Recap 3 Flashcards
LPS binding receptors
TLR4 = NLR inflammasome and produce ILB
CD14 = activate endocytosis
What are some secreted PRR
Collagenous lectin = mannan-binding lectins A et C
Ficolins
Surfactant proteins A (SP-A) et D
Conglutin (cattle)
What can NFkB and p38 induce (exception)?
Phagocytosis, DC activation, release inflamm cytokines, active innate immune system
TLR4 signaling = doesn’t engage MyD88 = form IFNy
TLR3 et 4 independent of MyD88
Through what do TLR and C-type lectin regulate innate and adaptive responses?
NFkB, TFAP-1, IRF
Mechanisms of NLR
Binding of NLR -> activate RIPK2 -> induce NFkB (facteur de transcription) = secretion of antimicrobial peptides, inflamm mediators, MAPK active for gene transcription and regulation of autophagy
Composition of NALP3 inflammasome
Release of
Multimeric protein units consits of NLR sensing molecule, ASC adaptor protein, caspase 1
Release of IL1B, IL18, IL33
What are alarmins?
Sulfate, hyaluronan, heat schock protein (HSP60), Gp96 (endoplasmic reticulum), fibronectin, fibrinogen, SP-A
Generate inflammation against neoplastic cells, toxins, mechanical injury
Can induce NLRP3
TNF and IL1 induce endothelial expression of integrin ligand :
1. VCAM-1
2. ICAM-1
3. PECAM-1
4. JAM A-B-C
- VCAM-1 - ligand for B1 integrin VLA4
- ICAM = LFA-1, MAC-1
- PECAM = on endothelial cell membrane
- JAM = mediate adherence activity
Where does leucocytes migration happen?
Mainly in postcapillary venules
Organisation of filopodia of leucocytes for migration
Polymerization of actin at the leading edge (VLA3 binds fibronectin) and localization of myosine at the back (tail anchored by LFA1)
Molecules causing mast cells degranulation
Fce-R to IgE
Substance P (released from C-reactive nerve fibers)
Granules of eosinophils
Small = arylsulphatase, acid phosphatase, MMP, gelatinase
Primary
Large Sp secondary = Major basic protein (MBP = inhibe heparin), cationic protein, eosinophil-derived neurotoxin, eosinophil peroxydase, histamine, lysosomal enzyme
Eosinophils produce which cytokine
IL1 à 6, 8-10-12-16, GM-CSF, TGFa et B, chemokines
Chemoattractants of eosinophils
Histamine
Eosinophil chemotactic factor A (from mast cells)
C5a
IL4-5-13
Chemokines (CCL5/RANTES, CCL11/eotaxin)
NK cells (sentinel) receptors and products
CD161 not CD3
Type I = 95% express CD56 produce IFNy
Type II = lack CD56 produce IL4, IL5, IL13 (Th2 response)
Regulation of active and inactive NK (sentinel)
IL21 regulates differenciation
Inactive stimulated by Flt-3 ligand, IL4, IL12, IL15, IL21
Activated leads to upregulation of CD16 and IFNy
R for NK-LT
CD3+
Recognize CD1d = induce release of IFNy, IL4, GM-CSF
Subtypes of IgG y Fc-R
ITAM domain = macro activation
ITIM domain = inhibe activation
How are ROS produced ? Damage cell?
Rapid assembly and activation of a multicomponent oxidase called NADPH oxidase = réduit NADPH en O2-
Damage through lipids peroxydation, cross-link of proteins, oxide thiol groups on methionine and cysteine, cleave glycoconjugates, directly damage DNA
Microbicide action of neutrophils
Azurophilic granules contain MPO = converts H2O2 to HOCl (hypochlorite = bleach)
Destroy microbes by halogenation or peroxidation
Antioxidant
1. Enzymatic
2. Non enzymatic endogene
3. Non enzymatic dietary
- SOD, catalase, thioredoxin, peroxiredoxin, glutathione peroxidase
- Ceruloplasmin, transferrin, metallothionein, uric acid, melatonin
- VitA, C, E, lycopenes, flavonoids, resveratol, genistein, anthocyanin, naringenin, reserpines
Action of NO
VasoD, inhibe platelets aggregat, inhibe mast cell induced inflammation, oxidizes lipids, regulates chemotaxis
In macrophages interacts with superoxide to generate ONOO-
What do neutral proteases of neutrophils do?
Cleave C3 and C5 complement and release kinin-like peptide from kininogen
What do macrophages contain?q
Acid hydrolase, collagenase, elastase, phospholipase, plasminogen activator
What does lyzozyme do?
Hydrolyzes the muramic acid-N-acetylglucosamine bond found in the glycopeptide coat of all bacteria
Action of defensin, cathelicidin
Forms pores in microbial membrane
Affects chemotaxis and activation of adaptive response
Action of elastase, inhibition
Hydrolyzes bacterial cell wall and tissue elastin
A1-antitrypsin = major inhibitor of neutrophil elastas e
What does the release of deoxyadenosine by Staph aureus do?
