Anti Citrullinated Protein Antibodies-IgG variable domain glycosylation in rheumatoid arthritis

Rheumatoid arthritis (RA) is an auto-inflammatory disease, affecting ~1% of the world population. RA is hallmarked by the presence of autoantibodies, one of the well-known autoantibodies in RA are the anti-citrullinated protein antibodies (ACPA). ACPA is highly specific for RA and about 70-80% of the RA patients are positive for ACPA. Previously, we discovered that ACPA-IgG are extensively glycosylated in the variable (V) region. In this thesis, we determined that over 90% of the ACPA-IgG carries glycans in the v-domain were as only 17% of the conventional IgG carries additional glycans. Additionally, the glycans were highly sialylated. Intriguingly, we also showed that the glycans are introduced via somatic hyper mutations in the germinal center reaction. Furthermore, we discovered that ACPA-IgG v-domain glycosylation is a predictive marker for the development of ACPA positive RA. Lastly, we found that the binding strength is not influenced by the glycans but it influences the amount of available binding sites. Nevertheless, the ACPA-BCR still overcome negative selection which might suggest that the glycans can trigger an alternative way for positive selection in the germinal center. This will be subject for further studies regarding the role of ACPA-IgG v-domain glycosylation. LUMC / Geneeskund

Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

Pathophysiology and treatment of rheumatic disease

Replacing the AMOR with the miniDOAS in the ammonia monitoring network in the Netherlands

In this paper we present the continued development of the miniDOAS, an active differential optical absorption spectroscopy (DOAS) instrument used to measure ammonia concentrations in ambient air. The miniDOAS has been adapted for use in the Dutch National Air Quality Monitoring Network. The miniDOAS replaces the life-expired continuous-flow denuder ammonia monitor (AMOR). From September 2014 to December 2015, both instruments measured in parallel before the change from AMOR to miniDOAS was made. The instruments were deployed at six monitoring stations throughout the Netherlands. We report on the results of this intercomparison. Both instruments show a good uptime of ca. 90 %, adequate for an automatic monitoring network. Although both instruments produce 1 min values of ammonia concentrations, a direct comparison on short timescales such as minutes or hours does not give meaningful results because the AMOR response to changing ammonia concentrations is slow. Comparisons between daily and monthly values show good agreement. For monthly averages, we find a small average offset of 0.65 ± 0.28 µg m−3 and a slope of 1.034 ± 0.028, with the miniDOAS measuring slightly higher than the AMOR. The fast time resolution of the miniDOAS makes the instrument suitable not only for monitoring but also for process studies

Anticipated and experienced discrimination amongst people with schizophrenia, bipolar disorder and major depressive disorder: a cross-sectional study.

BACKGROUND: The unfair treatment of individuals with severe mental illness has been linked to poorer physical and mental health outcomes. Additionally, anticipation of discrimination may lead some individuals to avoid participation in particular life areas, leading to greater isolation and social marginalisation. This study aimed to establish the levels and clinical and socio-demographic associations of anticipated and experienced discrimination amongst those diagnosed with a schizophrenia and comparator severe mental illnesses (bipolar and major depressive disorders). METHODS: This study was a cross-sectional analysis of anticipated and experienced discrimination from 202 individuals in South London (47% with schizophrenia, 32% with depression and 20% with bipolar disorder). RESULTS: 93% of the sample anticipated discrimination and 87% of participants had experienced discrimination in at least one area of life in the previous year. There was a significant association between the anticipation and the experience of discrimination. Higher levels of experienced discrimination were reported by those of a mixed ethnicity, and those with higher levels of education. Women anticipated more discrimination than men. Neither diagnosis nor levels of functioning were associated with the extent of discrimination. Clinical symptoms of anxiety, depression and suspiciousness were associated with more experienced and anticipated discrimination respectively. CONCLUSIONS: The unfair treatment of individuals with severe mental illnesses remains unacceptably common. Population level interventions are needed to reduce levels of discrimination and to safeguard individuals. Interventions are also required to assist those with severe mental illness to reduce internalised stigma and social avoidance

