Lecture 4 Flashcards
What do Pattern recognition receptors do
They recognise things common to microbes (MAMPs and DAMPs)
Features of microbe-associated molecular patterns
-They’re shared by many microbes
-They’re distinct from “self”
-They’re critical for survival/ function of pathogens
-Conserved
What are damaged-associated molecular patterns
They’re alarm signals from the body’s own cells.
Host components released during injury (cancer, heart attack and cell damage)
Examples of MAMPs in bacteria
Bacteria:
(-VE): Lipopolysaccharides
(+VE): Lipotechoic acid
Flagellins
Unmethylated CpG in DNA
N-formylated proteins
Examples of MAMPs in fungi
Chitin
Beta-glucans
Examples of MAMPs in viruses
dsRNA
Examples of MAMPs in protozoa
GPI-linked proteins
Mannose-rich glycans
Examples of DAMPs
-Fragments of extracellular matrix proteins (e.g. fibronectin)
-Exposed phosphatidylserine (component of lipid bilayer found inside)
-Mitochondrial components
-Uric acid (build up with excess purines caused by stress)
-DNA
What are the classes of Pattern recognition receptors
-Soluble receptors (found in the tissue, e.g. Mannose binding lectin)
-Cytoplasmic receptors (found in the cytosol e.g. NOD-like receptors)
-Membrane receptors (e.g. lectin receptors, chemotactic receptors and Toll-like receptors)
What does MAMP binding lead to in membrane receptors
It may initiate phagocytosis, chemotaxis or signalling.
For example, macrophage mannose receptor, CD14.
What do chemotactic receptors recognise
Chemoattractants. For example, F-met-leu-phe receptor recognise N-formylated polypeptides produced by bacteria
What do Toll-like receptors do
They’re sensors that signal the presence of microbial components.
The stages of toll-like receptor binding
- The macrophage expressed receptors for many bacterial constituents
- Bacteria binding to macrophage receptors initiates the release of cytokines and small lipid mediators of inflammation
- Macrophages engulf and digest bacteria to which they bind
Features of Toll like receptors
- Ancient pathogen recognition systems
-10 in humans, each recognising distinct MAMPs
-They can be found on the cell surface or endosome
PAMP for TL1
Lipopeptides
PAMP for TLR2
Glycolipids
PAMP for TLR3
dsRNA
PAMP for TLR4
LPS
PAMP for TLR5
Flagellin
PAMP for TLR9
unmethylated CpG
What’s the structure for TLR3
-Horseshoe shape formed by leucine-rich repeats. The inner surface has a Beta-sheet structure and forms the ligand binding domain.
The horseshoe bit recognises MAMP
What are NOD-like receptors
They’re a large group of cytoplasmic receptors that recognise bacterial components (e.g. peptidoglycan flagellin)
What do NOD-like receptors do
They signal expression of pro-inflammatory cytokines
They trigger the assembly of inflammasomes (cytokines that induce inflammation)
Whats the structure of NOD-like receptors
They’re structurally similar to proteins found in plants (nucleotide-binding oligomerization domains)
What are RIG-I-like receptors
They’re viral sensors that detect viral RNA produced within host cells. They signal expression of interferons
What do macrophages/mast cells release
-Inflammatory mediators that increase blood flow and vascular permeability
-Chemoattractants that attract phagocytes into tissues
-Cytokines which are Small proteins that induce other cells to help deal with the infection
What are the four classic signs of inflammation and what are they caused by
Redness, swelling, heat and pain
-Release of inflammatory mediators
-Dilation of local blood vessels
-Increased permeability and blood flow
-Immune cell migration into inflammatory site
Examples of inflammatory mediators
-Lipid mediators e.g. prostaglandins (stimulate dilation of blood vessels)
-Vasoactive amines e.g. histamine (chemicals that cause dilation of blood vessels)
-Chemoattractants e.g. Fmet-leu-phe (help phagocytes move into tissues)
-complement proteins e.g. C5A
-Cytokines e.g. TNF
What is acute inflammation
Beneficial in dealing with infection/ injury (comes on rapidly but goes down rapidly)
What is chronic inflammation
It’s caused by chronic infection e.g. TB or other conditions e.g. autoimmune disease. It can be damaging
What are cytokines crucial for
They control the immune responses in innate and adaptive immunity.
They regulate immune responses by changing cell behaviour or gene expression
Features of cytokines
They’re small proteins
They’re known as the hormones of the immune response (trigger changes in the body)
Most act locally
They can be produced by many cell types in response to immune activation
They act on cells bearing specific cytokine receptors
The expression of cytokines and their receptors is tightly regulated to prevent damage to own body’s tissues
IL-1 family
Most produced as inactive precursors that must be cleaved by inflammasomes. They’re important in inflammation
Haematopoietin (cytokine)
Includes factors involved in leukocyte differentiation e.g. gm-csf but also IL-2, IL-4, IL-6
Interferons (cytokines)
They’re involved in responses to viruses
TNF family (cytokines)
TNF alpha (many are transmembrane proteins that are shed and important in inflammation. These are very toxic
Chemokines (cytokines)
Involved in cell movement (e.g. IL-8)
Type 1 interferons
-Many cell types make type 1 interferons after viral infection and induce expression of interferon stimulated genes
Type 2 interferons
Including IFN-gamma
modulates immune responses.
They’re made by neutrophils, NK cell and T cells
They play a primary role in adaptive immunity
Increases expression of MHC1 and MHC2
IFN-gamma made by T helper cells activated macrophages in response to intracellular pathogens
