Innate immunity Flashcards
Definition inflammation
Local accumlation of fluid, plasma proteins and leukocytes
caused by infection, injury or chemical irritation
Signs of inflammation
RCDT
rubor (redness)
calor (heat)
dolor (pain)
tumor (swelling)
pro-inflammatory cytokines
IL-1, IL-6 and TNF-alpha
adhesion. chemokines, immune cells, luid, proteins
fever, acute phase proteins, leukocyte production
septic shock
Effect: IL-1 and TNF-alpha
- adhesion molecules on EC upregulated (permeability)
- vasodilation in combination with other mediators (histamine, prostaglandine from mast cells)
- chemokine expression induced
- recruitment of immune cells, fluid and plasma proteins
Effect of IL-1, IL-6 and TNF-alpha
PROTECTIVE:
- fever: immune cell activity up, growth rate down, rest
- acute phase protein synthesis: opsonisation, complement activation
PATHOGENIC:
- systemic TNF-alpha leads to septic shock
–> HR down, permeability and vasodilation up –> BP DOWN
–> systemic blood coagulation and impaired perfusion leads to multi-organ failure
types of antimirobial products
Lysozymes
Defensins
Cathelicidins
Histatins
Lysozymes
cleave bacterial peptidoglycan in gram-positive bacteria
present in saliva, tears, paneth cells (intestinal crypts) and phagocytes
Defensins
form pores in cell membranes of microbes (e.g. gramnegative bacteria, viruses)
hydrophobic and hydrophilic end, positive charge –> allignment within the membrane and pore formation
can also bind e.g. glycoproteins and PREVENT VIRAL ENTRY
in mucosa, skin, paneth cells and phagocytes
Cathelicidins
skin, GIT and respiratory tract, phagocytes
Histatins
saliva
cell-associated membrane bound PRR
SIGNALLING: TLR, N-formyl met-leu-phe receptors
PHAGOCYTOTIC: CLR, scavenger
cell associated
membrane bound + signalling
TLR
N-formyl met-leu-phe receptors
cell associated
membrane bound + phagocytotic
CLRs
scavenger receptors
cell associated cytosolic PRRs
RLRs
STING pathway
NLRs
TLRs
types
activation pathway and effect
cell associated, membrane bound and signalling
cell surface -> 1, 2, 4, 5 and 6 -> bacterial and fungal cell wall
endosomal -> 3, 7, 8 and 9 -> nucleic acid (viral, bacterial)
Ligand binding -> dimerization -> TIR domain recruits MyD88 or TRIF -> TRAF6 activation -> inflammatory and antiviral genes
cell surface -> NFkB and AP-1 -> inflammatory genes
endosomal -> IRFs > antiviral genes
cell surface TLRs
1, 2, 4, 5 and 6
detect bacterial infections and activate NFkB and AP-1
expression of pro-inflammatory cytokines TNF-alpha, IL1 and IL6
chemoines
endothelial adhesion molecules
costimulatory molecules for adaptive immunity
Acute Inflammatory Response
Atimulation Of Adaptive Immunity
endosomal TLRs
3, 7, 8 and 9
detect viral infections
activate IRFs and expression of antviral genes
Type I IFNs –> alpha and beta
induction of the Antiviral Response
N-formyl met-leu-phe receptors
call associated
membrane bound signalling
on plasmamembranes of phagocytes
recognize peptides containing N-formyl-methionyl residues (= first AA in bacterial peptides)
CLRs
cell associated
membrane bound phagocytosing
on phagocytes
binds mannose and fructose on carbohydrates
- Type I: DEC-205
- Type II: dectins, DC-SIGN
- soluble
Scavenger receptor
cell associated
membrane bound and phagocytosing
on plasmamembranes of phagocytes
binds microbial diacylglycerides
RLRs
cell associated
cytosolic signalling
recorgnizes viral RNA -> recognized intracellular viruses
RIG-1 (uncapped RNA) and MDA-5 (dsRNA)
contain CARD domain (caspase -> apoptosis and IRF)
ROBUST ANTIVIRAL RESPONSE
STING pathway
cell associated
cytosolic signalling
stimulator of IFN-genes in response to cytoslic DNA
cGAS binds DNA -> produces cGAMP -> activates STING on ER -> IRF3 and NFkB mediated type I IFN (a&b) production
RIG-1
RLR
(cell associated, cytosolic signalling)
binds short uncapped ss or dsRNA
CARD domain -> apoptosis and IRFs
ROBUST ANTIVIRAL RESPONSE
MDA-5
RLR
(cell associated, cytosolic signalling)
binds dsRNA
CARD domain -> apoptosis and IRFs
ROBUST ANTIVIRAL RESPONSE
NLRs
cell associated
cytosolic signalling
recognizes bacterial cell wall
Leu-rich repeats for ligand bindig, NOD-domain and variable N-terminal domain
CARD in NOD receptors, PYR in NLRP3
NOD 1&2
IkB degradation and NFkB activation
NOD2 lof mutation -> Chron’s disease
