B-cell Development and Primary Antibody Deficiencies

B lymphocytes are generated throughout life from hematopoietic stem cells in bone marrow, and contribute to the immune system by the production of antigen-specific antibodies (immunoglobulins; Ig). Two distinct phase of B-cell development can be distinguished: 1) antigen-independent precursor-B-cell differentiation in bone marrow, and 2) antigendependent B-cell maturation in peripheral lymphoid organs. The aim of precursor-B-cell differentiation is to generate a functional Ig receptor by V(D)J recombination of the genes encoding the Ig heavy (IgH) and Ig light (Ig. or Ig.) chains. When a precursor-B-cell succeeds in creating a functional Ig receptor, it will migrate to the periphery and become part of the naive B-cell pool. Because every precursor-B-cell creates a unique Ig receptor, the peripheral B-cell pool bears a diverse repertoire of specific receptors for antigen. Naive B lymphocytes are short-lived cells and because new cells are continuously generated, there is a high turnover. However, once a naive mature B-lymphocyte recognizes antigen with its specific Ig receptor, it will undergo clonal proliferation and differentiation, thereby generating a large number of plasma cells that produce and secrete antigen-specific Igs. During this response, the B-cell initiates additional molecular mechanisms to adapt and optimize the antigen-binding affinity and the effector function of its Ig molecule. Generation of a large repertoire of B lymphocytes and the response of one of these B lymphocytes to antigen is a multi-step process for which multiple proteins are required. The lack of one of these proteins leads to a problem with the humoral immunity of the individual, which is seen in patients with primary antibody deficiency diseases. These children or young adults carry rare inherited disorders and are subject to multiple, recurrent (mainly) bacterial infections. Several genetic defects have been identified in patients with a primary antibody deficiency. In many patients, however, the B-cell defect is not well understood. The studies in this thesis address several aspects of B-cell development and defects that lead to primary antibody deficiency diseases

Clathrin Heavy Chain subunits coordinate endo- and exocytic traffic and affect stomatal movement

The current model for vesicular traffic to and from the plasma membrane is accepted but the molecular requirements for this coordination are not well defined. We have identified the has1 mutant, which has a stomatal function defect, as a clathrin heavy chain 1 (CHC1) mutant allele and show that it has a decreased rate of endocytosis and growth defects that are shared with other chc1 mutant alleles. We used chc1 alleles and the related chc2 mutant as tools to investigate the effects clathrin defects have on secretion pathways and plant growth. We show that secretion and endocytosis at the plasma membrane is sensitive to CHC1 and CHC2 function in seedling roots, and that chc mutants have physiological defects in stomatal function and plant growth that have not been previously described. These findings suggest that clathrin supports specific functions of multiple cell types. Stomata movement and gas exchange is altered in chc mutants, indicating clathrin is important for stomatal regulation. The aberrant function of chc mutant stomata is consistent with the growth phenotypes observed under different water and light conditions, which are also similar to those of the secretory SNARE mutant, syp121. The syp121 and chc mutants have impaired endo- and exocytosis compared to wild type, indicating a link between SYP121-dependent secretion and clathrin-dependent endocytosis at the plasma membrane. Our findings provide evidence that clathrin and SYP121 functions are important for the coordination of endo- and exocytosis, and have an impact on stomatal function, gas exchange, and vegetative growth in Arabidopsis

The Northern Home Front During the Civil War

Reviewer Antointette G. van Zelm writes that The Northern Home Front During the Civil War is engagingly written and chock full of American voices. Both the diversity and dissension that characterized the Northern populace come through prominently

Decreased memory B cells and increased CD8 memory T cells in blood of breastfed children

Background: Breastfeeding provides a protective effect against infectious diseases in infancy. Still, immunological evidence for enhanced adaptive immunity in breastfed children remains inconclusive. Objective: To determine whether breastfeeding affects B- and T-cell memory in the first years of life. Methods: We performed immunophenotypic analysis on blood samples within a population-based prospective cohort study. Participants included children at 6 months (n=258), 14 months (n=166), 25 months (n=112) and 6 years of age (n=332) with both data on breastfeeding and blood lymphocytes. Total B- and T-cell numbers and their memory subsets were determined with 6-color flow cytometry. Mothers completed questionnaires on breastfeeding when their children were aged 2, 6, and 12 months. Multiple linear regression models with adjustments for potential confounders were performed. Results: Per month continuation of breastfeeding, a 3% (95% CI -6, -1) decrease in CD27+IgM+, a 2% (95 CI % -5, -1) decrease in CD27+IgA+ and a 2% (95% CI -4, -1) decrease in CD27-IgG+ memory B cell numbers were observed at 6 months of age. CD8 T-cell numbers at 6 months of age were 20% (95% CI 3, 37) higher in breastfed than in non-breastfed infants. This was mainly found for central memory CD8 T cells and associated with exposure to breast milk, rather than duration. The same trend was observed at 14 months, but associations disappeared at older ages. Conclusions: Longer breastfeeding is associated with increased CD8 T-cell memory, but not B-cell memory numbers in the first 6 months of life. This transient skewing towards T cell memory might contribute to the protective effect against infectious diseases in infancy

Combined ecological risks of nitrogen and phosphorus in European freshwaters

Eutrophication is a key water quality issue triggered by increasing nitrogen (N) and phosphorus (P) levels and potentially posing risks to freshwater biota. We predicted the probability that an invertebrate species within a community assemblage becomes absent due to nutrient stress as the ecological risk (ER) for European lakes and streams subjected to N and P pollution from 1985 to 2011. The ER was calculated as a function of species-specific tolerances to NO3 - and total P concentrations and water quality monitoring data. Lake and stream ER averaged 50% in the last monitored year (i.e. 2011) and we observed a decrease by 22% and 38% in lake and stream ER (respectively) of river basins since 1985. Additionally, the ER from N stress surpassed that of P in both freshwater systems. The ER can be applied to identify river basins most subjected to eutrophication risks and the main drivers of impacts