4 research outputs found
Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease
Bruton’s tyrosine kinase (Btk) is a signaling molecule involved in development and
activation of B cells through B-cell receptor (BCR) and Toll-like receptor (TLR)
signaling. We have previously shown that transgenic mice that overexpress human Btk
under the control of the CD19 promoter (CD19-hBtk) display spontaneous germinal
center formation, increased cytokine production, anti-nuclear autoantibodies (ANAs),
and systemic autoimsmune disease upon aging. As TLR and BCR signaling are
both implicated in autoimmunity, we studied their impact on splenic B cells. Using
phosphoflow cytometry, we observed that phosphorylation of ribosomal protein S6, a
downstream Akt target, was increased in CD19-hBtk B cells following BCR stimulation
or combined BCR/TLR stimulation, when compared with wild-type (WT) B cells. The
CD19-hBtk transgene enhanced BCR-induced B cell survival and proliferation, but had
an opposite effect following TLR9 or combined BCR/TLR9 stimulation. Although the
expression of TLR9 was reduced in CD19-hBtk B cells compared to WT B cells, a
synergistic effect of TLR9 and BCR stimulation on the induction of CD25 and CD80 was
observed in CD19-hBtk B cells. In splenic follicular (Fol) and marginal zone (MZ) B cells
from aging CD19-hBtk mice BCR signaling stimulated in vitro IL-10 production in synergy
with TLR4 and particularly TLR9 stimulation, but not with TLR3 and TLR7. The enhanced
capacity of CD19-hBtk Fol B cells to produce the pro-inflammatory cytokines IFNγ and
IL-6 compared with WT B cells was however not further increased following in vitro BCR
or TLR9 stimulation. Finally, we used crosses with mice deficient for the TLR-associated
molecule myeloid differentiation primary response 88 (MyD88) to show that TLR signaling
was crucial for spontaneous formation of germinal centers, increased IFNγ, and IL-6
production by B cells and anti-nuclear autoantibody induction in CD19-hBtk mice. Taken
together, we conclude that high Btk expression does not only increase B cell survival
following BCR stimulation, but also renders B cells more sensitive to TLR stimulation,
resulting in increased expression of CD80, and IL-10 in activated B cells. Although
BCR-TLR interplay is complex, our findings show that both signaling pathways are crucial
for the development of pathology in a Btk-dependent model for systemic autoimmune
disease
Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome : a consensus statement from the FD/MAS international consortium
Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients’ advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally