Lecture 10: The humoral arm of the innate immune system Flashcards
Thursday 31st October 2024
What is the problem with the adaptive immune response?
- It takes about 7 to 10 days, which is too slow
- This is why we only rely on our INNATE immune system for protection in the first few critical hours or days after pathogen challenge
What are the 3 lines of the innate immune system?
- Physical and chemical barriers
- Cell-intrinsic responses
- Specialised proteins and specialised cells, which aren’t specific to any pathogen
What do the chemical and physical barriers include?
- Thick layer of keratinised dead cells – skin
- Tight junctions between epithelial cells
- Acidic stomach pH
- Mucus layers
What do the cell-intrinsic responses include?
- Pathogen-induced phagocytosis
- Degradation of dsRNA
What do the specialised proteins and specialised cells include?
Professional phagocytes – neutrophils, macrophages
NK (natural killer) cells
The complement system
Are the innate immune responses specific to particular pathogens?
No, they are not particular to specific pathogens
What types of surfaces are mucus layers found on?
- Moist environments, such as…
- Skin
- ## Epithelial surfaces lining respiratory, intestinal, and urinary tracts
What does a mucus layer on moist epithelial surfaces protect against?
microbial, mechanical, and chemical insults
Give an example of a fish that also produces a mucus layer on the skin
Hagfish (slime eel)
What is the mucus layer made from?
The mucus layer is made from secreted mucins and other glycoproteins
What makes mucus layers slippery?
The fact that they’re water soluble
What is the benefit of mucous layers being slippery?
This makes it harder for pathogens to attach to mucous-coated epithelia
What are defensins?
Small (12-50 amino acids in length) positively-charged antimicrobial peptides, which have hydrophobic or amphipathic helical domains (where the positive charges lie on one face of a coil, and hydrophobic residues lie along another).
Do the defensins in the mucus layer have antimicrobial activity?
Yes. They have wide antimicrobial activity and can kill or inactivate many antimicrobials.
‘There are multiple defensins, grouped into multiple classes, so there is a wide repertoire of targets’. Is this true?
Yes
Is it true that β-defensins are less efficient than α-defensins ?
Yes
What is the general mechanism of defensins?
- Their hydrophobic domains or amphipathic helices may enter into the core of the lipid membrane of the pathogen and destabilise it, leading to cell lysis
- Following membrane disruption, the positive charges may interact with (negatively-charged) nucleic acids in the pathogen
(mechanism is still somewhat uncertain)
How do defensins lyse pathogens, but not our own epithelial surfaces?
They are much more active on membranes that do not contain cholesterol (our membranes contain cholesterol)
Why is it difficult for pathogens to acquire resistance to defensins?
Because they work relatively non-specifically
what deos PAMPs stand for?
Pathogen-Associate Molecular Patterns
What happens when pathogens breach the epithelial barrier?
The innate immune system recognises molecules (pathogen-associated or microbe-associated immunostimulants) that are common to many pathogens, but essentially absent in the host.
What are the various classes of PAMPs that are recognised by human cells?
N-formylmethionine (fMet) is used for bacterial translation initiation. Proteins containing fMet also attract neutrophils
Peptidoglycans from bacterial cell walls
Bacterial flagellae
Lipopolysaccharide (LPS) from Gram-negative bacteria
Mannans, glucans and chitin from fungi
‘CpG’ (5’-A/G p A/G p C p G p C/T p C/T-3’) motifs in bacterial or viral DNA
What are PAMPs recognised by?
PAMPs are recognised by soluble receptors in the blood called and by cellular receptors/toll like receptors
What do blood recpetors/PRRs do when they detect PAMPs in the blood?
Perform direct killing and aid in phagocytosis
Which PAMPs are recognised by blood recptors?
peptidoglycans
mannans, glucans and chitin
Which PAMPs are recognised by Toll-like receptors (membrane-bound)?
lipopolysaccharide (LPS)
‘CpG’ motifs
flagellae
An ‘alarm’ system will then be activated
What do blood recptors and toll-like recptors fall under the category of?
Pattern Recognition Receptors (PRRs)
What happens when toll-like recptors on the cell membrane recognise PAMPs?
An alarm system is activated inside the cell
Is it true that complement activation targets pathogens for lysis?
Yes
What is complement ?
about 20 soluble proteins that are activated sequentially upon infection
lectin pathway (complent pathway)
- Complerments of units C2(proenzyme) and C4
- mannose and fucose binding
proteins - Amplification
Alternative pathway (complement)
- Components B and D
- AMplification
What is C3 activated by?
amplified by the enzymatic cleavage reaction. could be by the lectin pathway or by the alternative pathway
C3 is important. what happens if you have deficiencies in C3?
repeated bacterial disease
Wh yis C3 a pivotal proteolysis?
Because it produces 2 fragments . C3a and C3b
What does the smaller C3a do?
- Calls for help.
- Attracts phagocytes and lymphocytes, stimulating inflammation
What does C3b do?
It binds covalently to the pathogen’s plasma membrane
What does pathogen-bound C3b do?
- It activates C5, C6, C7, and C8 in a local cascade of reactions at the marked membrane.
-
What happens once complement C9 is activated?
It starts inserting into the membrane
C9 pore breaches the membrane and C9 multimers form a membrane-attack complex
The pores allow fluid to pass through, causing the membrane to swell and lyse
Toll like receptors…
An ancinet alarm system
Where are most TLRs found?
Most TLRs are on the cell membrane of EPITHELIAL CELLS AND MACROPHAGES, DENDRITIC CELLS AND NEUTROPHILS.
what is toll?
Toll is a Drosophila trans-membrane protein with a large extracellular domain with repeating motifs (leucine-rich repeats) that are versatile binding motifs for a variety of proteins.
What happens when toll receptors bind to pathogenic fungi ?
Binding to pathogenic fungi sends a signal to the nucleus that results in expression of antifungal defensins.
What does TLR4 bind to?
LPS
What does TLR5 bind to?
FLAGELLUM
What does TLR9 bind to?
CpG motifs in DNA
What happens after toll like receptors bind to their targets?
Signals to the nucleus follow this binding, resulting in transcription of hundreds of genes, especially those that promote inflammation.
Drosphila
extracelelluar domain - signalling pathways- tunr on genes i.e defensins genes
extracelelluar domain - signalling pathways- tunr on genes i.e defensins genes
Is it true that defensins and TLRs are ancient immune system components?
Yes
Defensins and TLRs are Ancient Immune System Components
- Proteins related to TLRs and defensins are apparently involved in innate immunity in all multicellular organisms.
- In plants, for example, membrane receptors with leucine rich repeats and domains homologous to the cytosolic domains of TLRs are required for resistance to fungal, viral and bacterial pathogens.
- This suggests that defensins and TLRs pre-date the ancestral split between animals, fungi and plants, estimated at 1576 +/- 88 Ma (million years ago).
Give an evasion of the innate immune system example
- Neisseria Gonorrhoeae, gram negative diplococcus
- Intracellular bacteria can cause problems in the brain
- Capsule lacks LPS and has lipooligosaccharide (LOS)
-N. gonorrhoeae can utilize host-derived sialic acid to sialylate its LOS
- N. gonorrhoeae with sialylated LOS are less invasive than those with nonsialylated LOS but are more resistant to the bactericidal effects of serum.
- Human cells also display sialylated glycoproteins, so in effect, N. gonorrhoeae can masquerade as us, evading the innate immune system
