Innate Immunity Host Defense and Immunopathology David M
- Slides: 45
Innate Immunity, Host Defense, and Immunopathology David M. Mosser, Ph. D. dmosser@umd. edu
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/S 0092867400801725
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-1 Rmediated 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 i. NOS 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 0 s 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 -065 X. 2012. 01146. x/full
Many TLRs Fig. 3 -11, pt. 1. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman.
TLR structure Fig. 3 -10. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman. TIR = Toll, IL-1 receptor domain
Nuclear translocation of NF-k. B following bacterial infection of macrophages Untreated (dark nuclei) R. equi – infected LPS-treated Macrophages counterstained red NF-k. B (p 65) stained in green
Macrophage cytokine production TNF, IL-1, IL-6, IL-8, IL-12…
Dendritic cell maturation (following TLR ligation) MHC Class II CD 40 CD 86 (B 7. 2) Immature Mature Increased MHC Increased CD 40 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. 1600065 X. 2010. 00978. x/abstract Fig. 3 B & 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. 3 A. From De Brito et al. J Clin Immunol 30: 280291, 2010. Available at link. springer. com/article/10. 1007%2 Fs 10875009 -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/PMC 36623 18/pdf/emmm 0005 -0762. pdf Cp. G TH 1 response R-848 Ig. E 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. 2 A, top. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Fig. 2 A, bottom. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Fig. 2 B. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l DC maturation Co-stim Cytokines
Binding, uptake, and Ag presentation of NPs by mouse DCs Fig. 4 A. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Particle uptake Fig. 4 B. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l T cell proliferation Fig. 4 C. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l 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%2 Fs 12026012 -8317 -3 Bacterial Peptidoglycans (top 2 NLRC) NLRP 3 (middle NLRP)
NLRP 3 Inflammasome Assembly Fig. 3. From Schroder, K. and Tschopp, J. Cell 140: 821 -832, 2010. Available at www. cell. com/retrieve/pii/S 0092867410000759 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. 1600065 X. 2008. 00730. x/abstract NLRP 3 NLRC 4 NLRP 1
Inflammasomes Anthrax lethal toxin ATP Pore-forming toxins Crystals Flagellin T 3 SS and T 4 SS 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. ds. DNA Francisella DNA: also RIGI and MAVS
NLRP 3 inflammasome Fig. 1. From Leemans et al. Immunol Rev 243: 152 -162, 2011. Available at http: //onlinelibrary. wiley. com/doi/10. 1111/j. 1600065 X. 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/S 09680004 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/S 09680004 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/B 978012394590 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%2 Fs 12026012 -8272 -z
NLRP 6 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/PMC 3140910/ Fig. 4, G-I. From Elinav et al. Cell 145: 745 -757, 2011. Freely available at www. ncbi. nlm. nih. gov/pmc/articles/PMC 3140910/
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/v 13/n 10/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-immunol 020711 -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 (6 th Ed. ). 2007. New York: Freeman.
Chemokine binding to its receptor Fig. 2. 32. From Janeway’s Immunobiology (5 th 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 (5 th ed). 2001. New York: Garland Sci.
CXC Chemokines Fig. 3. 22. From Janeway’s Immunobiology (5 th ed). 2001. New York: Garland Sci.
Chemoattractants (3) 1. Formylated peptides f. Met-leu-phe 2. Complement anaphylotoxins C 5 a, C 3 a 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 (6 th Ed. ). 2007. New York: Freeman.
Chemokine receptors as activation markers Fig. 13 -3. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman.
CCR 5 and CXCR 4 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/S 0166354209003945
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
GR 1+ Monocytes Produce O 2 and 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. 3 A. 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/v 8/n 12/abs/nri 2448. 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 O 2 - and NO production - microbicidal IL-12/23 – Th 1 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/v 480/n 7375/full/nature 10653. html
Mosser Lab – University of Maryland Xia Zhang, MD/Ph. D. Ricardo Goncalves, DVM/Ph. D Justin Edwards Ziyan Yang Heather Cohen Rahul Suresh Bryan Flemming Bess Gerhart
- Difference between acquired immunity and innate immunity
- Innate immunity first line of defense
- 1st line of defense immune system
- Innate immunity first line of defense
- Innate immunity first line of defense
- Salmonella life cycle
- Assis prof
- Innate immunity examples
- Non specific innate immunity
- Innate immunity
- Innate immunity
- Definitive host vs intermediate host
- 3 lines of defense immunity
- Nonspecific host defense mechanism
- "host defense"
- What is organizeyourpeople
- "host defense"
- "host defense"
- "host defense"
- "host defense"
- "host defense"
- Nonspecific defense mechanisms
- Humoral and cell mediated immunity difference
- Chapter 13 lymphatic system and immunity
- Define immunity in microbiology
- Chapter 16 lymphatic system and immunity
- Chapter 22 lymphatic system and immunity
- Difference between innate and learned behavior
- Active artificial immunity
- Innate and learned behavior
- Imprinting biology example
- Innate and learned behavior
- Innate and acquirable qualities with examples
- Which is not a combination of innate and learned behavior
- Malt organs
- Effector mechanism of humoral immunity
- Nonspecific vs specific immunity
- Canra passed
- Adaptive noise immunity
- Keva immunity booster benefits
- Iec 61967-4
- Wepapers
- Acquired immunity definition
- Odibate
- Active vs passive immunity
- Non specific immunity