Serum SmD autoantibody proteomes are clonally restricted and share variable-region peptides

This article is under embargo for 12 months from the date of publication [Publication date: 7 Jan 2015] in accordance with publisher copyright policy.Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)- region peptide signatures to be derived from human autoantibodies present in complex serum mixtures. Here, we analysed the clonality and V-region composition of immunoglobulin (Ig) proteomes specific for the immunodominant SmD protein subunit of the lupus-specific Sm autoantigen. Precipitating SmD-specific IgGs were eluted from native SmD-coated ELISA plates preincubated with sera from six patients with systemic lupus erythematosus (SLE) positive for anti-Sm/RNP. Heavy (H)- and light (L)-chain clonality and V-region sequences were analysed by 2-dimensional gel electrophoresis and combined de novo database mass spectrometric sequencing. SmD autoantibody proteomes from all six patients with SLE expressed IgG1 kappa restricted clonotypes specified by IGHV3-7 and IGHV1-69 H-chains and IGKV3-20 and IGKV2-28 L-chains, with shared and individual V-region amino acid replacement mutations. Clonotypic sharing and restricted V-region diversity of systemic autoimmunity can now be extended from the Ro/La cluster to Sm autoantigen and implies a common pathway of anti-Sm autoantibody production in unrelated patients with SLE

Age-Related Immunity to Meningococcal Serogroup C Vaccination: An Increase in the Persistence of IgG2 Correlates with a Decrease in the Avidity of IgG

Contains fulltext : 97618.pdf (publisher's version ) (Open Access)Background All children and adolescents between 1 and 19 years of age in The Netherlands received a single meningococcal serogroup C conjugate (MenCC) vaccine in 2002. During follow-up 4–5 years later, the persistence of MenC polysaccharide-specific IgG was found to be dependent on age of vaccination with higher IgG levels in the oldest immunized age categories. Methods and Findings Two cross-sectional population-based serum banks, collected in 1995/1996 and in 2006/2007, were used for this study. We measured MenC polysaccharide-specific IgM, the IgG1 and IgG2 subclasses and determined the avidity of the IgG antibodies. We report that the age-related persistence of IgG after immunization with the MenCC vaccine seemed to result from an increase of IgG2 levels with age, while IgG1 levels remained stable throughout the different age-cohorts. Furthermore, an age-related increase in IgM levels was observed, correlating with the persistence of IgG antibodies with age. It is noteworthy that the increase in IgG2 correlated with a reduced IgG-avidity with age. Conclusion These date indicate that the classical characteristics of a T-cell-dependent antibody response as elicited by protein based vaccines might not be completely applicable when conjugate vaccines are administered to older children and adolescents up to 18 years of age. The response elicited by the MenCC vaccine seemed to be more a mixture of both T cell dependent and T cell independent responses in terms of humoral immunological characteristics

Immunity against Neisseria meningitidis Serogroup C in the Dutch Population before and after Introduction of the Meningococcal C Conjugate Vaccine

Contains fulltext : 88187.pdf (publisher's version ) (Open Access)BACKGROUND: In 2002 a Meningococcal serogroup C (MenC) conjugate vaccine, with tetanus toxoid as carrier protein, was introduced in the Netherlands as a single-dose at 14 months of age. A catch-up campaign was performed targeting all individuals aged 14 months to 18 years. We determined the MenC-specific immunity before and after introduction of the MenC conjugate (MenCC) vaccine. METHODS AND FINDINGS: Two cross-sectional population-based serum banks, collected in 1995/1996 (n = 8539) and in 2006/2007 (n = 6386), were used for this study. The main outcome measurements were the levels of MenC polysaccharide(PS)-specific IgG and serum bactericidal antibodies (SBA) after routine immunization, 4-5 years after catch-up immunization or by natural immunity. There was an increasing persistence of PS-specific IgG and SBA with age in the catch-up immunized cohorts 4-5 years after their MenCC immunization (MenC PS-specific IgG, 0.25 microg/ml (95%CI: 0.19-0.31 microg/ml) at age 6 years, gradually increasing to 2.34 microg/ml,(95%CI: 1.70-3.32 microg/ml) at age 21-22 years). A comparable pattern was found for antibodies against the carrier protein in children immunized above 9 years of age. In case of vaccination before the age of 5 years, PS-specific IgG was rapidly lost. For all age-cohorts together, SBA seroprevalence (> or =8) increased from 19.7% to 43.0% in the pre- and post-MenC introduction eras, respectively. In non-immunized adults the SBA seroprevalence was not significantly different between the pre- and post-MenC introduction periods, whereas PS-specific IgG was significantly lower in the post-MenC vaccination (GMT, age > or =25 years, 0.10 microg/ml) era compared to the pre-vaccination (GMT, age > or =25 years, 0.43 microg/ml) era. CONCLUSION: MenCC vaccination administered above 5 years of age induced high IgG levels compared to natural exposure, increasing with age. In children below 14 months of age and non-immunized cohorts lower IgG levels were observed compared to the pre-vaccination era, whereas functional levels remained similar in adults. Whether the lower IgG poses individuals at increased risk for MenC disease should be carefully monitored. Large-scale introduction of a MenCC vaccine has led to improved protection in adolescents, but in infants a single-dose schedule may not provide sufficient protection on the long-term and therefore a booster-dose early in adolescence should be considered

