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Innate Immunity, Host Defense, and Immunopathology
David M. Mosser, Ph.D.
[email protected]
Innate Immunity
It all started here….
Fig. 5.
From Lemaitre et al. Cell 86: 973–983, 1996.
Freely available at
www.cell.com/retrieve/pii/S0092867400801725
Innate immune responses via toll-like receptors
Toll-Like Receptors
*Genetically pre-determined
*Pattern recognition receptors
*Constitutively expressed on
phagocytes
*Signaling pathway similar to IL-1Rmediated NF-κB activation
Pathogen-associated molecular
patterns (PAMPs)
*Associated with pathogen, not host
*Indispensable to pathogen survival
*Highly conserved among pathogens
NF-κB
*Nuclear transcription factor
*Contributes to IL-12, TNFα, and
iNOS transcription activation
Fig. 2.
From Medzhitov, R.
and Janeway, C, Jr. N
Engl J Med 343(5):
338-344, 2000.
Available at
www.ncbi.nlm.nih.gov
/pubmed/10922424
PAMPs and DAMPs: signal 0s that spur autophagy and immunity
Fig. 1.
From Tang et al. Immunol Rev 249(1): 158175, 2012.
Available at
onlinelibrary.wiley.com.proxygw.wrlc.org/d
oi/10.1111/j.1600-065X.2012.01146.x/full
Many TLRs
Fig. 3-11, pt. 1.
From Kindt, Goldsby, and Osborne. Kuby
Immunology (6th Ed.). 2007, New York: Freeman.
TLR structure
Fig. 3-10.
From Kindt, Goldsby, and Osborne. Kuby
Immunology (6th Ed.). 2007, New York: Freeman.
TIR = Toll, IL-1 receptor domain
Nuclear translocation of NF-kB following
bacterial infection of macrophages
Untreated (dark nuclei)
R. equi – infected
LPS-treated
Macrophages counterstained red
NF-kB (p65) stained in green
Macrophage cytokine production
TNF, IL-1, IL-6, IL-8, IL-12…
Dendritic cell maturation (following TLR ligation)
MHC Class II
CD40
CD86 (B7.2)
Immature
Mature
Increased MHC
Increased CD40
Increased co-stim
TLR ligands as adjuvants… improving CMI !/?
Fig. 5.
From Duthie et al. Immunol Rev 239: 178-196, 2011.
Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2010.00978.x/abstract
Fig. 3B & C.
From Baldwin et al J Immunol
188: 2189-2197, 2012
Available at
Fig. 6.
From Baldwin et al J Immunol
188: 2189-2197, 2012
Available at
TLR ligands as adjuvants… preventing allergy
Fig. 3A.
From De Brito et al. J Clin Immunol 30: 280291, 2010.
Available at
link.springer.com/article/10.1007%2Fs10875009-9358-9
Fig. 1, A&B, and H&L.
From Xirakia et al. Am J Respir Crit Care Med
181: 1207-1216, 2010.
Freely available at
www.ncbi.nlm.nih.gov/pmc/articles/PMC36623
18/pdf/emmm0005-0762.pdf
CpG TH 1 response
IgE
R-848 lung inflammation
Delivery of antigen and TLR agonists to APCs
using nanoparticles
Nanoparticles
Antigen + TLR ligand
Targeting molecule
DC-targeted TLRLs enhance maturation and activation
of human DCs in vitro
Fig. 2A, top.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
DC maturation
Fig. 2A, bottom.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
Co-stim
Fig. 2B.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
Cytokines
Binding, uptake, and Ag presentation of NPs
by mouse DCs
Fig. 4A.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
Particle uptake
Fig. 4B.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
T cell proliferation
Fig. 4C.
From Tacken et al. Blood 118: 6836-6844, 2011.
Freely available at
bloodjournal.hematologylibrary.org/content/118/26/6836.full
IFN-γ production
“Preserving the sanctity of the cytosol”
Cytosolic PRRs
Fig. 1.
From Chamaillard et al. Cell Microbiol 5: 481-592, 2003.
Freely available at
http://onlinelibrary.wiley.com/doi/10.1046/j.14625822.2003.00304.x/full
CARD domain
containing proteins
(Note: outdated nomenclature)
The NLR family
(Nucleotide-binding and oligomerization domain-like receptors)
Fig. 1.
From Yeretssian, G. Immunol Res 54: 25-36, 2012.
Available at
http://link.springer.com/article/10.1007%2Fs12026012-8317-3
Bacterial
Peptidoglycans
(top 2 NLRC)
NLRP3
(middle NLRP)
NLRP3
Inflammasome
Assembly
Fig. 3.
From Schroder, K. and Tschopp, J. Cell
140: 821-832, 2010.
Available at
www.cell.com/retrieve/pii/S0092867410000759
IL-1 and IL-18
secretion
Proteolytic cleavage to secrete IL-1, IL-18, and IL-33
Fig. 1.
From Lamkanfi, M. and Dixit, VM. Immunol Rev 227: 95-105, 2009.
Available at onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2008.00730.x/abstract
NLRP3
NLRC4
NLRP1
Inflammasomes
Anthrax lethal toxin
ATP
Pore-forming
toxins
Crystals
Flagellin
T3SS and T4SS
Pseudomonas
Fig.
From Ulland, TK and Sutterwala, FS. The inflammasomes:
Activation of the inflammasome by bacterial pathogens. In:
Progress in Inflammation Research. 2011. Springer: Basel, p.
37-50.
dsDNA
Francisella
DNA: also
RIGI and MAVS
NLRP3 inflammasome
Fig. 1.
