Innate immune system Flashcards
What are the two arms of immune system?
Adaptive and innate immune system. They recognise pathogens differently
indivual T/B cells express high selective receptors for pathogens whereas innate cells are less selective
Describe innate immune cell recognition
Recognise a broad class of molecules, ie. not selective.
There is not memory so less rapid response
Recognition by innate cells stimulates inflammation and the start of the immune response
What are PAMPS?
pathogen assiocated molecular patterns; molecules expressed on microbes unique to pathogen not expressed on host mammalian cells.
Eg LPS lipids, RNA, DNA of prokaryotic organisms
They are recognised by pattern recognition receptors on innate cells. These are not specific. They are invariant and don’t change to select specific PAMPs.
What is a patern recognition receptor on an innate cell?
Toll like receptor
What are some pattern recognition receptors on an innate cell?
Toll like receptor
C-type lectins
Describe innate immune cell recognition
Recognise a broad class of molecules, ie. not selective.
There is not memory so less rapid response
Recognition by innate cells stimulates inflammation and the start of the immune response; it is first line of defence.
What are PAMPS?
pathogen assiocated molecular patterns; molecules expressed on microbes unique to pathogen not expressed on host mammalian cells.
Eg LPS lipids, RNA, DNA of prokaryotic organisms
They are recognised by pattern recognition receptors (PRR) on innate cells. These are not specific. They are invariant and don’t change to select specific PAMPs.
What are some pattern recognition receptors (PRR) on an innate cell?
Toll like receptor
C-type lectins
NOD like
DNA/RNA receptors
What is a cytokine? What is their function?
They are small proteins that allow immune cell communication. They are produced by cells of immune system which go on to stimulate cells via specific cytokine receptors.
Modulate immune cell function
Attract cells to specific locations
What happens is there is failure to resolve inflamation?
1) Fibrosis
2) Septic shock
3) Chronic inflammation
What changes in immune behaviour happen during resolution?
- increased vascular permeability causes swelling in body.
- vasodilation, cell recruitment causes redness on body
- cell recruitment and increase in cell metabolism causes heat on body
- sesntisation of pain receptors causes pain on body
- reduced movement and compromised organ function.
Describe innate role in inflammatory response
Dectection by tissue resident immune cells like macrophages. This leads to chemokine production, which then leads to immune cell recruitment of neutrophils, monocytes and macrophages.
What are the different classes of cytokines?
- chemokine
- interleukin
- TNF family
What is a cytokine? What is their function?
They are small proteins that allow immune cell communication. They are produced by cells of immune system which go on to stimulate cells via specific cytokine receptors. Also produced by epithelial, and endothelial cells
Modulate immune cell function but can target non immune cells.
Attract cells to specific locations
What are the different classes of cytokines?
-chemokine: mainly for cell recruitment
Classical to modulate immune function:
- interleukin
- TNF family
different immune cells produce different cytokines that act on other immune cell creating a complex network of signals.
Individual cytokines can be made by various types of cell to allow cross-communication between adaptive and innate.
What are the functions of cytokines?
- attract immune cells to specific locations
- activate and inactivate immune cells
What are the four main classes of Chemokines
Based on structure but they all have 2 cysteines and form disulphide bonds.
1) XCL- 2 types. Recruits T cells
2) CCL- 27 types. Recruits Monocytes, Mast cell, T cell, granulocytes.
3) CXCL- 17 types; depending on if there is ELR aminoacid sequence upstream determines which cell it recruits; No ELR it recruits T cell, B cell. If there is ELR sequence it recruits neutrophils.
4) CX3CL- 1 type: 3 amino acid in between cysteine.
How do chemokines recruit?
1) Homeostatic: immune cells to secondary immune organs like lymph nodes. Attraction of chemokines just under resting state
2) Inflammatory: attract to damage tissue.
Describe chemokine-neutrophil recruitment.
Macrophage releases CXCl-1 and 2 which diffuse toward blood vessels. This creates a gradient; high concentration next to macrophage but low concentration near vessel.
Neutrophils detect chemokine and travel up gradient
Macrohphage and neutrophil kill bacteria and produce cyokines. Neutrophils make defensins. to start accute phase responsse.
What is neutrophil de-granulation
release of stored in vesicles inside neutrophil like proteases antimicrobial peptides.
What are Antimicrobial peptides?
