117 research outputs found
Pleiotropic Effect of IL-6 Produced by B-Lymphocytes During Early Phases of Adaptive Immune Responses Against TB Infection
The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4 + IFN-γ +, Th17 +, and CD4 + CXCR5 + follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions
Host Genetics in Granuloma Formation: Human-Like Lung Pathology in Mice with Reciprocal Genetic Susceptibility to M. tuberculosis and M. avium
Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i) characteristics of susceptibility to two infections in vivo; (ii) architecture of lung granulomata assessed by immune staining; and (iii) expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis
Interleukin-11 Drives Early Lung Inflammation during Mycobacterium tuberculosis Infection in Genetically Susceptible Mice
IL-11 is multifunctional cytokine whose physiological role in the lungs during pulmonary tuberculosis (TB) is poorly understood. Here, using in vivo administration of specific antibodies against IL-11, we demonstrate for the first time that blocking IL-11 diminishes histopathology and neutrophilic infiltration of the lung tissue in TB-infected genetically susceptible mice. Antibody treatment decreased the pulmonary levels of IL-11 and other key inflammatory cytokines not belonging to the Th1 axis, and down-regulated IL-11 mRNA expression. This suggests the existence of a positive feedback loop at the transcriptional level, which is further supported by up-regulation of IL-11 mRNA expression in the presence of rIL-11 in in vitro cultures of lung cells. These findings imply a pathogenic role for IL-11 during the early phase of Mycobacterium tuberculosis-triggered disease in a genetically susceptible host
Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC
We present the first results of meson production in the K^+K^- decay channel
from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by
the PHENIX detector at RHIC. Precision resonance centroid and width values are
extracted as a function of collision centrality. No significant variation from
the PDG accepted values is observed. The transverse mass spectra are fitted
with a linear exponential function for which the derived inverse slope
parameter is seen to be constant as a function of centrality. These data are
also fitted by a hydrodynamic model with the result that the freeze-out
temperature and the expansion velocity values are consistent with the values
previously derived from fitting single hadron inclusive data. As a function of
transverse momentum the collisions scaled peripheral.to.central yield ratio RCP
for the is comparable to that of pions rather than that of protons. This result
lends support to theoretical models which distinguish between baryons and
mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be
submitted to Physical Review C as a regular article. Plain text data tables
for the points plotted in figures for this and previous PHENIX publications
are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm
J/psi production from proton-proton collisions at sqrt(s) = 200 GeV
J/psi production has been measured in proton-proton collisions at sqrt(s)=
200 GeV over a wide rapidity and transverse momentum range by the PHENIX
experiment at RHIC. Distributions of the rapidity and transverse momentum,
along with measurements of the mean transverse momentum and total production
cross section are presented and compared to available theoretical calculations.
The total J/psi cross section is 3.99 +/- 0.61(stat) +/- 0.58(sys) +/-
0.40(abs) micro barns. The mean transverse momentum is 1.80 +/- 0.23(stat) +/-
0.16(sys) GeV/c.Comment: 326 authors, 6 pages text, 4 figures, 1 table, RevTeX 4. To be
submitted to PRL. Plain text data tables for the points plotted in figures
for this and previous PHENIX publications are (or will be) publicly available
at http://www.phenix.bnl.gov/papers.htm
Measurement of Single Electron Event Anisotropy in Au+Au Collisions at sqrt(s_NN) = 200 GeV
The transverse momentum dependence of the azimuthal anisotropy parameter v_2,
the second harmonic of the azimuthal distribution, for electrons at
mid-rapidity (|eta| < 0.35) has been measured with the PHENIX detector in Au+Au
collisions at sqrt(s_NN) = 200 GeV. The measurement was made with respect to
the reaction plane defined at high rapidities (|eta| = 3.1 -- 3.9). From the
result we have measured the v_2 of electrons from heavy flavor decay after
subtraction of the v_2 of electrons from other sources such as photon
conversions and Dalitz decay from light neutral mesons. We observe a non-zero
