445 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 [...
Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is
crucial for precursor (pre-B) cell differentiation in humans. In this
study, we show that during the transition of large cycling to small
resting pre-B cells in the mouse, Btk-deficient cells failed to
efficiently modulate the expression of CD43, surrogate L chain, CD2, and
CD25. In an analysis of the kinetics of pre-B cell differentiation in
vivo, Btk-deficient cells manifested a specific developmental delay within
the small pre-B cell compartment of about 3 h, when compared with
wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient
large cycling pre-B cells showed increased IL-7 mediated expansion and
reduced developmental progression into noncycling CD2(+)CD25(+) surrogate
L chain-negative small pre-B cells and subsequently into Ig-positive B
cells. Furthermore, the absence of Btk resulted in increased proliferative
responses to IL-7 in recombination-activating gene-1-deficient pro-B
cells. These findings identify a novel role for Btk in the regulation of
the differentiation stage-specific modulation of IL-7 responsiveness in
pro-B and pre-B cells. Moreover, our results show that Btk is critical for
an efficient transit through the small pre-B cell compartment, thereby
regulating cell surface phenotype changes during the developmental
progression of cytoplasmic mu H chain expressing pre-B cells into immature
IgM(+) B cells
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-
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