L2- Flashcards
What can we see about inflammation in evolution?
It is very well conserved. It is an ancient branch of immunology existing to at least some extent in all metazoan organisms.
What are the characteristics of inflammation?
Swelling, redness, recruitment of leukocytes
How is inflammation classified?
Acute or Chronic depending upon duration and cellular responses (chronic doesn’t get down to resolving part)
Summarise the first, second and third lines of defense?
1st: skin, mucous membranes, normal microbiota
2nd: phagocytes, inflammation, fever, antimicrobial peptides
3rd: specialized lymphocytes, antibodies
What are the two groups of danger signals?
Pathogenic: PAMPs
Non-pathogenic: DAMPs
Examples of Pathogen Associated Molecular Patterns? (PAMPs)
Bacterial endotoxin (TLR4) Peptidoglycan (TLR2) Flagellin (TLR5) Single stranded viral RNA (TLR7/8) Double stranded viral DNA (TLR9)
Examples of Damage Associated Molecular Patterns? (DAMPs)
Heat shock proteins (HSPs) Uric acid crystals (gout) ATP (shouldn't be extracellular) DNA Beta-amyloid (alzheimer) Some cytokines (IL1, HMGB1)
How do innate cells recognize threats?
Pattern Recognition Receptors (PRRs)
What are the main 4 groups of innate immune cells?
- Macrophages and monocytes (includes tissue-specific macrophages i.e. microglia)
- Granulocytes: Eosinophil, Neutrophil, Basophil
- Dendritic cells (DCs)
- Innate Lymphoid cells
How does phagocytosis happen?
Bound material is internalized in phagosomes fuses with lysosome and broken down in this phagolysosomes
What are some examples of cytokines?
Lymphokines- produced by lymphocytes, coordinate T cell responses
Interleukins- produced by mainly leukocytes.
Chemokines- induce chemotaxis. Required for recruitment of immune cells to infected/injured tissue
What are the two main groups of phagocytic receptors?
- C-type lectins:
- dectin-1:bind to beta-1,3-linked glucans (fungi?)
- mannose receptor:bind to mannosylated ligands - Scavenger receptors:
recognise anionic polymers and acetylated low density lipoproteins.
Class A: SR-A I, SR-A II. MARCO
Class B: CD36
What are the three main structural parts of Membrane bound receptors: (TLRs)Toll-like receptor?
Leucine-Reach Repeats LRRs)
Transmembrane domains
Toll-IL-1 receptor (TIR) domain
(it’s a dimer)
As a general rule what do TLRs recognise at the plasma membrane, or the endosome membrane?
Plasma membrane- recognise Bacterial and Fungal PAMPs
Endosomal membrane- recognise viral PAMPs
What do TLRs activate?
transcription factors: NF-kb, AP-1 and IRF to induce expression of cytokines and interferon.
They can stimulate anti-viral or anti-bacterial responses, depending which one they activate.
signalling tlrs IKK complex mechanism…
.
What are the main cytosolic receptors?
- RIG-like helicases (retinoic acid inducible gene 1): viral recognition.
- cGAS (cyclic-CMP-GMP synthase): viral recognition, self-recognition (self DNA).
- Nod-like receptors (NLRs): bacterial and endogenous DAMPs, NOD1/2s, inflammasome forming
What are the RIG-1 helicases?
Can find two of them:
- RIG-1: recognises mainly ssRNA
- MDA-5: recognises mainly dsRNA.
They both need an adaptive protein called MAVS. MAVS is in the mitochondria
What does cGAS do?
Contains a nucleotidyltransferase domain and two major DNA-binding domains.
Absence of DNA, cGAS exists in an autoinhibited state.
(protein called sting induces the inflammatory response in this process)
Nod-like receptors:
NOD1 and NOD2?
Cytosolic.
Have LRR, NOD and CARD domains. (nod2 has 2 card domains)
They recognise bacterial proteins.
nod1 recognises dipeptide in peptidoglycan, nod2 recognises muramyl dipeptide which is in all bacteria.
NOD2 mechanism?
Needs to form complex in the cytosol,
… 36 minutes.
Nod2 mutations and disease?
Loss of function- If nod2 is mutated, you can’t recognise mdp anymore (muramyl dipeptide) in your gut so there’s no NF-kB signalling.
Causes Crohn’s Disease. (inflammatory bowel disease)
Can also have gain of function- sense mdp, excessice NF-kB signalling. Blau syndrome. Overinflammation, spontaneous inflammation of eyes, skin other places.
How does IL1B get secreted?
Doesnt have secretory signal. Pro-IL-1B needs processing and release to perform biological actions.
This is done by Caspase1.
Caspase1 is activated with the inflammasome.
Needs a second signal to be activated. big difference.
What’s different about Inflammasome forming NLRs (cytosolic receptors)?
Most cytokines present signals to be secreted by the classical secretory pathway (er, golgi, secretary vesicle)
But IL-1B and IL-18 (pro-inflammatory) do not have secretory signals.
Need second signal for inflammasome to be activated.
What is the inflammasome?
Molecular complex formed by:
NLR + Adaptor molecule + Effector molecule
NLRP3 + ASC + Caspase-1
CAPS: Cryopyrin Associated Periodic Syndromes?
Autosomal dominant.
Presence of just one copy of a mutated gene can cause the disease.
Leads to high levels of IL-1B secretion.
What is the treatment for CAPS?
Canakinumab- a monoclonal antibody.
Injected every 8 weeks.
Binds IL-1B so it can;t bind to the receptor.