Host defense peptides (HDP) can inactivate prokarotic cells and virus.
Positive charged residues interact with phospholipids
Hydrophobic residues insert into membrane
Disulphide bridges stabilise interaction
How do antimicrobial peptides act?
1) Disruption of membrane integrity
2) Bind to precursors of cell wall to stop cell wall formation and therefore stoppping bacterial replication.
3) Target intracellular proteins to disrupt cell functions
What are two types of HDP (Antimicrobial peptides)
1) Cathelicidin
2) Defensins- alpha, beta, delta
Describe the different types of defensins
Alpha defensin- more restricted, main expression from myeloid (ie neutrophil/macrophage) AND paneth cells
Beta defensin - found in both mammalian (vertebrates) and invertebrates.These are produced by macrophages, granulocyes, NK cells and epithelial cells.t
Delta defensin- cyclic peptide not linear, restricted; only identified in monkeys not in humans.
What are paneth cells?
immune cells hat function in small intestine and are responsible for secretion of antimicrobial alpha defensin molecules.
Describe classical cytokines
They modulate target cell function
Cytokines have specific receptors which are divided into four families depending on the receptor
What are the 4 different families of classical cytokines
-Type1
Describe classical cytokines
They modulate target cell function
Cytokines have specific receptors which are divided into four families depending on the receptor
Once secreted they can be autocrine or paracrine way.
What are the 4 different families of classical interleukins
- Type1
- Type 2; IL10 and inerferons
[Type 1 and 2 all signal under Jak/STAT signalling pathway. ]
- IL-17 family
- IL-1 family
[IL-17 and IL-1 family signal via NFkB/MAPK signalling]
-TNF family
What does autocrine action of cytokines refer to?
Cell secretes cytokine. The cytokine stimulates the same cell that secreted them.
IL10 secreted by macrophage, and restimulate macrophage and suppress cytokines
What does paracrine action of cytokines refer to?
Stimulate another immune cell type from the one one that secreted it.
IL12 secreted by macrophages and stimulates T cells
What does interleukin 7 (IL-7) do?
Homeostatis in immune system. This allows normal development of T and B cells
What are some proinflammatory interleukin cytokines?
IL-6
IL-1
Where there is a positive feedback loop during inflammation.
What are the three purposes of acute phase reaction?
1) Prevening spread of infections: complement, C-reactive and SAP proteins produced
2) Wound healing: Fibrinogen and promote coagulation
3) Preventing systemic inflammation: C reactive protein , SAP, protinases ect.
As a result keeps inflammation local and prevents inflammatory molecules being released into circulation.
What is pro resolution actor made during inflammation?
Pro resolution factor promote resolution and inhibit proinflammatory cytokines
Macrophage cytokines
Make cytokines from scratch- induce transcription and translate- as they don’t have pre-stored cytokine in vesicles in cell. Released in response to recognition.
Macrophage cytokines
Make cytokines from scratch- induce transcription and translate- as they don’t have pre-stored cytokine in vesicles in cell. Released in response to recognition.
They are made with pro-sequence which allows insertion into E.R, and secretion via vesicles.
What are the four ways to polarize a helper T cell?
1) Cytokine TGF-beta produces Treg cells which are immunosupressive.
2) Cytokine IL12 produces TH1 Cells: which promote killing by macrophages and responses to intracellular pathogens.
3) Cytokine IL4 produces TH2 cells: which promote antibody production.
4) Cytokine TNF-beta, IL6, IL23 (sustains cell), IL1-beta produces TH17 cells: which antifungal and antitumour activity
list the cytokines made by the macrophage
- IL-1-beta
- TNF
- IL-6
- IL-12
- IFN-beta
- IL-10
theses are released into circulation
Cytokines beyond infection
TNF, IL6, IL1 will travel to brain in blood to stimulate hypothalmus leading to productions of prostaglandins and cause fever.
They also stimulate Pituitary gland to release ACTH which acts on adrenal gland to make corticosteriods to turn off immune response.
They also travel to liver and initiate the acute phase response.
Cytokines beyond infection
TNF, IL6, IL1 will travel to brain in blood to stimulate hypothalmus leading to productions of prostaglandins and cause fever.
They also stimulate Pituitary gland to release ACTH which acts on adrenal gland to make corticosteriods to turn off immune response.
They also travel to liver and initiate the acute phase response.