From Leemans et al. Immunol Rev 243: 152-162, 2011.
Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2011.01043.x/full
Cytosolic nucleic acid recognition by the host
Fig. 1, a-c.
From Monie, TP. Trends Biochem Sci 38: 131-139,
2013.
Available at
www.sciencedirect.com/science/article/pii/S09680004
13000029
Many ways to activate…
Fig. 1.
From Monie, TP. Trends Biochem Sci 38: 131-139,
2013.
Available at
www.sciencedirect.com/science/article/pii/S09680004
13000029
Innate immune pathways
Fig. 8.1.
From Witte et al. Adv Immunol 113: 135-156, 2012.
Available at
www.sciencedirect.com/science/article/pii/B978012394590
7000026
Inflammasomes and gut homeostasis
Fig. 2.
From Zambetti et al. Immunol Res 53: 78-90, 2012.
Available at link.springer.com/article/10.1007%2Fs12026012-8272-z
NLRP6 inflammasome regulates colonic microbial
ecology and risk for colitis
Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ,
Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA.
Fig. 3, E-F.
From Elinav et al. Cell 145: 745-757, 2011.
Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3140910/
Fig. 4, G-I.
From Elinav et al. Cell 145: 745-757, 2011.
Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3140910/
The price of immunity
Fig. 1.
From Goldzmid, RS and Trinchieri, G. Nature Immunol 13: 932-938, 2012.
Freely available at www.nature.com/ni/journal/v13/n10/full/ni.2422.html
Autophagy and host defense
Fig. 2. From Kuballa et al. Annu. Rev. Immunol. 30: 611646, 2012.
Available at
www.annualreviews.org/doi/abs/10.1146/annurev-immunol020711-074948
Granuloma formation – inflammation!
Figure courtesy of Professor Wagner Tafuri, UFMG, Brazil.
Chemotaxis (margination)
Molecules involved in margination
Fig. 13-8.
From Kindt, Goldsby, and Osborne. Kuby
Immunology (6th Ed.). 2007. New York: Freeman.
Chemokine
Chemokine binding
to its receptor
Fig. 2.32.
From Janeway’s
Immunobiology
(5th ed). 2001.
New York: Garland
Sci.
IL-8
Chemokine receptor
(actually rhodopsin
from bacteria)
From
en.wikipedia.org/wiki
/Chemotaxis
CC Chemokines
Fig. 3.22.
From Janeway’s
Immunobiology (5th ed). 2001.
New York: Garland Sci.
CXC Chemokines
Fig. 3.22.
From Janeway’s
Immunobiology (5th ed). 2001.
New York: Garland Sci.
Chemoattractants (3)
1.
Formylated peptides
fMet-leu-phe
2.
Complement anaphylotoxins
C5a, C3a
3.
Chemokines
CC Chemokines - many
CXC Chemokines - many
Simplified signal transduction
G protein-coupled receptors
Fig. 13-2.
From Kindt, Goldsby, and Osborne. Kuby
Immunology (6th Ed.). 2007. New York: Freeman.
Chemokine receptors as activation markers
Fig. 13-3.
From Kindt, Goldsby, and Osborne. Kuby
Immunology (6th Ed.). 2007, New York: Freeman.
CCR5 and CXCR4 chemokine receptors as coreceptors for HIV
Fig 2.
From Tilton JC and Doms RW. Antiviral Res 85:95-100, 2010.
Available at
www.sciencedirect.com/science/article/pii/S0166354209003945
Monocytes
Fig. 1.
From Strauss-Ayali et al. J. Leukocyte Biol. 82: 244-252, 2007.
Freely available at http://www.jleukbio.org/content/82/2/244.long
GR1+ Monocytes Produce O2and Kill Leishmania major
Fig. 5, E & F.
From Goncalves et al. J Exp Med 208: 1253-1265, 2011.
Freely available at http://jem.rupress.org/content/208/6/1253.full
Fig. 3A.
From Goncalves et al. J Exp Med 208: 1253-1265, 2011.
Freely available at http://jem.rupress.org/content/208/6/1253.full
Exploring the full spectrum of macrophage activation
Fig. 1.
From Mosser, D.M. and Edwards, J.P. Nature Rev Immunol 8:
958-969, 2008.
Available at www.nature.com/nri/journal/v8/n12/abs/nri2448.html
IFN
LPS
2˚ (Ag-Ab)
IFN
LPS
Regulatory M (R-M)
Anti-inflammatory
IL-4/13
High Class II and APC function
Low TNF, IL-12/23
High IL-10
Classically activated (Ca-M)
Alternatively activated (AA-M)
MHC Class II – Antigen presentation
High O2- and NO production - microbicidal
IL-12/23 – Th1 response
TNF, IL-1, IL-6 – inflammation
Relatively low IL-10 production
Low MHC Class II – Poor APC
Low or absent NO production – Arginase
Lectin-like receptors and chitinases
Low to absent IL-12/23 production
Host Defense
Immune regulation
Wound healing
Regulatory Macrophages Rescue Mice
From Lethal Endotoxemia
Cold-induced metabolic adaptations require
alternatively activated macrophages
Fig. 2, a & d.
From Nguyen et al. Nature 480: 104-108, 2011.
Available at
www.nature.com/nature/journal/v480/n7375/full/nature10653.html
Mosser Lab – University of Maryland
Xia Zhang, MD/Ph.D.
Ricardo Goncalves, DVM/PhD
Justin Edwards
Ziyan Yang
Heather Cohen
Rahul Suresh
Bryan Flemming
Bess Gerhart