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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Allergy+Clin+Immunol
2015 ; 136
(5
): 1326-36
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Single-cell systems-level analysis of human Toll-like receptor activation defines
a chemokine signature in patients with systemic lupus erythematosus
#MMPMID26037552
O'Gorman WE
; Hsieh EW
; Savig ES
; Gherardini PF
; Hernandez JD
; Hansmann L
; Balboni IM
; Utz PJ
; Bendall SC
; Fantl WJ
; Lewis DB
; Nolan GP
; Davis MM
J Allergy Clin Immunol
2015[Nov]; 136
(5
): 1326-36
PMID26037552
show ga
BACKGROUND: Activation of Toll-like receptors (TLRs) induces inflammatory
responses involved in immunity to pathogens and autoimmune pathogenesis, such as
in patients with systemic lupus erythematosus (SLE). Although TLRs are
differentially expressed across the immune system, a comprehensive analysis of
how multiple immune cell subsets respond in a system-wide manner has not been
described. OBJECTIVE: We sought to characterize TLR activation across multiple
immune cell subsets and subjects, with the goal of establishing a reference
framework against which to compare pathologic processes. METHODS: Peripheral
whole-blood samples were stimulated with TLR ligands and analyzed by means of
mass cytometry simultaneously for surface marker expression, activation states of
intracellular signaling proteins, and cytokine production. We developed a novel
data visualization tool to provide an integrated view of TLR signaling networks
with single-cell resolution. We studied 17 healthy volunteer donors and 8
patients with newly diagnosed and untreated SLE. RESULTS: Our data revealed the
diversity of TLR-induced responses within cell types, with TLR ligand
specificity. Subsets of natural killer cells and T cells selectively induced
nuclear factor ? light chain enhancer of activated B cells in response to TLR2
ligands. CD14(hi) monocytes exhibited the most polyfunctional cytokine expression
patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced
cytokine patterns were shared among a group of healthy donors, with minimal
intraindividual and interindividual variability. Furthermore, autoimmune disease
altered baseline cytokine production; newly diagnosed untreated SLE patients
shared a distinct monocytic chemokine signature, despite clinical heterogeneity.
CONCLUSION: Mass cytometry defined a systems-level reference framework for human
TLR activation, which can be applied to study perturbations in patients with
inflammatory diseases, such as SLE.