IL6, TNF to Bone marrow to increase production of leukocyte cells for immune response
What is the acute phase reaction (APR) ?
Changes in plasma concentrations of specific proeins in response to inflammation.
What is the acute phase reaction (APR) ?
Changes in plasma concentrations of specific proteins in response to inflammation.
It is driven by cytokines TNF, and IL-1 IL-6 in circulation. They stimulate cells in liver to alter the protein synthesis.
This is not local, it is a SYSTEMIC effect
What is the acute phase reaction (APR) ?
Changes in plasma concentrations of specific proteins in response to inflammation.
It is driven by cytokines TNF, and IL-1 IL-6 in circulation. They stimulate cells in liver to alter the protein synthesis.
This is not local, it is a SYSTEMIC effect all around the body.
Describe the succession of acute phase proteins.
Some acute phase proteins (ARPs) are increased (positive APP) while others decreased (negative APPs)
Various protein are involved and so not all proteins are released at the same time:
1) Serum Amyloid A and C-reactive protein released first
2) Later, Fibrinogen and Hapotoglobin
What are the three purposes of acute phase reaction?
1) Prevening spread of infections: complement, C-reactive and SAP proteins produced
2)
List some acute response proteins involved in preventing systemic infection
- C reactive protein
- SAP
- Proteinase inhibitors which neutralise lysomal proteases from neutrophils
- Heptoglobin which prevents ion loss through binding
- Serum Amyloid A for lipid binding to stop
- Manganese superoxidase dismutase: A big infection means there are lots of free radicals form reactive oxygen species.
Acute phase response: C reactive protein
It is made of 5 produced in liver, as a result of IL6, IL1 via a transcriptional response.
It is formed of five identical subunit; its is a pentraxin and used as a marker in inflammation.
There are a various functions:
-opsinise bacteria through binding to bacteria cell walls. This helps engage complement and promote phagocytosis
- coats apoptotic cells to promote phagocytoses by macrophages or dendritic cells. Removal suppresses inflammation.
- it can dissociate and become monomeric, in which form it modulates monocytes and neutrophils
- marker for inflammation; it concentration in plasma.
Describe the two stage response of T cell polarization
Stage 1) Helper T cell must recognise Antigen presentation on MHC II on an antigen presenting cell. This is recognised by a T cell receptor (TCR) of a NAIVE CD4 T cell. This leads to proliferation!
Stage 2) Polarization happens in response to cytokines secreted by APC. Helper T cell now takes on specific characteristics for correct function for the stimulating pathogen.
What are the four ways to polarize a helper T cell?
1) Cytokine TGF-beta produces Treg cells which are immunosupressive.
2) Cytokine IL12 produces TH1 Cells: which promote killing by macrophages and reponses to intracellular pathogene
Give an example of related cyokines
IL12 is related to IL23. They are both hetrodimeric.
IL12 contains p35 and p40 subunits. IL23 shares p40 subunit (and has p19)
What happen when you knock out p19 in mice?
You therefore remove IL23 (p40 and p19) which in turn stops the production of TH17 cells (helper T cells)
Causes autoimmunity such as Multiple Sclerosis and Arthritis
Diseases caused by cytokines
Diseases caused by CHRONIC INFLAMMATION which is a result of too many pro-inflammatory cytokines (IL1)
1) Autoimmune
2) Autoinflammatory
3) Cardiovascular disease
4) Neurodegeneration
5) Diabetes- TYPE 2
Therapy: block the cytokine so it cannot function.
Give some examples of Autoinflammatory disorders
-Familial Mediterranean Fever (FMF)
Most these disease are due to a genetic mutation that increases IL-1 production.
Tumor Necrosis Factor (TNF) Receptor- associated periodic syndrome (TRAPS) CAUSED BY MUTATION OF TNF RECEPTOR
Describe cytokine directed therapy? What diseases do they treat?
Anti-TNF therapy involves binding to TNF with antibodies so it cannot simulate cells .
Rheumatoid arthritis, Crohns Disease.
Other cytokines IL1, IL6, IL23 also binded with antibody treatment.
Describe the benefits of IL-1ra in clinical treatment
IL-1ra binds to IL1 receptor without activating intracellular signalling so competitivly inhibits IL1.
DIRA: Deficiency of Interleukin-1 Receptor Antagonist is caused by point mutations that block IL-1ra in the body. And so this disease can be treated through additional IL-1ra.
