling across groups. This network’s activity was simultaneously linked to patients’ lesion volume, clinical disability and information-processing speed. Complementary analyses revealed that T-cell glucocorticoid signalling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress processing and T-cell stress hormone sensitivity are related to key severity measures of multiple sclerosis.

Summary Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology., Graphical abstract, Highlights • MDD patients display signs of metabolic imbalance on a systemic level • Mitochondrial respiration and glycolysis are decreased in T cells of MDD patients • Key cellular metabolic markers negatively correlate with depression severity • Increased expression of CPT1a in T cells correlates with many serum metabolites, Cellular neuroscience; Immunology; Metabolomics

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4

Summary: Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track “private” T cell clones associated with disease activity in autoimmunity. : Ramien et al. interrogate the immune repertoire in multiple sclerosis (MS) during pregnancy. They report a shift in T cell repertoire composition driven by a small number of “private” clones. This specific rather than global immunomodulation may help to explain the protective effect of pregnancy in human autoimmunity. Keywords: multiple sclerosis, pregnancy, T cell receptor α and β pairing, immunosequencing, repertoire sequencing, immune phenotyping, immune tolerance, human

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8(+) effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4(+) central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4(+) central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.