NLRP3
recognizes bacterial products and DMAPs
oligomerization and adaptors and caspase 1 form inflammosome
Casp1 cleaves pro-IL1b -> IL1b -> acute inflammation
contributes to Gout, Alzheimers, atherosclerosis, autoinflammatoric syndromes
Type I IFN and viruses
produced via IFR genes -> TLRs, RLRs and STAT
via NFkB -> NLRs, STING
induces ANTIVIRAL STATE
- induction of antiviral enzymes
- activate adoptive IS (MHC I upregulation)
receptors activating IFR genes
TLRs
RLRs/STAT
receptors activating NFkB
NLRs
STING
Antiviral state
induced via type I IFN
(induced by IRF or NFkB)
antivral enzymes
- PKR reduces viral protein sythesis
- 2’5’ oligo A synthesase degradation of viral RNA
- Mx proteins reduce gene expression and viral assembly
activate adapive IS via MHC I upregulation -> CD8+ activation
antiviral enzymes
PKR -> reduces viral protein synthesis
2’5’ oligoA synthesis -> degradation of viral RNA
Mx proteins -> reduces gene expression and virion assembly
Adaptive IS activation by IFN via
MHC I upregulation -> CD8+ activation
solubel PRRs
bind microbial structures in blood and extracellular fluids
opsonization
increase in inflammatory response
killing
acute phase proteins
complement system
acute phase protein
soluble PRR
produced by liver
acute phase response initiated by IL1, Il6 and TNF alpha
e.g. CRP: C-reactive protein, opsonin and activates complement, diagnostic factor for inflammations
CRP
C reactive protein
produced by the liver
acute phase protein
induced by IL1, IL6 and TNFa (acute phase response)
opsonin, activates complement, diagnostic factor for inflammation
Complement system
Function
soluble PRR
> 30 proteins synthesized mainly by liver
circulate inactive -> proteolytic cleavage in presence of pathogens (activation) -> cascade -> MAC formation
OPSONIZATION (C3b)
INFLAMMATION (C3a, C5a)
KILLING (C5b activates cascade -> 6,7,8,9 -> MAC)
Complement system
Activation
soluble PRR
> 30 proteins synthesized mainly by liver
circulate inactive -> proteolytic cleavage in presence of pathogens (activation) -> cascade -> MAC formation
ALTERNATIVE -> recognizes micorbes directly
CLASSICAL -> Ab
LECTIN -> mannose-binding lectin PRRS (CLRs)
Complement system
Receptors
soluble PRR
> 30 proteins synthesized mainly by liver
CR1: rec. C3b, on all immune cells (innate and adaptive)
CR3: iCRb (opsonin), on APCs
CR4: iC3b, on APCs but mainly DCs
CR2: C3dg & C3d (opsonin), on B cells and follicular T cells -> germline centers!
C3b function & receptors
Opsonization
recognized by CR1, CR3 and CR4 (iC3b)
CR2 recognizes C3dg & Cd also opsonins and recognized by B and FDCs (germline centers)
C3a
promotes inflammtion
increased permability and chemoatraction for phagocytes
C5a
promotes inflammtion
increased permability and chemoattrction for phagocytes
C5b
activates killing cascade -> C6-9
C9 essential for MAC formation and cell lysis
alternative pathway
complement activation via direct recognition of microbes
classical pathway
complement activation via recognition of Ab
lectin pathway
complement activtion via mannose-binding PRRs (CLRs)
CRP
acute phase protein
opsonin
activates complement
diagnostic factor for inflammation (1000x elevated)
mast cells
innate immune cells
tissue resident
contain granules with pro-infl mediators
express FceR1 -> bind IgE -> SENSITIZING
multivalent Ag can cross-link bound IgE -> Granule content release
crucial in ALLERGIC REACTIONS and their diagnosis (wheal and flare in prick test)
FceRI
recognizes IgE
expressed by mast cells
contributes to sensitizing of mast cells by IgE binding and triggering of granule release upon multivalen Ag-mediated cross-linking
cell essential for allergic reactions
mast cells via FceRI-IgE mediated sinsitization
granulocytes
innate immune cells
eosinophils, neutrophils and basophils
eosinophils: circulating, migration to infection and release of granule content, toxic to helminths!
basophils: circulate and migrate, otherwise similar to mast cells
neutrophils: phagocytosis and killing, NETosis, ADCC, regulation of T cells, …
basophils
innate immune cell, grnaulocyte
basophils: circulate and migrate, otherwise similar to mast cells
eosinophils
innate immune cells, granulocytes
circulating, migration to infection and release of granule content, toxic to helminths!
