Innate machanisms Flashcards
Lectures: -Week 1, day 2, lecture 2: Innate immunity - Pattern recognition receptors -Week 1, day 2, lecture 3: Innate immunity - The complement system
What are pattern recognition receptors?
Receptors that recognize patterns that are often found on pathogens
What is a PAMP?
Pathogen-associated molecular pattern, can be recognized by PRR’s
What is a DAMP?
Danger-associated molecular pattern; endogenous molecules that signal danger
What are the three main groups of PRR’s?
- Free receptors in the serum
- Membrane-bound signaling receptors
- Cytoplasmic signaling receptors
Which are the subgroups of the group of free PRR’s in the serum? (4)
- Complement proteins
- Pentraxins
- Collectins
- Ficolins
What are the subgroups of the membrane-bound PRR’s? (3)
- Toll-like receptors (TLR)
- C-lectin receptors (CLR)
- Scavenger receptors
What are the subgroups of the cytoplasmic PRR’s? (3)
- NOD-like receptors (NLR)
- RIG-I-like receptors (RLR)
- Cytosolic DNA sensors
What is the main structural difference between plasma membrane-bound TLR’s and endosomal membrane-bound TLR’s?
Plasma membrane-bound TLR’s are usually dimers, whereas endosomal TLR’s are usually monomers
What do plasma membrane-bound TLR’s recognize?
Patterns on the outside of pathogens
What do endosomal membrane-bound TLR’s recognize?
RNA/DNA in the cytosol
Why is TLR4 an important TLR?
Recognizes LPS -> major component of bacteria
In what way can TLR4 on multiple cells be activated by LPS from a single bacterium?
LPS-binding protein extracts LPS from the bacterium -> bacterium is not bound to one cell
What is an important adaptor molecule for intracellular TLR’s?
TRIF -> leads to the production of type I interferon via IRF3 activation
In what way does the system of TLR’s provide redundancy?
Many TLR’s use the same pathway -> a defect in one of the TLR’s does not prohibit the activation of the immune pathway
What do C- type lectin receptors (CLR’s) recognize? Against which class of pathogens are they especially effective?
Carbohydrate structures; often found on fungi -> important for defence against fungal infections
Where are CLR’s located?
CLR’s are always bound to the plasma membrane
What does the ‘C’ in C-type lectin receptors refer to?
Calcium-dependent
What is the main adaptor molecule for CLR signaling? What kind of response does it induce?
Syk; induces release of IL-23, resulting in a Th17 antimicrobial response that defends epithelial surfaces
What is a symptom of a CLR-mutation?
Frequent candida infections
What are the NOD-like receptors?
A family of receptors with similar NOD-like domains
Where are NLR’s located?
In the cytoplasm
When are NLR’s activated? What does this result in?
NLR’s are activated upon dimerization, resulting in the activation of NF-κB
When are TLR’s activated?
TLR’s are often activated upon dimerization
What is an inflammasome?
The inflammasome is a complex of molecules in the cytoplasm of the cell, activated by NLR’s
The inflammasome cleaves pro-IL-1β into IL-1β through the caspase-pathway
How is dimerization of NLR’s prevented when there is no pathogen present? How is this mechanism reversed upon encounter of pathogens?
NLR’s are chaperoned, these chaperons dissociate when the [K+] drops, which occurs upon infections
Which disease is (partly) the result of unwanted inflammasome activation?
Gout -> inflammasome activated by urate crystals
In what way can loss-of-function of NOD2 result in Crohn’s disease?
Loss-of-function of NOD2 results in abberant NF-κB activation in the gut
What are RLR’s?
RIG-I-like receptors
What do RLR’s recognize? How is this achieved?
Viral RNA, by recognizing triphosphate motifs on RNA that are protected by the cap on self-RNA
What happpens upon activation of RLR’s?
RLR’s bind to MAVS (mitochondrial antiviral signaling proteins), activating antiviral transcription factors
What do cytosolic DNA-sensors recognize? What does this result in?
Cytosolic DNA; activation results in release of IL-1 or IFN-I
What are they key effector functions of the complement system? (4)
- Elimination of immune complexes
- Opsonization
- Lytic destruction of micro-organisms
- Recruitment of inflammatory cells
Which tree complement pathways are there?
- Lectin pathway
- Classical pathway
- Alternative pathway
What is the common protein for all complement pathways (and ultimately leads to formation of the membrane-attack complex)?
C3
What is the classical complement pathway activated by?
Antigen-antibody complexes
What is the lectin complement pathway activated by?
Mannose binding lectin binding to pathogen surfaces
What is the alternative complement pathway activated by?
Pathogen surfaces
Which C3-convertase is used by the lectin pathway?
C4bC2a
Which C3-convertase is used by the classical pathway?
C4bC2a
In which way is the alternative complement pathway activated?
A tick-over mechanism constantly generates alternative C3-convertase C3BbBb
C3BbBb gets inactivated by host cell surfaces, but gets stabilized by pathogen surfaces by factor-P
What is the major amplification step of the complement sytem?
C3 amplification -> leads to cleavage of C5, leading to the formation of the membrane attack complex
What are the effects of the small cleavage products of the complement system? (3) What are these proteins called?
C3a, C4a & C5a are anaphylatoxins and result in
1. Initiation of inflammation by recruiting phagocytic cells to the site of infection
2. Increased vascular permeability -> extravasation of complement proteins, antibodies and immune cells
3. Stimulate phagocytosis (C5a)
Which complement protein is the main opsonin? Which cofactor is required for effective phagocytosis of pathogens marked by this protein?
C3b, requires the presence of C5a (soluble) in the area
Which complement proteins form the membrane attack complex?
C5-C9
Which mechanisms can cause excessive complement activation? (4)
- Uncontrolled/systemic infection
- Tissue damage
- Gain of function mutation
- Activating auto-antibodies
Which mechanisms can cause deficiency of the complement sytem? (3)
- Consumption (due to auto-immune disease)
- Loss of function mutation
- Neutralizing auto-antibodies
What can complement deficiencies lead to? (2)
- Higher susceptibility to infectious disease (mainly bacterial infections)
- Auto-immune diseases (SLE, hemolytic uremic syndrome, paroxysmal noctural haemoglobulinuremia)
How can a C1q deficiency lead to SLE?
Impaired clearance of immune complexes and apoptotic cells results in deposition, causing inflammation
What is the old way of complement testing? How does this work?
Hemolytic essays; addition of patient serum to sheep (classical pathway) or rabbit (alternative pathway) RBC’s and measuring the lysis through the amount of Hb released
What are the disadvantages of hemolytic complement testing? (3)
- Semi-quantitive
- Dependent on stable RBC
- Laborious
What is the current technique that is employed for complement testing? How does this work?
Immunoassay = ELISA; addition of patient serum to wells that contain the factors required for activation of the different pathways; this will lead to MAC formation, after wich the presence of this MAC-complex can be shown through secondary antibodies directed against the MAC
What can factor-specific immuno-assays of complement proteins be used for?
Analysis of individual complement factors to determine which factor might be disfunctional/disrupted
