Lecture 19: Innate Immunity Flashcards
5 cardinal signs of Inflammation
- Heat
- Redness
- Swelling
- Pain
- Loss of Function
Fever
- from strong proinflammatory response
- not DIRECTLY caused by pathogenic factors
- cytokines TNF, IL-1, IL-6 are potent inducers
- most pathogens replicate poorly in elevated temps
What are PAMPs?
- Pathogen-associated Molecular Patterns
- unique to particular classes of pathogens
- usually required for survival, cannot be hidden from surface
- not similar to self-Ags
Gram- PAMPs
Porin, Lipopolysaccharide, Lipoprotein
Gram+ PAMPs
Teichoic acid, lipoteichoic acid, peptidoglycan, lipoprotein
Mycobacteria PAMPs
lipoarabinomannan, porin, lipoprotein
Fungi PAMPs
manno-proteins, B-glucan, lipoprotein
Extracellular TLRs and what they recognize
TLR 1/2 - bacterial lipopeptides
TLR 2 - bacterial peptidoglycans
TLR 4 - LPS
TLR 5 - bacterial flagellin
TLR 2/6 - bacterial lipopeptides
Intracellular (endosome) TLRs and what they recognize
TLR 3 - dsRNA
TLR 7 - ssRNA
TLR 8 - ssRNA
TLR 9 - CpG DNA
MyD88, TRIF, IRF, NK-kB
MyD88 - activated by all TLRs, cause NK-kB/IRF act.
TRIF - activated by TLR3/4, cause NK-kB/IRF act.
IRF/NK-kB - transcriptional factors
TLR Deficiencies (MyD88 and IRAK-4 deficiency)
- defective TLRs = innate immune cell cannot kill microbe
- signaling defects = failure to produce cytokines
MyD88/IRAK-4 def: susceptibility to infection either by bacteria or viruses
Inflammasomes and NOD-like Receptors
NLR - scaffolding for signaling platform that activates NF-kB and MAPK pathway
Inflammasome - activates protease caspase 1
- process inactive cytokine precursors into active form (IL-1B and IL-18)
What two cytokines drive inflammation?
IL-1B and IL-18
NLRP3 Inflammasome and Gout
- IL-1B is key cytokine in gout; promotes neutrophil influx into synovium and joint fluid
- pathological hallmark of acute inflammatory attack
- Anti-IL-1 therapy used to treat gout patients
Necrosis and DAMPs
Necrosis: dirty cell death; swelling and rupture of cell membrane, causing inflammation
- strong DAMP release (endogenous danger molecules released from damaged/dying cells during NON-INFECTIOUS INFLAMMATION
- DAMPs recognized by PPRs (pattern recognition receptors)
Major DAMPs that activate NF-kB (3)
- HMGB1 (high mobility group box 1)
- receptor: TLR2/3
- Uric Acid
- receptor: NLRP3
- Heat Shock Proteins
- receptor: TLR2/4
ALL DAMPs stimulate TNF-alpha and IL-1 release
What signals allow do phagocytes recognize that allow them to begin phagocytosis?
- fMet via Formyl Peptide Receptor (PPR)
- receptor involved in chemotaxis
- phagocytes bind fMet bacterial proteins and use them to initiate phagocytosis
IL-10 and TGF-beta
Anti-Inflammatory cytokines
Sickness Behavior Syndrome
- systemic release of TNF-alpha, IL-1. IL-6
- lethargy, depression, fever, cognitive impairment, decreased social interaction
C3 convertase and roles of C3a/C3b
- convertase: C4bC2a; cleaves C3 into C3a and C3b
- C3a: inflammation, chemotaxis
- C3b: phagocytosis, C5 convertase formation
CLASSICAL PATHWAY
C5 convertase roles of C5a/C5b
- convertase: C4bC2aC3b
- C5a: inflammation
- C5b: MAC formation
What are CRP and SAA, and what do they help do?
- both are acute phase proteins
- C-reactive Protein and Serum Amyloid A show up in 100x increase during inflammation
- measurement of their levels helps diagnosis inflammation
Steps for Neutrophil into tissues
- TNF-alpha, IL-1 activate endothelial cells, which increase P and E selectin adhesion molecules
- Tethering - slow down/roll on epithelium
- P/E selectin and PSGL-1/ESL-1 mediated
- Tight Binding - integrin interactions (LFA-1/VLA-4 on neutrophil, ICAM-1/VCAM-1 on endothelial cells)
- Diapedesis - endothelium transmigration
- Chemotaxis - IL-8 controls migration to inflammatory sites
What is the most important chemokine for monocyte migration/infiltration into tissues? What happens to monocytes once they get into tissue?
MCP-1 (monocyte chemoattractant protein-1)
- become tissue macrophages; maturation controlled by cytokine microenvironment in tissue
Classical vs Alternative Tissue Macrophage activation
Classical (M1): microbial TLR-ligands, IFN-y
- microbicidal and proinflammatory
Alternative (M2): IL-4 and IL-13
- tissue repair and fibrosis
- play critical role in IMMUNOMODULATION
Type I Interferons (a/B IFNs) (Anti-viral Innate Immune Response)
- express proteins that interfere w/viral replication
- PKR –> no GDP recycling; blocks viral RNA translation
- Ribonuclase L –> viral RNA degradation
- activate NK cells
Natural Killer Cells (Anti-viral Innate Immune Response)
- recognize ligands on infected/stressed cells and kills them (eliminates reservoir of infection)
- killing ability inversely related to expression of MHC 1 on target cells (MHC present = PTK dephosphorylation = inactivation)
- produce IFN-y, activate macrophages
- use perforins and granzymes
What stress-associated molecules do NK Cells recognize on the surface of abnormal host cells?
MICA and MICB