neutrophils
innate immune cell, phagocyte and granulocyte
phagocytosis and killig of bacteria
NETosis
cell-cell contact with adaptive immune cells
degranulation and cytokine release effects T cells activating or suppressive
contain different ytpes of granule
phagocytes
innate immune cells
neutrophils and macrophages
recruited via IL1 and TNFa (by tissue-resident MO)
PRODUCTION of PRO-INF CYTO- and CHEMOKINES (IL1, IL6 and TNFa)
release chemokines -> integrin activation, chemoattraction
PHAGOCYTOSIS and KILLING: have phagocytotic PRRs (CLRs, scavenger), opsonin recognition (IgG, C3b, CRP) and killing via phagolysosome (oxidative burst)
bacterial resistance to phagolysis or destruction
phagocytes
recruitment
IL1 and TNFa by tissue-MO
activate nedothelial cells -> upregulation of ICAM-1 and selectins
bound by LFA-1 and carbohydrates on phagocytes
extravasation
migration along chemokine gradient
phagocytes
function
2 main functions
PRODUCTION of PRO-INF CYTO- and CHEMOKINES (IL1, IL6 and TNFa)
release chemokines -> integrin activation, chemoattraction
PHAGOCYTOSIS and KILLING: have phagocytotic PRRs (CLRs, scavenger), opsonin recognition (IgG, C3b, CRP) and killing via phagolysosome (oxidative burst)
phagocytes
disease
chronic granulomatose disease
mutationts in oxidase -> ROS production is impaired and therefore killing
characterized by recurrent infections
macrophages
innate immune cell, phagocyte
dominate later stages of innate immune cells (arrive after neutrophils but are longer-lived)
phagocytosis, killing, cytokine production, Ag presentation
tissue resident MO develop during embryonic development
other develop out of monocytes when recruited to inflammations
M1 and M2 subset
M2 = wound-healing and repair promoting, by IL4 and IL13 (TH2 cells), also pro-tumorigenic
macrophages
types
tissue resident -> produce IL1 and TNFa for phagocyte recruitment, developed in embryonic stages
other develop out of monocytes upon recruitment
M1 and M2 polarization
M2 = wound-healing and repair promoting, by IL4 and IL13 (TH2 cells), also pro-tumorigenic
macrophages
function
phagocytosis and killing
cytokine production
Ag presentation
neutrophils
function
phagocytosis and killing
NETosis
cell-cell contact with adaptive immune cells
degranulaton and cytokine release impacting T cells
dendritic cells
innate immune cell
bridge between innate and adaptive
sentinel (capture and process) and presenting
PRRs: CLRs for Ag reouting into cell (Dectin)
TLRs, NLRs, RLRs and CDS to mature DCs
MATURATION: Ag processing and presentation, PRR signalling for co-stimulator expression, change in receptor reservoir (CCR7 upregulated for migration along CD19/21 to lymph nodes
activate naive T cells in primary immune response
activate mature T cells in secondary immune reponse
dendritic cells
maturation
CLRs (dectin) mediate Ag processing and presentation
TLR, NLR, RLR and DCS recognize PAMPs and initiate maturation
(co-stimulator expression)
change in receptor reseroir -> CCR7 to migrate along CCL19/21 to lymph nodes
dendritic cell
function
sentinel and presenting
Ag presentation of MHC I and MHC II -> cross-presentation by cDC1 possible
acivation of naive T cells in primary immune response
acivation of mature T cells in secondary immune response
dendritic cell
subsets
pre-DC for conventintional, pre-pDC
cDC1: Ag CROSS PRESENTATION of exogenous Ag to CD8 (MHCI) and intraclelular pathogens (MHCI)
cDC2: extracellular pathogens to Cd4 on MHCII
CD3: extraclelular pathogens to CD4
pDC: plasmacytoid -> produce type I IFN -> antiviral
cDC1
pre-DC
Ag CROSS PRESENTATION of exogenous Ag to CD8 (MHCI) and intraclelular pathogens (MHCI)
cDC2
pre-CD
extracellular pathogens to Cd4 on MHCII
DC3
pre-DC
extraclelular pathogens to CD4 (MHCII)
pDC
pre-pDC
plasmacytoid -> produce type I IFN -> antiviral
NK cells
innate immune cells
KILLING of virus infected, injured or tumour cells via perforin
IFNg PRODUCTION: induced by IL12 by MO -> activates MO to kill phagocytosed microbes
ADCC: Ab activate NK cells
- IgG binds target and FcgRIII on NK
- antibody bridge
- NK activation -> apoptosis
IFNg production by NK cells
induced by IL12 from MO
activates MO to kill phagocytosed microbes
NK cells
killing mechanism
perforin-mediated
ADCC
Ab activating NK cells
IgG binding target and FcgRIII on NK cells -> Ab bridge
NK activation and apoptosis
FcgRIII
on NK cells
mediates ADCC
IgG bindig target and FcgRIII