Peace and Justice through a Feminist Lens: Gender Justice and the Women’s Court for the Former Yugoslavia

Post-conflict interventions to ‘deal with’ violent pasts have moved from exception to global norm. Early efforts to achieve peace and justice were critiqued as ‘gender-blind’—for failing to address sexual and gender-based violence, and neglecting the gender-specific interests and needs of women in transitional settings. The advent of UN Security Council resolutions on ‘Women, Peace and Security’ provided a key policy framework for integrating both women and gender issues into transitional justice processes and mechanisms. Despite this, gender justice and equality in (post-)conflict settings remain largely unachieved. This article explores efforts to attain gender-just peace in post-conflict Bosnia and Herzegovina (BiH). It critically examines the significance of a recent ‘bottom-up’ truth-telling project—the Women’s Court for the former Yugoslavia—as a locally engaged approach to achieving justice and redress for women impacted by armed conflict. Drawing on participant observation, documentary analysis, and interviews with women activists, the article evaluates the successes and shortcomings of responding to gendered forms of wartime violence through truth-telling. Extending Nancy Fraser’s tripartite model of justice to peacebuilding contexts, the article advances notions of recognition, redistribution and representation as crucial components of gender-just peace. It argues that recognizing women as victims and survivors of conflict, achieving a gender-equitable distribution of material and symbolic resources, and enabling women to participate as agents of transitional justice processes are all essential for transforming the structural inequalities that enable gender violence and discrimination to materialize before, during, and after conflict

Prevalence of sicca symptoms in a South Australian cohort with systemic sclerosis

Background: The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional anti-muscarinic-3 receptor (M3R)-blocking antibodies. Methods: A screening questionnaire was sent out to all patients on the South Australian Scleroderma Register from the years 1998-2006 to determine the prevalence of sicca symptoms. A subset of patients on the register had ocular sicca symptoms tested by use of Schirmer's strips to validate the accuracy of the questionnaire. Eight patients were tested for anti-M3R-blocking antibodies using a functional physiological assay. Results: One hundred and ninety-three SSc patients took part in this study. Sicca symptoms were present in 59% of patients with the limited form of SSc, compared with 49% of patients with the diffuse form and 40% of patients with the overlap syndrome. The use of anticholinergic medication or thyroxine was associated with higher sicca scores in SSc patients. SS-A and SS-B autoantibodies (seen in Sjögren's syndrome) were detected in eight patients in this study. The detection of anti-M3R-blocking antibodies correlated well to presence of sicca. Conclusion: This study confirmed that sicca symptoms are found in a high proportion of patients with SSc, especially those with the limited variant. Further testing of larger numbers of SSc patients with sicca for anti-M3R-blocking antibodies will be needed before more definitive conclusions can be drawn. Physicians should be made aware that sicca symptoms are a frequent cause of morbidity for SSc patients*

Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway▿

Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2−/− subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections

Flood Visualization for Urban Planning : An exploratory spatiotemporal visualization of storm water runoff in 2D and 3D

Modelling hydrologic processes is important for understanding how the water cycle works in different environments. Cities which undergo constant changes are subject to flood hazards resulting from severe rainfall. This paper aims to simulate severe rainfall, visualize the results, incorporating both spatial and temporal dimensions, and to make future recommendations for further studies on flood visualization. Visualizing the results from a rainfall simulation using GIS provides urban planners and others the means to view the dynamics of the surface runoff. At the same time, it makes accessible advanced querying and analytical tools. A hydrological model for the study area in Gävle, Sweden was used to simulate a 100-year rainfall. Through FME, the data was reduced, time-stamped and combined to a shapefile. Both 2D software, ArcGIS, and 3D software, ArcScene, were used for creating an animated flood visualization. This study shows that although 2D tested better by a group of planners and water professionals, the 3D was still considered more intuitive. The heightened sense of realism from 3D outweighs its drawbacks, and further studies are required to test different methods of 3D visualization.