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The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer's Disease (AD), amyloid-beta 42 (Aß42) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aß42 and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aß42 and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aß42 were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aß42 was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings.
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Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.
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Enfermedades del Sistema Nervioso Central , Trastornos por Estrés Postraumático , Humanos , Inflamación/etiología , Estrés Psicológico , MicroglíaRESUMEN
The aim was to evaluate the performance of the latest quantitative marker for intrathecal IgG synthesis and to compare it with other established markers used for the same purpose. We retrospectively applied Auer's and Reiber's intrathecal IgG synthesis formulae in a cohort of 372 patients under investigation for central nervous system demyelination who had undergone lumbar puncture and oligoclonal bands (OCBs) detection for demonstrating intrathecal IgG synthesis. A ROC analysis revealed Auer's formula had lower sensitivity (68%) compared to Reiber's formula (83%) and IgG index (89%), in our cohort of patients that exhibited normal to mildly elevated albumin quotients (4.48 ± 3.93). By excluding possible sources of errors, we assume that Auer's formula is less sensitive than other established tools for the "prediction" of the detection of OCBs in routine cerebrospinal fluid (CSF) analyses due to the mathematical model used. Given the ability of Reiber's hyperbolic formula to describe the blood-CSF IgG distribution across a wide range of blood-brain barrier functionality, its use and the use of similar formulae are recommended for the discrimination between CNS-derived and blood-derived molecules in clinical laboratories.
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BACKGROUND: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. METHODS: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. RESULTS: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96-1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006-1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). CONCLUSIONS: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.
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Background and Objectives: This article presents data from the ongoing Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study (ALBION) regarding baseline clinical characterizations and CSF biomarker profiles, as well as preliminary longitudinal data on clinical progression. Materials and Methods: As of March 2022, 138 participants who either were cognitively normal (CN, n = 99) or had a diagnosis of mild cognitive impairment (MCI, n = 39) had been recruited at the specialist cognitive disorders outpatient clinic at Aiginition Hospital. Clinical characteristics at baseline were provided. These patients were followed annually to determine progression from CN to MCI or even dementia. CSF biomarker data (amyloid ß1-42, phosphorylated tau at threonine 181, and total tau) collected using automated Elecsys® assays (Roche Diagnostics) were available for 74 patients. These patients were further sorted based on the AT(N) classification model, as determined by CSF Aß42 (A), CSF pTau (T), and CSF tTau (N). Results: Of the 49 CN patients with CSF biomarker data, 21 (43%) were classified as exhibiting "Alzheimer's pathologic change" (A+Τ− (Ν)−) and 6 (12%) as having "Alzheimer's disease" (A+T−(N)+, A+T+(N)−, or A+T+(N)+). Of the 25 MCI patients, 8 (32%) displayed "Alzheimer's pathologic change", and 6 (24%) had "Alzheimer's disease". A total of 66 individuals had a mean follow-up of 2.1 years (SD = 0.9, min = 0.8, max = 3.9), and 15 of those individuals (22%) showed a clinical progression (defined as a worsening clinical classification, i.e., from CN to MCI or dementia or from MCI to dementia). Overall, participants with the "AD continuum" AT(N) biomarker profile (i.e., A+T−(N)−, A+T−(N)+, A+T+(N)−, and A+T+(N)+) were more likely to clinically progress (p = 0.04). Conclusions: A CSF "AD continuum" AT(N) biomarker profile is associated with an increased risk of future clinical decline in CN or MCI subjects.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Biomarcadores , Progresión de la Enfermedad , Humanos , Treonina , Proteínas tauRESUMEN
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+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.
