Lecture 29; Trained Immunity Flashcards
Whats this emerging area of immunology?
The idea that the adaptive immune system can be trained.
Largely monocytes and macrophages, although some evidence for DCs
Specifically the evidence that a monocyte can have a heightened response to a pathogen following a previous exposure (broad memory)
Named as;
- Trained immunity or innate memory
Where does a lot of evidence come from for trained immunity?
vaccination studies
Whats driving the trained immunity?
Epigenetic changes
What two species are looked at today for main experimental evidence?
Droosphilia (no adaptive response)
Flat worms (no adaptive)
What does the use of S. pneumoniae in drosophilia demonstrate?
A sub-lethal infection with S. pneumoniae protects against reinfection with a lethal dose
How long after giving the sub lethal S. pneumoniae dose did the protection last?
i.e how long can they wait till they give the next dose and get the same protection?
They found the increased protection is long lived (14 days in this experiment)
(long term for the drosophila)
What two pathways did they test for being responsible for this heightened response?
Two pathways;
PGRP (like TNF)
and
TLR (peptidoglycan acts on this IMP.)
Antimicrobial pathways in Drosophila
Both act on NFkB
Which pathway was responsible for the heightened protection?
In Drosophila protection is specific for S. pneumoniae and dependent on the Toll pathway
What other invertebrate had elevated resistance to reinfection?
Planarians infected with Staphylococcus have elevated resistance to re-infection
Termed; Instructed Immunity
In the planarians, what did they find trained immunity was dependant on?
Trained immunity dependent on a specific peptidoglycan recognition protein
What early evidence for trained immunity in humans?
The BCG vaccine for TB
For BCG what reduces the odds of getting TB?
A specific immune response is not the protective mechanism
What was shown in mice regarding C. albicans?
If a mouse was injected with an A viralent strain then two weeks later with the viralent strain it was protected.
Not T cell dependant. (knockout)
If they knockout Monocytes, macros then they dont get this response
Whats required for trained immunity?
Macrophages
What happens with the C albicans when they knocked out T cells?
They had the same protective response therefore this process is independent of T cells. (shown in mice)
What is epigenetics?
- Now defined as the study of heritable changes in genome function without alteration to DNA sequence
- DNA modifications-methylation of cytosine residues
- Histone modifications- methylation, acetylation, phosphorylation
Can also modify Histone moelcules (the things that wrap up DNA)
What did they show when they gave LPS to the mouse primed from C. albicans?
That IL6 and TNFa were still heightened indicating that this trained immunity is broad recognition
What did invitro training of innate immunity show?
Trained monocytes have elevated production of pro-inflammatory cytokines (protection is broad)
Used range of PAMPS
What happened when they gave dead C. albicans and what did they find when they further isolated it?
Found that its the component of the cell wall that triggers this immunity training.
specifically; b-glucan alone can induce the trained phenotype
NOT MANNAN
What causes the range of macrophage phenotypes?
Epigenetic changes known to underpin macrophage functional heterogeneity
Changes in promoters (some act. some deact.)
What did they bind B glucan did to the epigenetics?
b-glucan alters epigenetic landscape in trained monocytes
specifically changes in H3K4me3 (methylation)
What epigenetics / genes were altered?
H3K4me3 marks elevated at promoter regions of important pro-inflammatory cytokines and PRRs
What did the epigenetic changes do?
Initial activation associated with specific marks
• Some marks remain after elimination of pathogen (latent enhancers)
• A stronger response upon re- challenge
Are all epigenetic changes to monocytes good?
No, some PAMPS can cause;
- unresponsiveness, immunotolerance
I.e low dose LPS
“endotoxin tolerance’
While others;
- heighten the inflam response
What was found to be essential for trained immunity?
Aerobic glycolysis necessary for functional reprogramming during trained immunity
What can changes in metabolic mode do in training stimuli?
Training stimuli induce changes in cellular metabolism that can influence epigenetic enzymes
What are the possible therapeutic uses?
Activation:
• e.g. new more effective vaccines
• Treatment of infections in infants (within 1st 3 months)
• Treatment of immune paralysis
Suppression:
• e.g. acute or chronic inflammatory diseases
