Immune sensing 1: Innate immunity Flashcards
What do the first and second danger signals recognised by innate immune cells tend to be?
quiz
The danger signals recognised by innate immune cells are (1) tissue damage and (2) microbial molecules.
(1) Pattern recognition receptors (PRRs) are able to recognise molecules released specifically from damaged or necrotic host cells. These molecules are referred to collectively as Damage associated molecular patterns (DAMPs). The presence of DAMPs indicates a wound which could provide an entry point for pathogens or that the host is already infected by a pathogen which is causing tissue damage.
(2) The presence of microbial products or molecules within the host is a clear sign of infection. PRRs are able to recognise essential core conserved molecules that are common to a range of different microbes. These molecules are called pathogen associated molecular patterns (PAMPs).
Which one of the four molecules described below make the best PAMP?
A scientist has just characterised a new bacteria infecting the intestine of humans. The new bacteria can be distinguished from all other bacterial species by its production of novel molecule A. Further characterisation led to the discovery of three more molecules (B, C, and D) that were conserved across various different bacterial groups. Of these, molecule B was an integral part of the cytoplasmic membrane and contained Lewis y and lewis x blood group structures similar to those found in human cells. To study the function of these molecules, recombinant bacteria were created in which the relevant gene was either deleted, or the sequence modified to change the molecules structure. Deleting or changing the structure of molecules A, B, and C resulted in non-infectious bacteria, whilst bacteria lacking molecule D were just as infectious as wild type
quiz
Molecule C
Although molecule B is conserved between different bacterial species, so could be used to recognise a range of different bacterial species, it has similarity to host molecules and thus could not be used to distinguish bacteria from host cells.
Which statements about PRR are correct?
-Only recognise microbial molecules
-Germline encoded, but can be adapted to recognise current infection
-A relatively small number of PRR are able to detect all microbes
-One PRR can recognise a range of different microbe
-Different innate immune cells express similar sets of PRRs
-Act as receptors and are only found on the cell surface
-Very broad recognition of invading microbes so can’t distinguish between viruses and bacteria
quiz
-False
-False
-True
-True
-True
-False
-False
PRRs can recognise both microbial molecules and host molecules released from damaged or necrotic cells. As PRRs recognise microbial molecules that are common to groups of microbes any one PRR can detect a range of different microbes. This means that you only need a small number of PRRs to detect a wide range of potential pathogens. Whilst some PAMPs are common to both viruses and bacteria (e.g. mannose), some PAMPs are specific to bacteria (e.g. LPS on gram- bacteria and lipoteichoic acid on gram+ bacteria) or viruses (e.g. double-stranded RNA). Thus whilst not able to identify exactly what pathogen the host is infected with, PRRs can identify the type of infecting pathogen. PRRs are encoded directly in the germline and because of this it is not possible to change the receptors you are born with, thus PRRs cannot adapt to the pathogens you are exposed to. Thus PRRs tend to recognise core evolutionarily conserved molecules as it is very difficult for the pathogen loose or change these molecules to evade recognition.
IFN-γ and TNF-α are two cytokines that promote inflammatory immune responses. Select which statements below refer to IFN-γ, TNF-α, or both
Activates macrophages
Secreted by macrophages
Recruits NK cells and neutrophils
Early warning role
Secreted by NK cells
Overproduction related to septic shock
Causes fever and cachexia
quiz
-Both
-TNF
-TNF
-TNF
-Both
-TNF
-TNF
TNF-α is secreted by macrophages and acts as an early warning cytokine and recruits NK cells and neutrophils to the infection site. NK cells produce IFN-γ and TNF-α and both of these cytokines are able to activate macrophages (although the lecture focussed on macrophage produced TNF-α). TNF-α has a range of systemic effects, particularly if infection becomes systemic, and can cause fever, cachexia, and sepsis leading to septic shock.
If you have a cut that then gets infected your innate immune cells will respond and initiate an immune response. Put the events below in the correct order.
- Macrophage increases phagocytic ability and sampling of environment
- NK cells produce IFN-g to further activate macrophages
- PRRs on Macrophage recognise PAMPs
- Bacteria enters wound
- Macrophages in resting state in skin
- Cut causes cell and tissue damage
- Neutrophils and NK cells are recruited to infection site to kill bacteria
- PRRs on Macrophage recognise DAMPs
- Macrophage increases its phagocytic ability and produces TNF-a
quiz
5
6
8
1
4
3
9
7
2
Macrophages are present in large numbers in the skin to act as sentinels scanning for infection via PRRs, and in the absence of infection they remain in a resting state. If you get cut then the damaged cells will release DAMPs that can be detected by PRRs on the macrophage resulting in macrophage activation (denoted by increased phagocytic activity and environmental sampling) as there is an increased potential for infection. If a bacteria or other pathogen enters the wound it will release PAMPs that the macrophage will again detect via PRRs. The macrophage will activate further, increasing its phagocytic activity again and releasing the warning cytokine TNF-α to recruit neutrophils and NK cells. The NK cells can then produce IFN-γ that further activates macrophages. As a note, macrophage activation is cumulative rather than an on/off process; the more activation signals a macrophage receives the more potent it will be become at killing and recruiting other immune cells.
What are DAMPs?
molecules produced by danger host cells
part of innate immunity
What are PAMPs?
common evolutionary conserved pathogen molecules
“Pathogen associated molecular pattern” (eg manose)
Part of innate immunity
How does the alternative pathway work?
C3b is spontaneously produced which binds to amino acids & hydroxyl groups on pathogen.
—> but C3b also can bind to normal cells so have to block C3b
How does the lectin pathway work?
manose binds lectin on pathogens but wont bind to healthy cells. This triggers C3b
What are the two main roles of phagocytosis?
- To sample environment
- To kill infected cells
How do macrophages and DCs differ?
DCs= migrate to interact with T cells in the lymph nodes
Macrophages= dont move from infection site and can kill, also talks to T cells but just at the infection site
What gets activated first DAMPs or PAMPs?
DAMPs. They are released from damaged cells and trigger innate response (macrophages) but not necessarily sign of infection. PAMPs are on pathogens and are a sign of infection and trigger stronger innate response.
Do PAMPs activate macrophages? And if so how?
Yes. PAMPs cause macrophages to be in an active state where they are larger, release cytokines, and kill instead of sample, and increase MHC expression
How do activated macrophages contribute to inflammation?
Release pro-inflammatory cytokines like TNF-a which recruit NK and neutrophils to the infection site
What does TNF-a do?
- recruits other innate cells
- causes fever
- tissue redness/ swelling