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Trastorno Depresivo Mayor , Esclerosis Múltiple , Biomarcadores , Estudios de Casos y Controles , Depresión/metabolismo , Trastorno Depresivo Mayor/complicaciones , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Aging is characterized by a functional shift of the immune system toward a proinflammatory phenotype. This derangement has been associated with cognitive decline and has been implicated in the pathogenesis of dementia. Diet can modulate systemic inflammation; thus, it may be a valuable tool to counteract the associated risk for cognitive impairment and dementia. The present study aimed to explore the associations between the inflammatory potential of diet, assessed with an easily applicable, population-based, biomarker-validated diet inflammatory index (DII), and the risk for dementia in community-dwelling older adults. METHODS: Individuals from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present cohort study. Participants were recruited through random population sampling and were followed up for a mean of 3.05 (standard deviation 0.85) years. Dementia diagnosis was based on standard clinical criteria. Those with baseline dementia or missing cognitive follow-up data were excluded from the analyses. The inflammatory potential of diet was assessed through a DII score that considers literature-derived associations of 45 food parameters with levels of proinflammatory and anti-inflammatory cytokines in the blood; higher values indicated a more proinflammatory diet. Consumption frequencies were derived from a detailed food frequency questionnaire and were standardized to representative dietary intake normative data from 11 different countries. Analysis of dementia incidence as a function of baseline DII scores was performed by Cox proportional hazards models. RESULTS: Analyses included 1,059 individuals (mean age 73.1 years, 40.3% male, mean education 8.2 years), 62 of whom developed incident dementia. Each additional unit of DII score was associated with a 21% increase in the risk for dementia incidence (hazard ratio 1.21 [95% confidence interval 1.03-1.42]; p = 0.023). Compared to participants in the lowest DII score tertile, participants in the highest one (maximal proinflammatory diet potential) were 3 (95% confidence interval 1.2-7.3; p = 0.014) times more likely to develop incident dementia. The test for trend was also significant, indicating a potential dose-response relationship (p = 0.014). DISCUSSION: In the present study, higher DII scores (indicating greater proinflammatory diet potential) were associated with an increased risk for incident dementia. These findings might avail the development of primary dementia preventive strategies through tailored and precise dietary interventions.
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Demencia , Dieta , Anciano , Estudios de Cohortes , Demencia/complicaciones , Demencia/epidemiología , Dieta/efectos adversos , Encuestas sobre Dietas , Femenino , Humanos , Vida Independiente , Inflamación/complicaciones , Masculino , Factores de RiesgoRESUMEN
Anti-SARS-CoV-2 spike RBD (receptor-binding domain) IgG antibody levels were monitored in 1643 volunteer healthcare workers of Eginition, Evangelismos, and Konstantopoulio General Hospitals (Athens, Greece), who underwent vaccination with two doses of COVID-19 BNT162b2 mRNA vaccine (Pfizer) and had no history of SARS-CoV-2 infection. Venous blood was collected 20-30 days after the second vaccine dose and anti-RBD IgG levels were determined using CMIA SARS-CoV-2 IgG II Quant (Abbott) on ARCHITECT i System or ADVIA Centaur SARS-CoV-2 IgG (Siemens) on Centaur XP platform. From the total population of 1643 vaccinees (533 M/1110 F; median age = 49; interquartile range-IQR = 40-56), 1636 (99.6%) had anti-SARS-CoV-2 IgG titers above the positivity threshold of the assay used. One-Way ANOVA Kruskal-Wallis H test showed a statistically significant difference in the median of antibody titers between the different age groups (p < 0.0001). Consistently, Spearman's correlation coefficient (r) for IgGs and age as continuous variables was -0.2380 (p = 1.98 × 10-17). Moreover, antibody titers were slightly higher by 1.2-mean fold (p = 3 × 10-6) in the total female population of the three hospitals (median = 1594; IQR = 875-2584) as compared to males (median = 1292; IQR = 671.9-2188). The present study supports that BNT162b2 vaccine is particularly effective in producing high anti-SARS-CoV-2 IgG levels in healthy individuals, and this humoral response is age- and gender-dependent.
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Neurobrucellosis presents in various clinical forms and should always be considered in neurological patients in highly endemic areas such as the Mediterranean basin. Establishing a diagnosis can be challenging since serological testing can sometimes yield negative results. We present a rare case of a seronegative relapse of neurobrucellosis in a patient who had been successfully treated for systemic brucellosis. Oligoclonal bands, an agglutination test, and 16S rRNA sequencing of cerebrospinal fluid proved essential in unmasking a confined central nervous system relapse. This case reinforces the need for establishing diagnostic criteria for neurobrucellosis, which could potentially include oligoclonal bands and an agglutination test on the cerebrospinal fluid.
