Theme 2 - innate 2a Flashcards
describe innate immunity
what triggers it
- first line of defence
- fast
- from birth
- triggered by: tissue damage from TRAUMA or INFECTION causes series of CELLULAR and CHEMICAL events which aim to limit SPREAD, ELIMINATE microorganisms and repair damage
what are the cells of the innate immune system
PHAGOCYTES - neutrophils - monocytes and macrophages - B cells - mast cells - eosinophils ANTIGEN PRESENTING CELLS - monocytes - macrophages - dendritic cells - (B cells) OTHERS - NK cells - innate lymphoid cells - NKT cells - gamma delta T cells - eosinophils - B1 cells
innate immunity comprises which 4 main types off defensive barriers/mechanisms
- anatomical
- physiological/chemical
- phagocytic/endocytic
- inflammatory
describe anatomical barriers in innate immunity
SKIN
- mechanical barrier preventing entry of microbes
- dead skin sloughs off
- acidic (pH 3-5)
- commensal microflora secrete BACTERIOCINS and METABOLITES eg LACTIC ACID
MUCOSAL SURFACES
- cilia propulsion (nasal/bronchial)
- mucus entrapment
- secretions: urine, saliva, tears, milk
- competition for ATTACHMENT and NUTRITION
- epithelial cells joined by tight junctions
describe physiological barriers in innate immunity
TEMPERATURE
- fever inhibits bacterial growth and aids our enzymes
LOW pH
- acid of stomach
CHEMICALS MEDIATORS/ANTIMICROBIAL
- proteins/enzymes: Lysozyme (in tears/saliva, cleaves peptidoglycans in of bacterial cell walls), Lactoferrin (binds essential nutrients, inhibiting bac/fungal growth)
- peptides: Defensins, Cathelicidins, Histadin, Dermicin
- S100 proteins
- surfactant proteins
what do S100 proteins do
Psoriasin:
- in secretions and on skin
- disrupts microbial cell membranes
- potent against E. coli but not S. aureus
what do surfactant proteins do
- found mainly in resp tract
- block bacterial surface components by BINDING to them
- have lubricating function
- SP-A, SP-D
what do defensins do
- POSITIVELY charged polypeptides that bind NEG charged microbial structures eg LPS, LTA
- aggregate to form pores in CYTOPLASMIC MEMBRANES
- activate complement-classical pathway
- found on skin and all mucosal surfaces
- most abundant protein in neutrophil granules
what are cathelicidins
- antimicrobial peptides that disrupt microbial membranes (esp bacteria)
- mainly on mucosal surfaces
who had a key role in phagocytosis
Ilya Metchnikoff- found some specialised cells have a role in defence
- studied ability of cells in transparent daphnia and starfish to SURROUND objects introduced to them
- described phagocytosis as WBC ‘eating’ foreign particles
what is cellular uptake for
what are the mechanisms used
- acquire nutrients
- sample surrounding env
- defence mech
Mechanisms: - pinocytosis
- macro-pinocytosis
- receptor-mediated endocytosis/phagocytosis
(most cells use PINO and RECEPTOR MEDIATED)
what is pinocytosis
- cell ‘drinking’
- brings in nutrients
- helps in osmoregulation
- molecules internalised by NON SPECIFIC invagination of plasma memb
- dep on external conc
what is macro-pinocytosis
- ‘larger gulps’
- same functions as pinocytosis
- potential role in recycling MEMBRANE RECEPTORS or PLASMA MEMBRANE
- helps ANTIGEN processing for immune response
- some microorganisms (viruses) use this to infect cells
what is receptor-mediated endocytosis
- the SPECIFIC uptake of a LIGAND, GF, HORMONE, IMMUNE COMPLEX
- clustering of receptors and association of CLATHRIN around ‘pits’ form endosomes
what is phagocytosis
what carries it out
- carried out by specialised cells that INTERNALISE, KILL and DIGEST PARTICULATE matter
- monocytes/macrophages, neutrophils, dendritic cells, eosinophils, B cells, mast cells
- clustering of cell surface receptors
- CYTOSKELETAL REARRANGEMENT and ENERGY
what are the 4 stages of phagocytosis
1 recognition
2 ingestion
3 digestion
4 exocytosis
what happens in the DIRECT recognition stage of phagocytosis
DIRECT (non-opsonic)
- Pattern Recognition Receptors (PRRs) on phagocytes bind to Pathogen Associated Molecular Patterns (PAMPs) or to Damage Associated Molecular Patterns (DAMPs) on particles/microbes
what does PRR stand for
Pattern Recognition Receptors