B-cell receptor sequencing of anti-citrullinated protein antibody (ACPA) IgG-expressing B cells indicates a selective advantage for the introduction of N-glycosylation sites during somatic hypermutation

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Observation of associated production of a ZZ boson with a DD meson in the~forward region

A search for associated production of a $Z$ boson with an open charm meson is presented using a data sample, corresponding to an integrated luminosity of $1.0\,\mathrm{fb}^{-`}$ of proton--proton collisions at a centre-of-mass energy of 7\,TeV, collected by the LHCb experiment. %% Seven candidate events for associated production of a $Z$ boson with a $D^0$ meson and four candidate events for a $Z$ boson with a $D^+$ meson are observed with a combined significance of 5.1standard deviations. The production cross-sections in the forward region are measured to be $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^0} = 2.50\pm1.12\pm0.22pb$$ $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^+} = 0.44\pm0.23\pm0.03pb,$$ where the first uncertainty is statistical and the second systematic.Comment: 18 pages, 2 figure

Measurements of the B+B^+, B0B^0, Bs0B_s^0 meson and Λb0\Lambda_b^0 baryon lifetimes

Measurements of $b$-hadron lifetimes are reported using $pp$ collision data, corresponding to an integrated luminosity of 1.0fb$^{-1}$, collected by the LHCb detector at a centre-of-mass energy of $7$Tev. Using the exclusive decays $B^+\to J/\psi K^+$, $B^0\to J/\psi K^*(892)^0$, $B^0\to J/\psi K^0_{\rm S}$, $\Lambda_b^0\to J/\psi \Lambda$ and $B^0_s\to J/\psi \phi$ the average decay times in these modes are measured to be $\tau_{B^+\to J/\psi K^+}$ = $1.637 \pm$ 0.004 $\pm$ 0.003 ps, $\tau_{B^0\to J/\psi K^*(892)^0}$ = $1.524 \pm$ 0.006 $\pm$ 0.004 ps, $\tau_{B^0\to J/\psi K^0_{\rm S}}$ = $1.499 \pm$ 0.013 $\pm$ 0.005 ps, $\tau_{\Lambda_b^0\to J/\psi \Lambda}$ = $1.415 \pm$ 0.027 $\pm$ 0.006 ps and $\tau_{B^0_s\to J/\psi \phi}$ = $1.480 \pm$ 0.011 $\pm$ 0.005 ps, where the first uncertainty is statistical and the second is systematic. These represent the most precise lifetime measurements in these decay modes. In addition, ratios of these lifetimes, and the ratio of the decay-width difference, $\Delta\Gamma_d$, to the average width, $\Gamma_d$, in the $B^0$ system, $\Delta \Gamma_d/\Gamma_d = -0.044 \pm 0.025 \pm 0.011$, are reported. All quantities are found to be consistent with Standard Model expectations.Comment: 28 pages, 4 figures. Updated reference

De geprotocolleerde Interapy-behandeling van depressie via het internet; resultaten van een gerandomiseerde trial

Psychologische behandelingen via internet bieden een nieuwe mogelijkheid voor de geestelijke gezondheidszorg. In samenwerking met de Stichting Mentrum ggz Amsterdam heeft Interapy een behandeling voor depressie via internet opgezet. De behandeling bestaat uit cognitief-gedragstherapeutische interventies, zoals psycho-educatie, schrijfopdrachten, registratie, activatie, het uitdagen van negatieve automatische gedachten en terugvalpreventie. Dit artikel beschrijft de procedure, de behandeling en de resultaten van een vergelijkende studie onder cliënten die matig tot ernstig depressief waren. De cliënten die direct actief werden behandeld (N = 32) verbeterden significant meer dan de cliënten in de psycho-educatieconditie (N = 14). Deze tweede groep kreeg de actieve behandeling ongeveer twaalf weken later. De effecten waren groot. In de actief behandelde groep liet 75 procent van de cliënten klinisch relevante verbetering zien, in de psycho-educatieconditie was dat percentage 36. Uit de follow-up na zes weken bleek dat de verbeteringen standhielden

Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation

The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease.Medicinal Chemistr