Enzymes that degrade NET
Mechanism of NET formation
ROS dependent activation of arginine deaminase that converts arginine to citrulline leading to chromatin decondensation
MPO and elastase enter nucleus = further decondensation
Role of IL17 + deficiency
Neutrophils recruitment
If absent = susceptible to fungal/bacterial and develop cold abcesses
Functions of HIF-1a
Promotes phagocytosis
Inhibe apoptosis
Release antimicrobial peptide
Granule protease
VEGF
Cytokine release
Inducible NO synthese (iNOS)
Opsonin-R on neutrophils membrane
Complement (CR1, CR3) and Fc-R (binds C3b, C3bi) -> active GTPase Rac1 and B2 integrin MAC1 -> induce kinase + mediate actin assembly = formation of filopodia -> phagocytosis
Fusion in phagocytosis mediated by
Calmodulin and SNARE
Effects of neural impulses in termination of acute inflammation
Neural impulses (cholinergic discharge) inhibit production of TNF in macrophages
Role of
1. PGE2
2. PGD2
3. PGF2
4. PGI2
5. TxA2
6. LTB4
7. LTC4-D4-E4
- PGE2 = fever
- PGD2 = vasoD, chemoattractant for neutrophils
- PGF2 = vasoC, smooth muscle contraction
- PGI2 = vasoD, inhibe platelet aggregation
- TxA2 = vasoC, platelet aggregation
- LTB4 = chemotactic, permeability, ROS, release lysosomal enzyme
- LTC4-D4-E4 = vasoC, bronchospams, permeability
Leukotriene more potent than histamine in vascular permeability
Th1 CD4 lymphocytes :
1. Induit par
2. Express
3. Produce
4. Role
- Driven by IL12
- Express T-bet
- Release IFNy
- Cell-mediated immune response
Th2 CD4 lympho
1. Induit par
2. Express
3. Produce
4. Role
- Forms in response of IL4, IL6, TSLP
- Express GATA-3
- Produce IL4-5-10-13
- Induce humoral response (asthma, atopy)
Th17 CD4 lymphocytes
1. Induit par
2. Express
3. Produce
4. Role
- Forms in response to TGFB, IL6, IL23
- Express Roryt
- Release IL17
- Bridge innate and adaptive response
Treg prod et role
Develop in thymus and in response to antigenic stimulation in the presence od TGFB
Modulate adaptive response to release of IL10
Follicular CD4 LT (TFH) role prod
Develop in presence of IL6 et IL21
Release IL21 = support LB development and AC production
TNF and IL1 production and functions
Produced by activated macro and DC
TNF (LT and mast cells)
IL1 (some epithelial cells)
Functions in endothelial activation, activation of leucocytes
Action :
SOCS
PTP (SHP-2)
PIAS
SOCS = inhibit JAK
PTP = JAK and STAT
PIAS = inhibe phospho STAT in nucleus
Functions of interferon
Inhibe viral replication, active NK cells and macro, increase AG-presentation to LT, increase resistance of host cells to viral infection
Mechanism of antiviral activity of IFNy type I
Based on expression of activation of ISGylation pathway, MxA protein, OAS1, RNase I, PKR
type 2 IFN (IFNy) action
Bind IFNy-R and signal through JAK and STAT to induce Th1 and Th17 response
Type 3 interferon produced by + mechanisms
Produced by intestinal and respiratory epithelial cells in response to viral infection
Release of viral RNA in infected cells = active RIG1 = mediate MAVS on mitochrondria = active p38, NFkB and IRE3 = produce type 3 IFN
HMGB-1 role
Released by monocytes and macrophages
Nuclear protein binds DNA to regulate gene expression
Released by nearly all cells during necrosis = release alarmin
Binds macrophage-R for products of RAGE and TLR2 and 4 -> release of TNFa and IFNy
Involved in hypothalamic fct, food aversion, hypophagia, anorexia, weight loss, sickness behavior
Chemokines (cytokines)
Only cytokines that bind to GPCR
CXC chemokines
Production
Inducer
IL8 secreted by active macrophages, endo cells = activation and chemotaxis of neutrophils
Induced by microbes IL1, TNF
C-C chemokines
Receptor
Production
Action
CCR receptor
Monocyte chemoattractant protein (MCP1, CCL2)
Eotaxin CCL11 = recruits eosinophils
Macrophages inflammatory protein MIP1a, CCL3
C chemokine lymphotoxin
Binds CR receptor
Lymphotactin XCL1 = relatively specific for lymphocytes
CX3C 2 forms
- Cell surface bound protein = induced on endothelila cells = strong adhesion of monocytes and LT
- Soluble form derived from proteolysis = chemoattractant
Chemokines receptors expressed on neutrophils
CXCR1
CXCR2 (binds IL8)
Monocytes chemokines ligands
CCL2-7-8-13
What is chemerin
Chemoattractant for DC and macrophages activated by cleavage and binds CMKLR1
Acute phase proteins
C-reactive protein = acid glycoprotein, haptoglobin, mannose0binding protein, firbinogen, a-antitrypsin, C3, C4, albumin
Action of :
1. Adiponectin
2. Lipoxin
3. Resolvin
4. Maresin
5. Annexin A1
6. Hydrogen sulfide
- Adiponectin = anti inflamm, insulin sensitization, antiapoptotic
- Lipoxin = active macro, alter neutro migration
- Resolvin = inhibe neutro transmigration
- Maresin = wound repair, reduce nerve sensitivity
- Annexin A1 = released from dead neutro, inhibe further neutro infiltration
- Hydrogen sulfide = apoptosis of neutrophils
Action of
1. C3a
2. C5a
3. C3b, C3bi
4. MAC
- C3a = vascular permeability by histamine release from masto
- C5a = anaphylotoxin, chemoattractant, expression of adhesion molecules, activates lipoxygenase pathway
- C3b, C3bi = opsonin through CR1 and CR3
- MAC = results from cleavage of C5 to form C5a et C5b
C5b = anchor for C6, C7, C8 = polymerize C9 into a tube inserted in lipid bilayer = channel for ions = water osmosis = lysis
What does an inherited deficiency in C1 inhibitors do?
Angioedema
Functions of PAF
Platelet aggregation
VasoC
Leucocytes adhesion
Bronchoconstriction
Complement involved in disposal of waste
C1q, C3, C4 fragments = clearance of immune complex and apoptotic cells
Functions of bradykinin
Permeability
Contraction of smooth muscle
VasoD
Pain
Stimule phospholipase A2 (AA metabolism)
Hypotension
Bronchoconstriction
M1 (classic) and M2 (alternatif) macrophages induced and action
M1 : induced by microbial, IFNy, TNF = role in destruction of microbes and inflammation
M2 : induced by IL4, IL13 = role in tissue repair and terminate inflamm (IL10, TGFB)
Mechanism of lymphocytes trafficking
Express L-selectin = migre in blood = enter 2nd lympho organs through high endothelial venules (HEV = produce CCL19, CCL21, CXCL12, CXCL13) = attract naive LT et LB expressing CCR7 (CCL19-21-R) and CXCR4 (CXCL12-R) and/or CXCR5 (R-CXCL13)
Only Peyer’s patch HEV express MadCAM1 = receptor for a4B7 adhesion expressed on LT and LB
S1P accumulate in lymphatic vessels (R- on LT, LB, NK-t, macro)
Differenciation of dendritic cells
- Immature DC (CD34+, CCR1, CCR5) migre to exposure -> Exposed to TNFa or TLR -> DC express CCR7 -> migrate in blood until recruited by HEV where lympho express CCL19, CCL20
- Migration under influence of cytokines +++CCL21
- Recruited by CCL3 et CCL4 released from lympho and macro
- Exposed to TNFa or TLR -> DC express CCR7 -> migrate in blood
Action of hepcidin and thrombopoietin
Hepcidin = small protein that reduces availability of iron to erythroid progenitors in bone marrow = anemia of chronic inflammation
Thrombopoietin = growth factor for megakaryocyte = thrombocytosis
Mechanism of tissue proliferation
Priming phase = mediated by IL6 produced by Kupffer (if liver) = compentent to receive GF
Growth factor phase = HGF, TGFa act on hepatocytes to activate gene transcription
Terminal phase = return to quiescence (TGFB)
Angiogenesis steps
- VasoD (NO, VEGF)
- Proteolysis of ECM, separe pericytes = vessel sprout
- Migration of immature endothelial cells
- Proliferation of endo cells to form solid endothelial tubules
- Maturation of endo cell, formation of lumina
- Formation of stalk cells and tip cells at the end of vascular buds
- Endo cells adhesion to adjacent cells and basal lamina and express R/ligands for leuco adhesion
- Recruit pericytes and smooth muscle to support
- Suppress endo proli/migration and end deposition of basement membrane
Role of these molecules in angiogenesis :
1. VEGF (++A)
2. FGF (+++FGF2)
3. Angiopoietin 1 et 2
4. PDGF and TGFB
5. Notch signaling
- VEGF (++A) = migration/proliferation endo cells (sprouting), vasoD, formation of lumen
- FGF (+++FGF2) = proliferation of endo cells, migration macro/fibroblasts + epithelial to cover wound
- Angiopoietin 1 et 2 = GF = maturation of vessels
- PDGF and TGFB = stabilize, connective tissue, recruit smooth muscle, suppress endo migration/prolif
- Notch signaling = regulate sprouting and branching of new vessels (VEGF stimule Notch ligand)
Molecules involved in the degradation of collagen and other ECM component
MMP1 à 3 = cleave fibrillar collagen
Gelatinase = degrade amorphous collagen and fibronectin
Stromelysin = degrade numerous ECM components
ADAM, cathepsin G, tPA, uPA
How does GC affect scarring?
Weaken scars due to inhibition of TGFB production and diminished fibrosis
