Pattern Recognition Receptors Flashcards
PAMPs
Pattern Associated Molecular Patterns
How innate immune cells detect pathogens
Molecules/structures specific for pathogenic bacteria, viruses, fungi, and not visible on host cells
What can act as a PAMP?
Lipids, polysaccharides, nucleic acids, proteins
Bacterial/fungal cell wall components, viral RNA, viral/bacterial DNA, bacterial flagella
One PAMP can be found in multiple pathogen species
DAMPs
Damage Associated Molecular Patterns
Host cell molecules or structures that are not normally visible to the immune system but which can be released from damaged or dying cells
MAMPs
Micro-organism Associated Molecular Patterns
Molecules or structures that are specific for microbes and not normally visible on host cells . Overlaps with PAMPs but includes structures found on commensal bacteria (bacteria in gut and lungs that are tolerated by the immune system)
Classes of PRR
Pattern Recognition Receptors (expressed on immune cells and sometimes T cells, B cells, and endothelial cells)
Membrane Receptors:
- Toll-like receptors
- C-type lectin receptors
Cytoplasmic receptors:
- Nod like receptors
- RNA receptors (RIG-I, Mda5)
- DNA receptors
Qualities of PRRs
Invariant, germline encoded
Recognises a broad class of ligands (not selective for individual pathogen sepcies)
Cannot undergo learned immune response
Qualities of T/B Cell Receptors
Sequence diversity due to VDJ recombination during cell development
Highly selective - clonal B/T cells are specific for a very defined antigen and thus a specific pathogen
Memory cells allow for learned immune response (slow initially, fast on end infection)
Is only 1 PAMP activated at a time?
No. Most pathogens express multiple PAMPs, and upon encountering an immune cell, several PRRs are likely to be activated - tailors the immune response to the pathogen.
Correct response to PRR activation is determined by the stage of inflammatory reaction - the effect of stimulating a PRR can be modified by other signals that the cell receives
Initial discovery that led to the discovery of Toll-like Receptors?
1890s - Richard Pfeiffer & Robert Koch
Discovery that bacterial endotoxins cause inflammation and fever
How was the immune system thought to function before the discovery of TLR?
Innate immune cells were passive and not activated by pathogens
Pathogens activated T cells > T cell activated B cell > antibody production > antibodies + complement coated pathogens > pathogens killed by cells of innate immune system (neutrophils, macrophages, dedritic cells)
Of what receptor family is TLR a part?
IL-1
What do the following TLRs bind to, with which adaptors, and where?
- TLR5
- TLR1/TLR2
- TLR2/TLR6
- TLR4
- TLR3
- TLR7
- TLR8
- TLR9
Cell membrane:
- Flagellin, Myd88
- Triacylated Lipopeptides, Myd88 and Mal (2nd adaptor, promotes Myd88 binding)
- Diacylated Lipopeptides, Myd88 and Mal (2nd adaptor)
- LPS (lipopolysaccharide), Myd88 and Mal (2nd adaptor) OR Trif and Tram (recruitment of Trif mediated by Tram)
Endosome:
- dsRNA, Trif
- ssRNA, Myd88
- ssRNA, Myd88
- CpG DNA, Myd88
TLR Structure
Extracellular: leucine rich repeat domain (LRR) (for ligand binding)
Intracellular: TIR (Toll/interleukin-1 receptor homology) domain (mediates interaction between TLRs and adaptor proteins; critical for initiating downstream signalling)
TIR domain is also present in TLR and IL-1 receptors and adaptor proteins
How does Myd88 and Mal signalling work?
Myd88 has a death domain, Mal does not. Mal therefore doesn’t signal effectively in the absense of Myd88
Both have a TIR domain
1. Death domains of Myd88 and IRAK4 interact
2. IRAK4 recruits and physophorylates IRAK1 and 2
3. IRAK1/2 interact with Traf6
4. Lys63 polyubiquitin chains are added to Traf6 and IRAK1
5. Lubac complex adds linear polyubiquitin
6. Tab2 and 3 (part of the Tak 1 complex) have c-terminal NZF domains that bind to Lys63 polyubiquitin
7. Tak1 activates the MAPK pathways
8. Tak1 phosphorylates and inactivates the IKK complex, allows activation of NFkappaB transcription factor
What is the Tak1 complex?
Consists of: Tak1 kinase and accessory subunits Tab1, Tab2, and Tab3
Tab1 pseudophosphatase is involved in regulating Tak1 activity in the cell
How does Trif dependent signalling work?
Trif activates Traf3 > activates Tbk1 > activates IRF3 (transcription factor) > stimulates production of interferon beta (IFN beta) > restimulates cells to induce transcription of type 1 IFN genes (induces anti-viral state in cells)
What can chronic inflammation lead to?
Autoimmune disorders
Autoinflammatory disorders
Diabetes
Neurodegeneration
Cardiovascular disease
COPD, asthma
