Summary
Background
B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic ...rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways.
Objective
We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation.
Methods
We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody‐secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT‐PCR.
Results
NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein–Barr virus‐induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody‐secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro.
Conclusions and Clinical Relevance
Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC‐mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell‐targeted therapies may provide new treatment options for CRSwNP.
Summary
Background
Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is ...excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐PA) in NPs. As t‐PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐PA would be a potential new strategy for the treatment of NPs.
Objective
The objective of this study was to determine whether short‐chain fatty acids (SCFAs) can induce t‐PA in airway epithelial cells via their known receptors GPR41 and GPR43.
Methods
We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein‐coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t‐PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA.
Results
Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐PA expression from two‐ to tenfolds. The strongest inducer of t‐PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t‐PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t‐PA by SCFAs was dependent upon both GPR41 and GPR43.
Conclusions and Clinical Relevance
Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
We report the first observation of the parity-violating gamma-ray asymmetry A_{γ}^{np} in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the ...Spallation Neutron Source at Oak Ridge National Laboratory. A_{γ}^{np} isolates the ΔI=1, ^{3}S_{1}→^{3}P_{1} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless effective field theory. We measured A_{γ}^{np}=-3.0±1.4(stat)±0.2(syst)×10^{-8}, which implies a DDH weak πNN coupling of h_{π}^{1}=2.6±1.2(stat)±0.2(syst)×10^{-7} and a pionless EFT constant of C^{^{3}S_{1}→^{3}P_{1}}/C_{0}=-7.4±3.5(stat)±0.5(syst)×10^{-11} MeV^{-1}. We describe the experiment, data analysis, systematic uncertainties, and implications of the result.
Summary
Background
Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not ...been fully elucidated. Dendritic cells (DCs) are major antigen‐presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied.
Objective
The objective of this study was to characterize DC subsets in CRS.
Methods
We used real‐time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry.
Results
Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were significantly elevated in NPs (n = 29). In contrast, CD207 mRNA was not elevated in NPs. Immunohistochemistry showed that CD1c+ cells but not CD303+ cells were significantly elevated in NPs compared to control subjects or patients with CRSsNP. Flow cytometric analysis showed that CD1a+ cells in NPs might be a subset of mDC1s and that CD45+CD19−CD1c+CD11c+CD141−CD303−HLA‐DR+ mDC1s and CD45+CD19−CD11c+CD1c−CD141high HLA‐DR+ mDC2s were significantly elevated in NPs compared to UT from controls and CRSsNP, but CD45+CD11c−CD303+HLA‐DR+ pDCs were only elevated in NPs compared to control UT.
Conclusion and Clinical Relevance
Myeloid DCs are elevated in CRSwNP, especially in NPs. Myeloid DCs thus may indirectly contribute to the inflammation observed in CRSwNP.
The NPDGamma experiment measures the asymmetry in γ-ray emission in the capture of polarized neutrons on liquid parahydrogen. The beam polarization is measured using 3He spin analysis, but this ...measurement does not account for the contribution of depolarization from spin–flip scattering primarily due to orthohydrogen in the bulk liquid. This is a systematic effect that dilutes the experimental asymmetry and is modeled using Monte Carlo. Methods for tracking neutron spin in MCNPX were developed in order to calculate the average neutron polarization upon capture for use as a multiplicative correction to the measured beam polarization for the NPDGamma experiment.
The NPDGamma experiment measures the parity-violating asymmetry in γ-ray emission in the capture of polarized neutrons on liquid parahydrogen. The sensitivity to the asymmetry for each detector in ...the array is used as a parameter in the extraction of the physics asymmetry from the measured data. The detector array is approximately cylindrically symmetric around the target and a step-wise sinusoidal function has been used for the sensitivity in the previous iteration of the NPDGamma experiment, but deviations from cylindrical symmetry necessitate the use of a Monte Carlo model to determine corrections to the geometrical factors. For the calculations, source code modifications to MCNPX were done in order to calculate the sensitivity of each cesium iodide detector to the physics asymmetry. We describe the MCNPX model and results from calculations and how the results are validated through measurement of the parity violating asymmetry of γ-rays from neutron capture on chlorine.
