MHC class II complexes sample intermediate states along the peptide exchange pathway

The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR- detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII’s ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual’s MHC restricted immune response

Background risk of breast cancer and the association between physical activity and mammographic density

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/ by/4.0

Performance studies of the Belle II Silicon Vertex Detector with data taken at the DESY test beam in April 2016

Belle II is a multipurpose detector currently under construction which will be operated at the next generation B-factory SuberKEKB in Japan. Its main devices for the vertex reconstruction are the Silicon Vertex Detector (SVD) and the Pixel Detector (PXD). In April 2016 a sector of the Belle II SVD and PXD have been tested in a beam of high energetic electrons at the test beam facility at DESY Hamburg (Germany). We report here the results for the hit efficiency estimation and the measurement of the resolution for the Belle II silicon vertex etector. We find that the hit efficiencies are on average above 99.5% and that the measured resolution is within the expectations

Performance studies of the Belle II Silicon Vertex Detector with data taken at the DESY test beam in April 2016

Belle II is a multipurpose detector currently under construction which will be operated at the next generation B-factory SuberKEKB in Japan. Its main devices for the vertex reconstruction are the Silicon Vertex Detector (SVD) and the Pixel Detector (PXD). In April 2016 a sector of the Belle II SVD and PXD have been tested in a beam of high energetic electrons at the test beam facility at DESY Hamburg (Germany). We report here the results for the hit efficiency estimation and the measurement of the resolution for the Belle II silicon vertex etector. We find that the hit efficiencies are on average above 99.5% and that the measured resolution is within the expectations

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity

MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange.

Presentation of antigenic peptides by major histocompatibility complex class II (MHC-II) proteins determines T helper cell reactivity. The MHC-II genetic locus displays a large degree of allelic polymorphism influencing the peptide repertoire presented by the resulting MHC-II protein allotypes. During antigen processing, the human leukocyte antigen (HLA) molecule HLA-DM (DM) encounters these distinct allotypes and catalyzes exchange of the placeholder peptide CLIP by exploiting dynamic features of MHC-II. Here, we investigate 12 highly abundant CLIP-bound HLA-DRB1 allotypes and correlate dynamics to catalysis by DM. Despite large differences in thermodynamic stability, peptide exchange rates fall into a target range that maintains DM responsiveness. A DM-susceptible conformation is conserved in MHC-II molecules, and allosteric coupling between polymorphic sites affects dynamic states that influence DM catalysis. As exemplified for rheumatoid arthritis, we postulate that intrinsic dynamic features of peptide-MHC-II complexes contribute to the association of individual MHC-II allotypes with autoimmune disease

Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case–control study

We examined the associations between sweets, sweetened and unsweetened beverages, and sugars and pancreatic cancer risk. We conducted a population-based case–control study (532 cases, 1,701 controls) and used multivariate logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Because associations were often different by sex, we present results for men and women combined and separately. Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk (total sweets: OR = 1.9, 95% CI: 1.0, 3.6; sweet condiments: OR = 1.9, 95% CI: 1.2, 3.1; chocolate candy: OR = 2.4, 95% CI: 1.1, 5.0; other mixed candy bars: OR = 3.3, 95% CI: 1.5, 7.3 for 1 + servings/day versus none/rarely). Sweets were not consistently associated with risk among women. Sweetened beverages were not associated with increased pancreatic cancer risk. In contrast, low-calorie soft drinks were associated with increased risk among men only; while other low-/non-caloric beverages (e.g., coffee, tea, and water) were unassociated with risk. Of the three sugars assessed (lactose, fructose, and sucrose), only the milk sugar lactose was associated with pancreatic cancer risk (OR = 2.0, 95% CI: 1.5, 2.7 comparing extreme quartiles). These results provide limited support for the hypothesis that sweets or sugars increase pancreatic cancer risk

Helicobacter pylori Seropositivity and Risk of Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide. Helicobacter pylori (H. pylori) is a risk factor for distal stomach cancer, and a few small studies have suggested that H. pylori may be a potential risk factor for lung cancer. To test this hypothesis, we conducted a study of 350 lung adenocarcinoma cases, 350 squamous cell carcinoma cases, and 700 controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) cohort of male Finnish smokers. Controls were one-to-one matched by age and date of baseline serum draw. Using enzyme-linked immunosorbent assays to detect immunoglobulin G antibodies against H. pylori whole-cell and cytotoxin-associated gene (CagA) antigens, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between H. pylori seropositivity and lung cancer risk using conditional logistic regression. H. pylori seropositivity was detected in 79.7% of cases and 78.5% of controls. After adjusting for pack-years and cigarettes smoked per day, H. pylori seropositivity was not associated with either adenocarcinoma (OR: 1.1, 95% CI: 0.75–1.6) or squamous cell carcinoma (OR: 1.1, 95% CI: 0.77–1.7). Results were similar for CagA-negative and CagA-positive H. pylori seropositivity. Despite earlier small studies suggesting that H. pylori may contribute to lung carcinogenesis, H. pylori seropositivity does not appear to be associated with lung cancer

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case–control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60–1.48), 0.96 (95% CI, 0.61–1.52), and 1.21 (95% CI, 0.75–1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54–1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3