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Epithelial Cells and
Their Role in Immunity
Dr. Irving Coy Allen
Virginia Tech
VA-MD Regional College of Veterinary Medicine
Department of Biomedical Sciences and
Pathobiology
Mucosal Immunology: An Overview
Animation Developed by Tom MacDonald
http://www.nature.com/ni/multimedia/mucosal/index.html
AB/PAS Staining Goblet Cell and Mucus Staining
Mock
Mock
AOM/DSS
AOM/DSS
Three Classes of Pattern-Recognition Receptors
Modified From: Osamu Takeuchi and Shizuo Akira; Immunological Reviews (2009)
TLR
RLR
TLR-7
TLR-3
MyD88
TRIF
RIG-I
NLR
MDA5
NLR
Inflammasome
MAVS
cleavage
IRF7
IRF3
NF-κB
Cytokine Genes
Type-I IFN Genes
pro-IL-1β
pro-IL-18
IL-1β
IL-18
NLRs in Intestinal Homeostasis
NLR SPECIFICITY
Inflammasome Forming NLRs
NLRP3
K+
ASC Speck
IFNγR
Cytosolic Gram
Negative
Bacteria
priming
STAT1
ROS
mtDNA
Ca2+
IFNαR
TLR3
Toxins
TLR4
DAMPs
IFN-β IFN-γ
LPS polyI:C
TNF
TNFR
ATP Crystals
LPS
Hypothetical
Non-Canonical
Inflammasome
Caspase-11
GBP5
Caspase-1
p10
pro-Caspase-1
NLRP3
Oligomer
pro-IL-1β
pro-IL-18
p20
IL-1β
IL-18
Pyroptosis
NLRP6
Menno van Lookeren Campagne & Vishva M. Dixit
Nature 474, 42–43 (02 June 2011) doi:10.1038/474042a
Pyroptosis
Nat Rev Microbiol. 2009 February ; 7(2): 99–109.
Pathogen Modulation of Inflammasome
Function
Inhibitory NLRs
Non-canonical
NF-κB
Signaling
Canonical
NF-κB
Signaling
TLR
MyD88
TRAF3
TRAF6
NIK
NLRC3
Cytosol
IKK-γ
NF-κB
CD40
NLRP12
IRAK1
NLRX1
Extracellular
IKK-α/α
IKK-α/β
IκB
p50 p65
p50 p65
NF-κB Binding Motif
p52 Rel
B
Inflammation
Migration
Differentiation
Invasiveness
Survival
p100 Rel
B
p52 Rel
B
NF-κB Binding Motif
Nucleus
Utilizing Mitochondria as Scaffolding
RNA
NLRX1
RIG-I
NLRX1
MAVS
RIG-I
NLRX1
MAVS
UQCRC2
TBK1
NLRX1
TUFM
ATG16L1
ATG5 ATG12
Mitochondria
IRF
IFN-I
IL-6
Autophagy
ROS
Computational modeling should prove highly useful to
elucidate the complex interplay between immunity,
metabolism and the microbiota, and provide insight on
pharmacokinetic and pharmacodynamic regulation of
new IBD therapies
 Predicting IBD prognosis is patient-specific, time sensitive and
often elusive, yet crucial for deciding effective treatment and
disease control.
 Mathematical and computational modeling offers a novel
perspective for identifying molecular targets aimed at the
development of more efficacious and safer personalized
interventions for IBD.
 Publically available microarray studies offer robust datasets for
calibrating, or fitting, mathematical equations to observed
biological phenomenon.
Computational Modeling:
PRRs and Epithelial Cell
Pathobiology
 Reconciling conflicting genomic results, integrating
transcriptomics, proteomics, flow cytometry and histology
data with specific clinical outcomes in patients with wellcharacterized gene variants through bioinformatics and
computational modeling approaches would provide an
invaluable assessment of TLR and NLR functionality among
heterogeneous populations of IBD patients.
 Computational modeling could be used to investigate cell
specificity of NLRs and the role of NLRs in sensing dysbiosis in
addition to mechanisms underlying modulation of T cell
differentiation by dysregulated NLR signaling.
Modeling:
Structure-Based Virtual Screening
(SBVS)
Questions?
Irving Coy Allen
[email protected]
http://upload.wikimedia.org/wikipedia/commons/0/0b/Burruss_Hall,_Virginia_Tech.JPG