- 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

- cell 'drinking' - brings in nutrients - helps in osmoregulation - molecules internalised by NON SPECIFIC invagination of plasma memb - dep on external conc

Theme 2 - innate 2a Flashcards by P Sreekumar

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

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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

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innate immunity comprises which 4 main types off defensive barriers/mechanisms

anatomical
physiological/chemical
phagocytic/endocytic
inflammatory

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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

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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

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what do S100 proteins do

Psoriasin:

in secretions and on skin
disrupts microbial cell membranes
potent against E. coli but not S. aureus

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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

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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

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what are cathelicidins

antimicrobial peptides that disrupt microbial membranes (esp bacteria)
mainly on mucosal surfaces

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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

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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)

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what is pinocytosis

cell ‘drinking’
brings in nutrients
helps in osmoregulation
molecules internalised by NON SPECIFIC invagination of plasma memb
dep on external conc

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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

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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

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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

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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