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Brucelosis , Pruebas de Aglutinación , Brucelosis/diagnóstico , Brucelosis/tratamiento farmacológico , Sistema Nervioso Central , Pruebas Diagnósticas de Rutina , Humanos , ARN Ribosómico 16SRESUMEN
L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤-0.7, p<0.001) and EPO (r≤-0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Dopa-Decarboxilasa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Enzima Convertidora de Angiotensina 2/genética , Área Bajo la Curva , Descarboxilasas de Aminoácido-L-Aromático , COVID-19/virología , Dopa-Decarboxilasa/genética , Regulación hacia Abajo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Eritropoyetina/genética , Eritropoyetina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nasofaringe/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Curva ROC , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Regulación hacia Arriba , Carga ViralRESUMEN
BACKGROUND: To investigate the association between frailty, Parkinson's disease (PD), and the probability of prodromal Parkinson's disease (prodromal PD) in Greek community-dwelling older individuals. METHODS: Parkinson's disease diagnosis was reached through standard clinical research procedures. Probability of prodromal PD was calculated according to the International Parkinson and Movement Disorder Society's research criteria for PD-free participants. Frailty was evaluated according to definitions of the phenotypic and multidomain approach. Logistic and linear regression models were performed to investigate associations between frailty (predictor) and the probability of prodromal PD, either continuous or dichotomous (≥30% probability score), or PD (outcome). RESULTS: Data from 1765 participants aged 65 and older were included in the present analysis. Parkinson's disease and prodromal PD prevalence were 1.9% and 3.0%, respectively. Compared to nonfrail participants, those who were frail, as identified with either the Fried frailty phenotype or Frailty Index had approximately 4 (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.54-10.89) and 12 times (OR 12.16, 95% CI 5.46-27.09) higher odds of having a PD diagnosis, respectively. Moreover, compared to the nonfrail, frail participants as identified with either the Fried frailty phenotype or Frailty Index had 2.8 (OR 2.83, 95% CI 1.09-7.37) and 8.3 times (OR 8.39, 95% CI 4.56-15.42) higher odds of having possible/probable prodromal PD, respectively. CONCLUSIONS: Frailty status was associated with prodromal PD and PD, suggesting common characteristics or underlying mechanisms of these conditions. Although prospective studies are warranted, acknowledging the possible association of frailty, PD, and prodromal PD may improve their clinical management.
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Envejecimiento , Fragilidad , Evaluación Geriátrica , Enfermedad de Parkinson , Síntomas Prodrómicos , Anciano , Envejecimiento/fisiología , Envejecimiento/psicología , Femenino , Fragilidad/diagnóstico , Fragilidad/epidemiología , Evaluación Geriátrica/métodos , Evaluación Geriátrica/estadística & datos numéricos , Grecia/epidemiología , Humanos , Vida Independiente/estadística & datos numéricos , Masculino , Examen Neurológico/métodos , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Prevalencia , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Evaluación de SíntomasRESUMEN
BACKGROUND: Listeria monocytogenes is an opportunistic pathogen of the central nervous system commonly associated with impaired cell-mediated immunity. We hereby present a case of adult neurolisteriosis where the only immunological feature persistently present was serum IgM deficiency, suggesting that non-specific humoral immunity may also play a central role in the control of neuroinvasion by Listeria monocytogenes. CASE PRESENTATION: A 62-year-old male who had never experienced severe infections presented with headache, nuchal rigidity and confusion. Neuroimaging was normal and lumbar puncture revealed pleiocytosis (760 leukocytes/mm3) and hypoglycorrhachia (34 mg/dL). The patient was treated empirically for bacterial meningitis. Indeed, further analysis of the CSF showed infection by Listeria monocytogenes, which was accompanied by reduced serum IgM levels that persisted well beyond the period of acute bacterial infection. Levels of IgG and IgA isotypes, along with peripheral blood counts of major leukocyte subsets, were at the same time largely preserved. Intriguingly, the absence of membrane-bound IgM on B cells was essentially complete in the acute post-infection period leading to a remarkable recovery after 12 months, suggesting that mechanisms other than defective membrane expression are underlying serum deficiency. CONCLUSIONS: As far as we know, this is the first reported case of neurolisteriosis associated with IgM deficiency in an adult individual without a history of severe infections or other underlying conditions. A possible role of circulating IgM against invasive disease caused by Listeria monocytogenes, particularly in the early course of host-pathogen interaction, is discussed.
