The Dectin-2 family of C-type lectin-like receptors : an update

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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Density-Independent Mortality and Increasing Plant Diversity Are Associated with Differentiation of Taraxacum officinale into r- and K-Strategists

Background: Differential selection between clones of apomictic species may result in ecological differentiation without mutation and recombination, thus offering a simple system to study adaptation and life-history evolution in plants. Methodology/Principal Findings: We caused density-independent mortality by weeding to colonizer populations of the largely apomictic Taraxacum officinale (Asteraceae) over a 5-year period in a grassland biodiversity experiment (Jena Experiment). We compared the offspring of colonizer populations with resident populations deliberately sown into similar communities. Plants raised from cuttings and seeds of colonizer and resident populations were grown under uniform conditions. Offspring from colonizer populations had higher reproductive output, which was in general agreement with predictions of r-selection theory. Offspring from resident populations had higher root and leaf biomass, fewer flower heads and higher individual seed mass as predicted under K-selection. Plants grown from cuttings and seeds differed to some degree in the strength, but not in the direction, of their response to the r- vs. K-selection regime. More diverse communities appeared to exert stronger K-selection on resident populations in plants grown from cuttings, while we did not find significant effects of increasing species richness on plants grown from seeds. Conclusions/Significance: Differentiation into r- and K-strategists suggests that clones with characteristics of r-strategists were selected in regularly weeded plots through rapid colonization, while increasing plant diversity favoured the selection of clones with characteristics of K-strategists in resident populations. Our results show that different selection pressures may result in a rapid genetic differentiation within a largely apomictic species. Even under the assumption that colonizer and resident populations, respectively, happened to be r- vs. K-selected already at the start of the experiment, our results still indicate that the association of these strategies with the corresponding selection regimes was maintained during the 5-year experimental period

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Correlates of major medication side effects interfering with daily performance: results from a cross-sectional cohort study of older psychiatric patients

Background: Polypharmacy is common among older persons who are also vulnerable to side effects. We aimed to characterize patients who on admission to a geriatric psychiatric hospital had major medication side effects interfering with daily performance. Methods: Cross-sectional cohort study of patients consecutively admitted to a geriatric psychiatric hospital from 2006, 06 December to 2008, 24 October. The UKU side effect rating scale was performed, and patients were divided into those with no/minor side effects versus those with major side effects. Blood levels of 56 psychotropic drugs and 27 safety laboratory tests were measured upon admission. Results: Of 206 patients included in the analysis, 70 (34%) had major side effects related to drug treatment. The most frequent side effects were asthenia (31%), reduced salivation (31%), concentration difficulties (28%), memory impairment (24%), and orthostatic dizziness (18%). The significant characteristics predicting major side effects were female gender (OR = 2.4, 95% confidence interval (CI) = 1.1–5.5), main diagnosis of affective disorder (OR = 4.3, 95% CI = 1.5–12.3), unreported use of psychotropic medications (OR = 2.0, 95% CI = 1.0–4.1), a higher number of reported psychotropic medications (OR = 1.7, 95% CI = 1.2–2.3), a higher number of reported medications for somatic disorders (OR = 1.2, 95% CI = 1.1–1.5), and a higher score on the Charlson comorbidity index (OR = 1.2, 95% CI = 1.0–1.4) (r2 = 0.238, p < 0.001). Conclusions: Clinicians should be especially aware of side effects related to drug treatment in geriatric psychiatric female patients with a high use of psychotropic and other medications and somatic comorbidity. Unreported use of psychotropic medications was also related to the risk for side effects, and clinicians should make an effort to ascertain all medications taken by geriatric psychiatric patients

Exploration of 27 plasma immune markers: A cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons

Background: The prevalence of major depression (MD) according to population studies is the same for old (65 years and older) and younger adults. In contrast, an elevated proportion of old MD patients are hospitalized compared to younger adults with MD, indicating a need to expand the characteristics of old inpatients with MD. To illustrate this point, the association between inflammation and MD in old psychiatric inpatients is sparsely investigated even though an association between inflammation and treatment resistance among younger adults with MD has been reported. In this study, we aimed to explore the plasma concentrations of 27 immune markers in old inpatients with MD, and our purpose was to expand the understanding of inflammatory mechanisms in these patients. Methods: Prior to electroconvulsive treatment of MD, we compared 64 inpatients with unipolar MD (mean age 75.2 years) and 18 non-depressed controls (mean age 78.0 years). Symptoms characterizing MD were assessed by the Hamilton Rating Scale of Depression (HRSD)-17, and the immune markers from peripheral blood plasma were analysed using multiplex assay technology. For statistical analysis of data, we used the independent samples median test, independent samples t-test, χ2-test, receiver operating characteristic curve analyses, stepwise discriminant analysis, and multivariate linear regression. Results: Twenty-two immune markers representing pro- and anti-inflammatory, adaptive and trophic signalling had higher concentrations in the inpatients compared to the controls. Only the four immune markers IL-1β, IL-5, IL-10 and IL-15 had concentrations below the lower detection limit in a considerable portion (above 20%) of the patient cases. A combination of the concentration in plasma of TNF, vascular endothelial growth factor (VEGF), IL-1β, IL-7 and monocyte chemotactic protein (MCP)-1, correctly classified 98.4% of the depressed patients and 83.3% of the non-depressed controls. Plasma concentration of TNF and VEGF were associated with the HRSD-17 scores (p = 0.017 and 0.005, respectively). Conclusions: Our results indicate that several inflammatory mechanisms may be highly activated in old psychiatric inpatients with MD, and indicate that immune markers may contribute to a more comprehensive understanding of MD in old persons.</p

Additional file 3: of Exploration of 27 plasma immune markers: a cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons

Table S3. Dataset supporting. Data on all characteristics and the concentrations of all 27 immune markers of 64 patients and 18 controls. (XLSX 25 kb

Additional file 2: of Exploration of 27 plasma immune markers: a cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons

Table S2. Correlation among the immune markers and the HRSD-17. Correlation among IL-1β, IL-7, MCP-1, TNF, VEGF and the HRSD-17. (DOCX 17 kb

Additional file 1: of Exploration of 27 plasma immune markers: a cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons

Table S1. Characteristics of the patients. The variables; HRSD-17, age, BMI, CIRS-G, gender, number of drugs and current depression in weeks are compared between patients with and without physical diseases affecting the immune system activity. (DOCX 15 kb