what does PAMPs stand for
Pathogen Associated Molecular Patterns
what does DAMPs stand for
Damage Associated Molecular Patterns
what happens in the INDIRECT recognition stage of phagocytosis
(opsonic)
- receptors on phagocytes bind OPSONINS coating the surface of particulate matter/microbes
give some exaples of PAMPs
LPS on G-ve
glycolipids, peptidoglycans and lichotechoeic acid on G+ve
Flagellin
in what situations may DAMPs be expressed
- our own cells that have gone wrong
- cell may have undergone necrosis and released ssRNA
- short chain f.a in diet
- if a cell is apoptotic then it may express PHOSPHATIDYLSERINE, RNA, HDL and VITRONECTIN on surface of damaged/apoptosic cells
- clearing and tissue/limb development
what are the main types of PRRs
C type lectin receptor
Scavenger receptors
Toll-like receptors
Others:
NOD-like receptors
RIG-like recepotrs
AIM2-like receptors
what does lectin have specificity for
what do C type lectin receptors
what does the mannose receptor do
- lectin has specificity for CARBOHYDRATE
Mannose receptor: - bind mannose
- on surface of most macrophages and DCs
- 8 extracellular domans and cytoplasmic tail
what do C type lectin receptors
what does the dectin-1 receptor do
- binds beta1-3 glucan
- expressed on a wide variety of myeloid lineage cells
what do C type lectin receptors
what does the DC-SIGN receptor do
- binds mannans on bacteria, fungi and parasites
what do scanvenger receptors do
where is SR-A found
they bind APOPTOTIC/NECROTIC cells
- mainly bind DAMPs
SR-A
- found on all macrophages and some endothelial cells, binds modified low density LIPOPROTEIN (eg ox LDL)
what do scanvenger receptors do
where is SR-B found
- includes CD36 on endothelium, DC, platelets, MC and macrophages
- bind altered ‘self’ molecules eg ox LDL/vimentin
- also recognises some PAMPs
identified in what
how
what was identified
what do toll-like receptors do
- identified in Drosphila
- TLR4 identified using mous knockouts
describe toll like recepotrs
- leucine rich repeats of external domain specific for a set of PAMPs or DAMPs
- can be HOMO or HETERO dimers
- memb bound but some sample the contents of endocytic vesicles
- most cells have INTRACELLULAR TLRs- detect DNA/RNA associated with viruses and induce TYPE I INTERFERONS (cytokines w/ antiviral effects)
- cell surface TLRs expressed by IMMUNE cells and strongly associated w/ bac/fungal inf
- MOs, Mφs and DCs have all TLRs
- B cells, T cells and granulocytes have fewer Endothelium, adipocytes etc only express TLR4
what are the other cytoplasmic PRRs
NOD
NOD-like receptors
- Family of 23 members divided into 3 main groups (B,C and P)
- interact with intracellular PAMPs and DAMPs
- Activate the NFkB pathway and autophagy
what are the other cytoplasmic PRRs
RIG-like
- bind viral dsRNA and so detect viral replication
- initiate anti-viral cytokine (type 1 interferons)
what are the other cytoplasmic PRRs
AIM-like and cGAS/STING
- Bind DNA molecules from bacteria and viruses
- Induce production of anti-viral and inflammatory cytokines
when NLRs and ALRs clump together what do they form
‘inflammasome’resulting in the production of pro-inflammatory cytokines such as Interleukin-1 and 18 (IL-1 and IL-18) – this can result in a special form of self-death called pyroptosis
what is opsonisation
- post recognition, attachment may be enhanced by OPSONINS such as IgG (antibody), fragments of Complement and lectins
- opsonin ‘coats’ microbe/cell
- Acute phase proteins (C reactive protein-CRP) have structure similar to Complement component 1 & activate Classical Complement pathway by attaching to microorganisms
- AB, complement and lectin receptors on phagocytes mediate INGESTION through binding to the opsonins
what is an antibody (Fc) receptors
- recognise the CONSTANT REGION of antiobodies
- family of FcgammaR (recognise IgG)
- Different varieties expressed on different phagocytes
what is an complement receptors
- bind components of classical, alternative and lectin complement pathways
- CR1, CR2, CR3, CR4, C3a/4a and C5aR are expressed by a variety of phagocytes•Main ones involved in phagocytosis are CR1, 3 and 4
