353 research outputs found
Bestrijden of gedogen: moleculen maken het verschil
Rede,
uitgesproken ter gelegenheid
van het aanvaarden van
het ambt van bijzonder hoogleraar
met als leeropdracht Immuniteit van de Long
aan het Erasmus MC, faculteit van de
Erasmus Universiteit Rotterdam
op 25 november 201
Cellular maturation defects in Bruton's tyrosine kinase-deficient immature B cells are amplified by premature B cell receptor expression and reduced by receptor editing
In the mouse, Bruton's tyrosine kinase (Btk) is essential for efficient
developmental progression of CD43(+)CD2(-) large cycling into
CD43(-)CD2(+) small resting pre-B cells in the bone marrow and of
IgM(high) transitional type 2 B cells into IgM(low) mature B cells in the
spleen. In this study, we show that the impaired induction of cell surface
changes in Btk-deficient pre-B cells was still noticeable in kappa(+)
immature B cells, but was largely corrected in lambda(+) immature B cells.
As lambda gene rearrangements are programmed to follow kappa
rearrangements and lambda expression is associated with receptor editing,
we hypothesized that the transit time through the pre-B cell compartment
or receptor editing may affect the extent of the cellular maturation
defects in Btk-deficient B cells. To address this issue, we used 3-83 mu
delta transgenic mice, which prematurely express a complete B cell
receptor and therefore manifest accelerated B cell development. In
Btk-deficient 3-83 mu delta mice, the IgM(+) B cells in the bone marrow
exhibited a very immature phenotype (pre-BCR(+)CD43(+)CD2(-)) and were
arrested at the transitional type 1 B cell stage upon arrival in the
spleen. However, these cellular maturation defects were largely restored
when Btk-deficient 3-83 mu delta B cells were on a centrally deleting
background and therefore targeted for receptor editing. Providing an
extended time window for developing B cells by enforced expression of the
antiapoptotic gene Bcl-2 did not alter the Btk dependence of their
cellular maturation. We conclude that premature B cell receptor expression
amplifies the cellular maturation defects in Btk-deficient B cells, while
extensive receptor editing reduces these defects
B Cell Signaling and Activation in Autoimmunity
Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...
Decoding the genetic and epigenetic basis of asthma
Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility is strongly influenced by genetics. Given its high prevalence and our incomplete understanding of the mechanisms underlying disease susceptibility, asthma is frequently studied in genome-wide association studies (GWAS), which have identified thousands of genetic variants associated with asthma development. Virtually all these genetic variants reside in non-coding genomic regions, which has obscured the functional impact of asthma-associated variants and their translation into disease-relevant mechanisms. Recent advances in genomics technology and epigenetics now offer methods to link genetic variants to gene regulatory elements embedded within non-coding regions, which have started to unravel the molecular mechanisms underlying the complex (epi)genetics of asthma. Here, we provide an integrated overview of (epi)genetic variants associated with asthma, focusing on efforts to link these disease associations to biological insight into asthma pathophysiology using state-of-the-art genomics methodology. Finally, we provide a perspective as to how decoding the genetic and epigenetic basis of asthma has the potential to transform clinical management of asthma and to predict the risk of asthma development.</p
Aberrant B Cell Signaling in Autoimmune Diseases
Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells
Role of Bruton's tyrosine kinase in B cells and malignancies
Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-
3D genome organization during lymphocyte development and activation
Chromosomes have a complex three-dimensional (3D) architecture comprising A/B compartments, topologically associating domains and promoter-enhancer interactions. At all these levels, the 3D genome has functional consequences for gene transcription and therefore for cellular identity. The development and activation of lymphocytes involves strict control of gene expression by transcription factors (TFs) operating in a three-dimensionally organized chromatin landscape. As lymphocytes are indispensable for tissue homeostasis and pathogen defense, and aberrant lymphocyte activity is involved in a wide range of human morbidities, acquiring an in-depth understanding of the molecular mechanisms that control lymphocyte identity is highly relevant. Here we review current knowledge of the interplay between 3D genome organization and transcriptional control during B and T lymphocyte development and antigen-dependent activation, placing special emphasis on the role of TFs
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