single electron v_2 with a 90% confidence level in the intermediate p_T region.Comment: 330 authors, 11 pages text, RevTeX4, 9 figures, 1 tables. Submitted
to Physical Review C. Plain text data tables for the points plotted in
figures for this and previous PHENIX publications are (or will be) publicly
available at http://www.phenix.bnl.gov/papers.htm
Regulation of the Transglutaminase I gene
The transglutaminase I (TGase I) gene encodes an enzyme that catalyzes the cross-linking of structural proteins involved in the formation of the cornified envelope during squamous cell differentiation. To identify DNA elements important for the transcriptional control of the TGase I gene, we analyzed the ability of a 2.9-kilobase pair (kb) upstream regulatory region to control the expression of a reporter gene in vivo and in vitro. Transgenic mice bearing the pTG(-2.9kb)CAT construct exhibited the same pattern of tissue-specific expression of CAT as reported for TGase I. Deletion analysis in transiently transfected rabbit tracheal epithelial cells indicated that two sequences from bp -490 to -470 and from -54 to -37 are involved in the activation of TGase I transcription. Point mutation analysis and mobility shift assays showed that the sequence located between -54 and -37 is a functional Sp1-like transcription element. Sp1 and Sp3, but not Sp2, are part of nuclear protein complexes from differentiated RbTE cells binding to this site. The element TGATGTCA between bp -490 and -470 is contained in a larger 22-bp palindrome and resembles the consensus cAMP response element-binding protein (CREB)/AP-1 element recognized by dimeric complexes of members of the CREB, ATF, Fos, and Jun families. Mutations in this sequence greatly reduced promoter activity. Supershift analysis identified CREB1, JunB, c-Fos, Fra-1, and c-Jun in protein complexes isolated from differentiated rabbit tracheal epithelial cells binding to this site. Our study shows that the Sp1- and CREB/AP-1-like sites act in concert to stimulate transcription of the TGase I gene. The 2.9-kb promoter region could guide expression of specific genes in the granular layer of the epidermis and could be useful in gene therapy
Systematic Studies of the Centrality and sqrt(s_NN) Dependence of dE_T/deta and dN_ch/deta in Heavy Ion Collisions at Mid-rapidity
The PHENIX experiment at RHIC has measured transverse energy and charged
particle multiplicity at mid-rapidity in Au+Au collisions at sqrt(s_NN) = 19.6,
130 and 200 GeV as a function of centrality. The presented results are compared
to measurements from other RHIC experiments, and experiments at lower energies.
The sqrt(s_NN) dependence of dE_T/deta and dN_ch/deta per pair of participants
is consistent with logarithmic scaling for the most central events. The
centrality dependence of dE_T/deta and dN_ch/deta is similar at all measured
incident energies. At RHIC energies the ratio of transverse energy per charged
particle was found independent of centrality and growing slowly with
sqrt(s_NN). A survey of comparisons between the data and available theoretical
models is also presented.Comment: 327 authors, 25 pages text, 19 figures, 17 tables, RevTeX 4. To be
submitted to Physical Review C as a regular article. Plain text data tables
for the points plotted in figures for this and previous PHENIX publications
are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm
Centrality Dependence of Charm Production from Single Electrons in Au+Au Collisions at sqrt(s_NN) = 200 GeV
The PHENIX experiment has measured mid-rapidity transverse momentum spectra
(0.4 < p_T < 4.0 GeV/c) of single electrons as a function of centrality in
Au+Au collisions at sqrt(s_NN) = 200 GeV. Contributions to the raw spectra from
photon conversions and Dalitz decays of light neutral mesons are measured by
introducing a thin (1.7% X_0) converter into the PHENIX acceptance and are
statistically removed. The subtracted ``non-photonic'' electron spectra are
primarily due to the semi-leptonic decays of hadrons containing heavy quarks
(charm and bottom). For all centralities, charm production is found to scale
with the nuclear overlap function, T_AA. For minimum-bias collisions the charm
cross section per binary collision is N_cc^bar/T_AA = 622 +/- 57 (stat.) +/-
160 (sys.) microbarns.Comment: 326 authors, 4 pages text, 3 figures, 1 table, RevTeX 4. To be
submitted to Physical Review Letters. Plain text data tables for the points
plotted in figures for this and previous PHENIX publications are (or will be)
publicly available at http://www.phenix.bnl.gov/papers.htm
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