Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration

Behandeling en stigmamanagement bij opzettelijke zelfverwonding: het smalle pad tussen te veel en te weinig interveniëren

Opzettelijke zelfverwonding wordt gedefinieerd als de intentionele directe beschadiging van het eigen lichaam, zonder bewuste suïcidale intentie. De behandeling varieert van gedwongen opname in een psychiatrische instelling (in het Britse Gemenebest), tot een permissieve aanpak zonder behandeling en uiteenlopende behandelingsmogelijkheden er tussenin. Eerst wordt de gepastheid van de mate van interveniëren besproken in functie van verschillende diagnosen. Het tweede gedeelte van het artikel bespreekt het advies dat door hulpverleners verstrekt wordt aangaande de omgang met wonden en littekens en aangaande de mogelijkheden voor een (gewezen) zelfverwonder om het stigma van een deviante identiteit te vermijden. Een rondvraag bij Belgische hulpverleners bracht aan het licht dat velen onder hen adviseren om littekens te verbergen, terwijl er anderzijds aanwijzingen zijn dat niet-verbergen een teken van herstel is. Aangezien verbergen en smoesjes verzinnen ook kunnen leiden tot de instandhouding van een deviante identiteit, wordt gewezen op meer gepaste vormen van stigmamanagement

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies

A novel two-step mechanism for removal of a mitochondrial signal sequence involves the mAAA complex and the putative rhomboid protease Pcp1

The yeast protein cytochrome c peroxidase (Ccp1) is nuclearly encoded and imported into the mitochondrial intermembrane space, where it is involved in degradation of reactive oxygen species. It is known, that Ccp1 is synthesised as a precursor with a N-terminal pre-sequence, that is proteolytically removed during transport of the protein. Here we present evidence for a new processing pathway, involving novel signal peptidase activities. The mAAA protease subunits Yta10 (Afg3) and Yta12 (Rca1) were identified both to be essential for the first processing step. In addition, the Pcp1 (Ygr101w) gene product was found to be required for the second processing step, yielding the mature Ccp1 protein. The newly identified Pcp1 protein belongs to the rhomboid-GlpG superfamily of putative intramembrane peptidases. Inactivation of the protease motifs in mAAA and Pcp1 blocks the respective steps of proteolysis. A model of coupled Ccp1 transport and N-terminal processing by the mAAA complex and Pcp1 is discussed. Similar processing mechanisms may exist, because the mAAA subunits and the newly identified Pcp1 protein belong to ubiquitous protein families

Adverse Effects of Outcome Monitoring Feedback in Patients With Personality Disorders: A Randomized Controlled Trial in Day Treatment and Inpatient Settings

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Concept mapping of indicators for treatment allocation in patients with personality disorders

In dit onderzoek werden met behulp van de ‘concept-mapping’-methode patiëntkenmerken gevonden die van belang zijn bij de indicatiestelling voor psychotherapeutische behandeling bij persoonlijkheidsstoornissen. De concept map-methode omvat zowel kenmerken van kwalitatief als kwantitatief onderzoek en heeft als doel om een complex onderwerp visueel te presenteren en op te delen in een aantal onderliggende concepten. In dit onderzoek werd met behulp van de concept map-methode een literatuuronderzoek naar indicatiestelling geïntegreerd met kennis van 29 experts op het gebied van indicatiestelling en/of persoonlijkheidsproblematiek. Het doel was om een beperkt aantal concepten te bepalen die van belang zijn voor de indicatiestelling bij persoonlijkheidsproblemen. De conceptmap resulteerde in acht clusters: (1) ernst van de psychiatrische symptomatologie, (2) ernst van de (structurele) persoonlijkheidspathologie, (3) ego-adaptieve vermogens, (4) motivatie en vermogen tot het aangaan van een werkrelatie, (5) sociale context, (6) socio-demografische variabelen, (7) traumatisering en (8) behandelgeschiedenis en somatiek. In dit rapport wordt gedetailleerd verslag gedaan van de concept-map procedure en worden de uitkomsten gedetailleerd besproken

Childhood trauma, midbrain activation and psychotic symptoms in borderline personality disorder

Childhood trauma is believed to contribute to the development of borderline personality disorder (BPD), however the mechanism by which childhood trauma increases risk for specific symptoms of the disorder is not well understood. Here, we explore the relationship between childhood trauma, brain activation in response to emotional stimuli and psychotic symptoms in BPD. Twenty individuals with a diagnosis of BPD and 16 healthy controls were recruited to undergo a functional MRI scan, during which they viewed images of faces expressing the emotion of fear. Participants also completed the childhood trauma questionnaire (CTQ) and a structured clinical interview. Between-group differences in brain activation to fearful faces were limited to decreased activation in the BPD group in the right cuneus. However, within the BPD group, there was a significant positive correlation between physical abuse scores on the CTQ and BOLD signal in the midbrain, pulvinar and medial frontal gyrus to fearful (versus neutral) faces. In addition there was a significant correlation between midbrain activation and reported psychotic symptoms in the BPD group (P<0.05). These results show that physical abuse in childhood is, in individuals with BPD, associated with significantly increased activation of a network of brain regions including the midbrain in response to emotional stimuli. Sustained differences in the response of the midbrain to emotional stimuli in individuals with BPD who suffered childhood physical abuse may underlie the vulnerability of these patients to developing psychotic symptoms