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Huésped Inmunocomprometido , Inmunoglobulina M/deficiencia , Meningitis por Listeria/inmunología , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
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.
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Esclerosis Múltiple/sangre , Complicaciones del Embarazo/sangre , Linfocitos T/inmunología , Adulto , Biomarcadores/sangre , Femenino , Humanos , Inmunofenotipificación , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/inmunología , Embarazo , Complicaciones del Embarazo/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/clasificaciónRESUMEN
Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11ß-hydroxysteroid dehydrogenase type 1; 11ß -HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1ß, or TNF-α. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes.
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Trastorno Depresivo Mayor/inmunología , Monocitos/inmunología , Transducción de Señal/inmunología , Esteroides/inmunología , 11-beta-Hidroxiesteroide Deshidrogenasas/inmunología , Adolescente , Adulto , Trastorno Depresivo Mayor/patología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/patología , Receptores de Glucocorticoides/inmunología , Receptores de Mineralocorticoides/inmunología , Linfocitos T/inmunología , Factores de Transcripción/inmunologíaRESUMEN
While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case-control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/- cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vß repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR ß chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.
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Trastorno Depresivo Mayor/inmunología , Neuroinmunomodulación/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.
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Embarazo/inmunología , Receptores de Glucocorticoides/inmunología , Linfocitos T/inmunología , Animales , Autoinmunidad , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Tolerancia Inmunológica , Ratones Endogámicos C57BL , Progesterona/inmunologíaRESUMEN
Clinical observations in human autoimmune diseases such as multiple sclerosis (MS) suggest a pivotal role of sex-related factors in the etiopathogenesis. These include a female preponderance in MS incidence and an increasing sex bias over time, a parent-of-origin effect in MS inheritance, and the protective effect of pregnancy on disease activity. The complex interplay of factors contributing to these clinical phenomena, however, is incompletely understood and may include sex hormones as well as genetic or epigenetic sex differences. While genetic and hormonal effects are impossible to study independently in humans, novel mouse models have started to unravel the cause-effect relationship between individual sex-related factors and autoimmunity. Here, we present the evidence for mechanisms underlying sex differences in the immune system and the central nervous system (CNS) and how these might help to explain some of the clinically observed sex differences in MS. A better understanding of the molecular underpinnings may ultimately help to devise sex-specific treatment strategies as well as highlight novel avenues for therapy in both sexes.
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Esclerosis Múltiple , Animales , Autoinmunidad , Sistema Nervioso Central , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Embarazo , Caracteres SexualesRESUMEN
OBJECTIVE: Multiple sclerosis and major depressive disorder frequently co-occur but depression often remains undiagnosed in this population. Self-rated depression questionnaires are a good option where clinician-based standardized diagnostics are not feasible. However, there is a paucity of data on diagnostic accuracy of self-report measures for depression in multiple sclerosis (MS). Moreover, head-to-head comparisons of common questionnaires are largely lacking. This could be particularly relevant for high-risk patients with depressive symptoms. Here, we compare the diagnostic accuracy of the Beck Depression Inventory (BDI) and 30-item version of the Inventory of Depressive Symptomatology Self-Rated (IDS-SR30) for major depressive disorder (MSS) against diagnosis by a structured clinical interview. METHODS: Patients reporting depressive symptoms completed the BDI, the IDS-SR30 and underwent diagnostic assessment (Mini International Neuropsychiatric Interview, M.I.N.I.). Receiver-Operating Characteristic analyses were performed, providing error estimates and false-positive/negative rates of suggested thresholds. RESULTS: Data from n = 31 MS patients were available. BDI and IDS-SR30 total score were significantly correlated (r = 0.82). The IDS-SR30total score, cognitive subscore, and BDI showed excellent to good accuracy (area under the curve (AUC) 0.86, 0.91, and 0.85, respectively). CONCLUSION: Both the IDS-SR30 and the BDI are useful to quantify depressive symptoms showing good sensitivity and specificity. The IDS-SR30 cognitive subscale may be useful as a screening tool and to quantify affective/cognitive depressive symptomatology.