The NPDGamma experiment measures the parity-violating asymmetry in gamma-ray emission in the capture of polarized neutrons on liquid parahydrogen. The sensitivity to the asymmetry for each detector ...in the array is used as a parameter in the extraction of the physics asymmetry from the measured data. The detector array is approximately cylindrically symmetric around the target and a step-wise sinusoidal function has been used for the sensitivity in the previous iteration of the NPDGamma experiment, but deviations from cylindrical symmetry necessitate the use of a Monte Carlo model to determine corrections to the geometrical factors. For the calculations, source code modifications to MCNPX were done in order to calculate the sensitivity of each cesium iodide detector to the physics asymmetry. We describe the MCNPX model and results from calculations and how the results are validated through measurement of the parity violating asymmetry of gamma-rays from neutron capture on chlorine.
Liquid hydrogen is a dense Bose fluid whose equilibrium properties are both calculable from first principles using various theoretical approaches and of interest for the understanding of a wide range ...of questions in many-body physics. Unfortunately, the pair correlation function g(r) inferred from neutron scattering measurements of the differential cross section dsigma/dOmega from different measurements reported in the literature are inconsistent. We have measured the energy dependence of the total cross section and the scattering cross section for slow neutrons with energies between 0.43 and 16.1 meV on liquid hydrogen at 15.6 K (which is dominated by the parahydrogen component) using neutron transmission measurements on the hydrogen target of the NPDGamma collaboration at the Spallation Neutron Source at Oak Ridge National Laboratory. The relationship between the neutron transmission measurement we perform and the total cross section is unambiguous, and the energy range accesses length scales where the pair correlation function is rapidly varying. At 1 meV our measurement is a factor of 3 below the data from previous work. We present evidence that these previous measurements of the hydrogen cross section, which assumed that the equilibrium value for the ratio of orthohydrogen and parahydrogen has been reached in the target liquid, were in fact contaminated with an extra nonequilibrium component of orthohydrogen. Liquid parahydrogen is also a widely used neutron moderator medium, and an accurate knowledge of its slow neutron cross section is essential for the design and optimization of intense slow neutron sources. We describe our measurements and compare them with previous work.
Summary
Background
Chronic rhinosinusitis (
CRS
) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (
NP
s). One of the features of
NP
...s is excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐
PA
) in
NP
s. As t‐
PA
is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐
PA
would be a potential new strategy for the treatment of
NP
s.
Objective
The objective of this study was to determine whether short‐chain fatty acids (
SCFA
s) can induce t‐
PA
in airway epithelial cells via their known receptors
GPR
41 and
GPR
43.
Methods
We performed immunohistochemistry (
IHC
) to determine whether receptors for
SCFA
s, known as G protein‐coupled receptor 41/free fatty acid receptor 3 (
GPR
41/
FFAR
3) and
GPR
43/
FFAR
2, are expressed in nasal tissue. Primary normal human bronchial epithelial (
NHBE
) cells were stimulated with different concentrations of
SCFA
s to test induction of t‐
PA
, which was analysed by expression of
mRNA
and protein. Mediation of responses by
SCFA
receptors was evaluated by specific receptor gene silencing with si
RNA
.
Results
Immunohistochemistry study revealed that airway epithelial cells expressed
GPR
41 and
GPR
43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐
PA
expression from two‐ to tenfolds. The strongest inducer of t‐
PA
from
NHBE
cells was propionic acid; cells stimulated with propionic acid released t‐
PA
into the supernatant in its active form. Gene silencing of
GPR
41 and
GPR
43 revealed that induction of t‐
PA
by
SCFA
s was dependent upon both
GPR
41 and
GPR
43.
Conclusions and Clinical Relevance
Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐
PA
via
GPR
41 and
GPR
43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
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