T1 L3: Innate immune defences & inflammation 2 Flashcards
What are the functions of neutrophils?
- Phagocytosis
- Reactive oxygen species and nitrogen species
- Antimicrobial peptides
What are functions of macrophages?
- Phagocytosis
- Antigen presentation
- Reactive oxygen and nitrogen species
- Cytokines
- Complement proteins
What are the functions of dendritic cells?
- Antigen presentation
- Costimulatory signals
- Reactive oxygen species
- Interferons
- Cytokines
What are the functions of Natural killer cells?
- Lysis of viral-infected cells
- Interferons
- Macrophage activation
- Granzyme
- Perforin
What are the 4 stages of phagocytic recruitment?
- Rolling
- Activation
- Adhesion
- Transendothelial migration
What is the function of cytokines, chemokines and adhesion molecules in phagocytic recruitment?
- Cytokines dilate local blood vessels
- Chemokines attract monocytes and neutrophils to the infection
- Cell adhesion molecules (ICAM-1 and VCAM-1) are upregulated on the endothelium which bind to integrins on the leukocytes
What are the 3 phagocytic cells in the blood?
Neutrophils
Dendritic cells
Macrophages
Name some opsonins
- Complement components like C3b
- Collectins like mannose-binding lectin
- Antibodies
Name some phagocytic receptors
- Complement receptors
- Fc receptors
- Mannose receptor
- Scavenger receptors
What are some antimicrobial mechanisms of phagocytes?
- pH 3.5-4
- Toxic oxygen derived products like O2-, H2O2, 1O2, -OH, OCl-
- Toxic oxygen derived products like NO
- Antimicrobial peptides
- Enzymes: lysozymes that digest cell walls, acid hydrolases that break down ingested microbes
- Competitors in neutrophils like lactoferrin which sequesters iron needed for bacteria to grow
What are neutrophil extracellular traps (NET’s)?
When some activated neutrophils undergo a cell death called NETosis. During this, nuclear chromatin is released from cells which traps microorganisms and aids phagocytosis
Name some Pattern recognition receptors (PRR’s)
- C type receptors (CLR’s)
- Toll-like receptors (TRL’s)
- NOD-like receptors (NLR’s)
- Rig-I like receptors (RLR’s)
- Cytosolic DNA sensors (CDS)
What are pattern recognition receptors (PRR’s)?
They are receptors able to recognise conserved structures called pathogen-associated molecular patterns (PAMP’s)
What are DAMP’s?
Damage associated molecular patterns
They’re molecules released from necrotic cells
What are C type lectin receptors (CLR’s)?
They bind to glycan structures present on pathogens such as bacteria, fungi, viruses, and parasites
They’re expressed by most cells that phagocytose microbes. They assist in phagocytosis and induce inflammatory cytokine production
Eg. Mannose-binding lectin (MBL)
What are Toll-like rectors (TLR’s)?
A type of pattern recognition receptors important against fungal and bacterial infections
They have an extracellular LRR domain to which the pathogen binds and then a cytosolic side with a TIR-domain which forms hetro/homodimers when activated
What are the 2 main categories of Toll-like receptors?
Cell surface: respond to exogenous bacterial products like lipopolysaccharide (LPS), Flagellin, and Lipoteichoic acid
Endosomal: respond to endogenous viral products like dsRNA, ssRNA, and DNA
They will also react to host ligands and cause autoimmune conditions
What is Waldenstrom macroglobulinemia?
A rare non-Hodgkin lymphoma caused by a MyD88 mutations causing cells growth and survival
Mutation causes B-cells to make large amounts of IgM that causes excess bleeding, vision problems and headaches. The lymphoma cells proliferate in the bone marrow causing anaemia, neutropenia and thrombocytopenia
What is MyD88?
A molecule part of the TLR signalling cascade used by TLR adapter proteins
Not used by TLR3
What happens with a MyD88 deficiency?
A study found that patients suffered from recurrent life-threatening pyogenic bacterial infections but were otherwise healthy and had normal resistance to other microbes
The children developed immunity with age due to innate immunity
What happens if you’re deficient in TLR3?
Recurrent herpes simplex encephalitis (HSE)
This is the only TLR that cannot be compensated for
Name TLR’s involved in disease
HIV: TLR 8 Sepsis: TLR2 and 4 TB: TLR 2 and 4 Systemic lupus erythematosus: TLR7, 8, and 9 Alzheimer's: TLR 2 and 4 Atherosclerosis: TLR 2 and 4
How are TLR’s used to treat disease?
- Aldar is a TLR7 agonist used to treat genital warts and melanoma
- Ragweed pollen which is TLR9 is used to treat allergy
- Drugs are being studied to supress TLR4 in sepsis
What are Nod-like receptor’s (NLR’s)?
They are cytoplasmic pattern recognition molecules
They have a leucine rich domains which bind to peptidoglycan
What are the 2 major groups of NLR’s?
NLRC’s: caspase recruitment domain
Eg. NLRC1 (NOD1), and NLRC2 (NOD2)
NLRP’s: Pyrin domain
What do NOD 1 and NOD2 detect?
NOD1: detects ends parts of chain called iE-DAP found mainly on gram-negative bacteria
NOD2: detects core part of chain found on gram-positive and gram-negative bacteria
Name some mutations of NOD2
NOD 2 gain of function: early onset sarcoidosis where granulomas develop in the organs of the body
NOD2 loss of function: susceptibility of Crohn’s disease
How do NLRP’s work?
They sense danger
NLRP3 is activated by cellular stress like K+ efflux, reactive oxygen species, lysosomal damage. It forms an inflammasome essential for IL-1 and IL-18 secretion
What is frustrated phacocytosis?
When the phagocyte attempts to phagocytose something that it cant like metal and then ends up getting stuck and causing inflammation
What are cryopyrin-associated periodic syndromes (CAPS)?
Rare mutations on the NLRP3 gene causing over production of IL-1
What is Muckle wells syndrome?
They occur spontaneously or be triggers by cold, heat, fatigue, or other stresses. It causes too much IL-1 to be produced
Symptoms: fever, rash, arthralgia, conjunctivitis, uveitis, sensorineural deafness, potentially life-threatening amyloidosis
Can be treated with Anakinra (IL1 receptor agonist)
What is familial cold autoinflammatory syndrome
1 in a million
Triggered by exposure to cold. It causes too much IL-1 to be produced
Symptoms: fever, urticarial rash with headache, sometimes conjunctivitis
Can be treated with Anakinra (IL1 receptor agonist)
What are RIG-I-like receptors (RLR’s)?
They are sensors of RNA containing which is an intermediate for viruses
RIG-I: binds to single stranded RNA containing 5’ triphosphate. in our body, it’s capped so is left alone
MDA5: recognises long double stranded RNA. Important for Picornavirus detection. Mutations are rare but are associated with IFN related diseases like systemic lupus erythematosus and Aicardi-Goutières syndrome
What is Aicardi-Goutières syndrome ?
A condition affecting the white matter of the brain. It’s a type of encephalopathy.
Kills most of the males because it’s x-linked
What are cytosolic DNA sensors?
They’re part of the cGAS-STING pathway
It recognises double stranded DNA from viruses and triggers activation of interferon type 1
What is stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI)?
An autoinflammatory disease caused by a STING gain of function mutation causing increased amounts of Interferon 1.
It causes inflammation throughout the body especially in the skin, blood vessels, and lungs
What is an acute phase response?
It’s induced by cytokines such as TNF, IL-6 and 1 during infection and inflammation
These proteins are produced by the liver and they help activate complement and induce opsonisation/phagocytosis
Raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are characteristic of the acute phase response
