Activation of Innate Immunity Flashcards
Neutrophils vs macrophages/dendritic cells
Neutrophils only kill microbes
Macrophages/dendritic cells kill microbes and present the antigen to T-helper cells
PRR’s of innate immune system
Pattern-recognition receptors
Recognize a PAMP (pathogen-associated molecular pattern) that is on pathogens but not human cells
Bridge between innate and adaptive
PRR’s cause activation and maturation of APC → antigen is presented to naive T cell →secreted cytokines assist development and maturation of T-cell
Where are Toll-like receptors (TLRs) found?
On surface of macrophages, dendritic cells, mast cells
They recognize pathogens, activate TF’s that enhance pro-inflammatory cytokines
What determines the type of immune response?
The cytokines made by macrophages determine the PRR (pattern recognition receptor) that is used
Which cells are considered to be the sentinel (resident) cell of innate immunity?
Tissue macrophages
What happens when bacteria enters and encounters effector cell?
Bacteria enters, activate EFFECTOR CELLS which secrete CYTOKINES→ ↑ vasodilation and permeability → helps inflammatory cells to enter tissue from blood → infected tissue becomes inflamed, causing redness, heat, swelling, pain
Which mediator causes vasodilation and increased vascular permeability?
Histamine
Complement
Lysis of pathogen (make holes in cell)
Cytokines
Activation of immune cells
Lysozyme
Bacterial wall destruction
Leukotrienes and prostaglandins
Vasodilation and vascular permeability
What is in respiratory tract and eyes that prevents infection?
Lysozyme (nasal secretions) and in tears
What are some leukocytes?
Neutrophils, monocytes, tissue macrophages, eosinophils
Innate immune system
NK cells are lymphocytes
True
Innate immune system
Kill via PERFORIN
Neutrophils
First to arrive at tissue damage → release granules to control bacterial growth
Macrophages
Release inflammatory mediators
Eosinophils
Contain cationic granule proteins, fight parasites
Neutrophils and monocytes enter tissue through what?
Through post-capillary venules except parenchymal tissues (liver, lungs, kidney) where all blood cells enter through capillaries
How Neutrophils Come to Tissue
Inflammation-activated ENDOTHELIAL CELLS cause → ↑ E-selectin (ES) and P selectin (PS) adhesion molecules
- Neutrophils have receptors for these two (ES and PS)
1. Neutrophils slow down and roll along endothelium (the ligand of neutrophil and selectin of endothelial cells interact)
2. Tight binding-integrins (leukocyte) and Integrin ligands (endothelial cells)
3. Diapedesis- transmigration through endothelium
4. Chemoattractant (IL-8) controls migration of neutrophils to inflammatory site
Integrin Activation (like riding bike through fresh cement which slows you down)
- Integrins on blood leukocytes are normally in a low-affinity state (bent)
- When leukocytes are rolling, chemokines on endothelial surface bind to the chemokine receptors on the leukocyte and they signal, which activates the leukocyte integrins
- This ↑ affinity of integrins (extended conformation) and their ligands on endothelial cells
Steps in getting Leukocytes through endothelial cell wall
- Capture (Selectins e.g. E-selectin)
- Rolling ( “ “ )
- Activation (Chemokines e.g. IL-8, MCP-1)
- Arrest (Adhesion molecules e.g. VCAM-1, ICAM-1)
- Firm adhesion ( “ “ )
- Transmigration
What is involved in the activation of integrins on monocytes?
IL-8
What does the following neutrophil granule (there are several) do?
Cathepsin G
Cathepsin G
-Ser protease that digests collagen and proteoglycans
What does the following neutrophil granule (there are several) do?
Defensins
Defensins: highly positively charged (i.e. cationic). Create pore in bacteria membrane (effective against all gram +/- bacteria, fungi, enveloped viruses)
Located primarily in GI and lower respiratory tracts (neutrophils contain defensin)
What does the following neutrophil granule (there are several) do?
BPI
BPI (bactericidal permeability increasing protein)
↑ permeability of bacterial membrane
What does the following neutrophil granule (there are several) do?
Lysozyme and lactoferrin
Lysozyme and lactoferrin
Bactericidal or bacteriostatic proteins
Transmigration of Monocytes
Steps 1-3 (rolling, firm adhesion, diapedesis) are same as neutrophils
Chemoattractants for monocytes are macrophage inflammatory protein-1α (MIP-1α) and MIP-1β
Monocytes mature into tissue macrophages
Macrophages and neutrophils are phagocytic cells
Classically Activated Macrophages (MΦ) are induced by what? (2)
Induced by TLRs and by cytokine IFN-γ
What do classically activated MΦ do?
Called M1
Inflammation and destroy microbes
Alternatively Activated Macrophages (MΦ) are induced by what? (2)
Induced by IL-4 and IL-13
What do alternatively activated MΦ do?
Called M2
Tissue repair and control inflammation
What do phagocytes use to help distinguish self from non-self?
PRR (pattern recognition receptor)
N-formylmethjionyl peptide (fMet) is in prokaryotes but NOT in eukaryotes
What happens when Toll-like receptors are triggered in phagocytes?
→ production of cytokines and ROS → kill microbes
What happens when Mannose receptors are triggered in phagocytes?
→ production of ROS and cytokines OR phagocytosis → killing
What activates NK cells?
IL-12 (made by macrophages)
What do NK cells secrete that activates phagocytosis and killing of pathogens by macrophages?
IFN-γ
NK cells use what kind of MHC?
MHC class 1
Inhibitory receptor is “ON” if cell is normal (no changes in class 1 MHC)
In virus-infected cell, the level of class 1 MCH is decreased b/c virus inhibits class 1 MCH expression
Complements
30 proteins (C1, C2, C3 etc)
3 distinct pathways. All pathways → C3b→ activates C5 → cascade → MAC (membrane attack complex) → kills pathogen by creating holes in membrane
C3 convertase formation
Classical formation initiated by binding of IgM or 2 IgG’s on microbial surface
- C1 binds to IgM or IgG on bacteria
- C1 cleaves C2 and C4
- C4b can covalently attach to microbial surfaces
- C2a binds to C4b and creates → C3 CONVERTASE
What is role of C3b?
Formation of C5 convertase
What is role of C3a?
Inflammation and chemotaxis
Formation of C5 convertase
- C3 convertase activates C3 → C3a and C3b
- C3b put onto bacteria surface (think star wars on crater)
- C3b serves as opsonin (“tag”) and ↑ phagocytosis
- C3b + C3 convertase → complex→C5 convertase (C4b, 2a, 3b)
- C5 convertase→C5→C5a (enhance inflammation) or C5b (MAC complex)
What does C5a do?
anaphylatoxin
Enhance inflammation
What does C5b do?
MAC complex
Formation of Membrane Attack Complex (MAC)
C5→C5a (enhance inflammation) or C5b (MAC complex)
MAC complex: C5b, C6, C7, C8, lots of C9
Purpose: makes transmembrane channels that lead to cell lysis
C5 convertase → C5b → +C6,C7,C8 → C5b678 + C9 (x10-16) → MAC
*How complements protect body from pathogens
Acute Phase Proteins (APP)
- Systemic acute-phase response
- Accompany inflammation
- Made by hepatocytes
- Production is regulated by cytokines (IL-6)
- Functions: highly variable and diverse
What regulates Acute Phase Proteins? (APP)
IL-6
