Acute Inflammation Flashcards
Who expresses P selectins? Where are they stored? What stimulates their expression?
Platelets (alpha granules), endothelium (WP bodies), and monocytes; Histamine and thrombin
What do selectins bind to? What does this interaction result in?
Sialyl Lewis X-modified glycoproteins; Rolling
What stimulates the conversion of integrins on leukocytes to their high affinity state? What cleaves the L-selectins off the leukocytes?
Chemokines (IL-8) from WP bodies; ADAM17
What are the ligands for integrins? Where are they expressed? What induces their expression?
ICAM and VCAM; endothelial cells; TNF, IL-1, Substance P
What are the beta1 integrin(s)? What ligand does it bind to? Who expresses beta1 integrins?
VLA-4; VCAM-1; monocytes and T cells
What are the beta2 integrin(s)? What ligand does it bind to? Who expresses beta2 integrins?
LFA-1 and MAC-1; ICAM-1; All leukocytes
What is the other name for beta1 integrins?
CD49CD29
What is the other name for beta2 integrins?
CD11CD18
What do chemokines bind on endothelial cells?
Proteoglycans
Mediators involved in leukocyte activation
TNF, IL-1, IL-6 (cytokines), C5a, IL-8 (chemokines), PAF, PDGF (from platelet alpha granules)
Diapedesis ligands on endothelial cell and receptors on leukocytes
PECAM-1 (CD31) to itself
JAM A to JAM A or LFA-1
JAM C to JAM B or MAC-1
Most potent endogenous chemoattractants; what do they bind to on leukocytes? Result?
Cytokines (IL-8)
C5a
Leukotriene B4, also 5HETE and PGD2
G-protein-coupled receptors
Polymerization of actin at front and myosin at back
In leukocyte activation, what is the end result?
Increase in cytosolic Ca and activation of enzymes like Protein kinase C and phospholipase A2
What are the major opsonins? What recognizes opsonins?
IgG, C3b, MBL and collectins (C type lectins); phagocytes have high affinity receptors
What enzyme produces ROS in phagocytosis? What converts H2O2 to hypochlorite to kill microbes in neutrophils?
NADPH oxidase; myeloperoxidase from primary granule
What converts superoxide anion to peroxynitrite radical in macrophages? What does iNOS do?
NO; converts arginine to NO
Two types of granules in neutrophils; what do they contain?
Primary: MPO, proteases, lysozyme, defensins
Secondary: beta2 integrins and above
Most important antiprotease; primary purpose
Alpha 1 antitrypsin; inhibits neutrophil elastase
What initiates NET formation?
ROS activation of arginine deaminase to convert arginine to citrulline, causing chromatin decondensation
Part of adaptive immune response that is crucial for acute inflammation
Th17 cells and IL17!
What receptors do mast cells have? Who also expresses these?
FcepsilonRI for IgE, which cluster and crosslink; basophils
What do mast cells degranulate in response to? (4)
Physical injury, heat, cold
Crosslinking of IgE by antigens
Complement products (C3a and C5a)
Substance P
What do mast cells store in preformed granules
Histamine, tryptase, TNF-alpha, cytokines, GFs
What do mast cells synthesize?
PGD2, PAF, heparin, cytokines, C-C chemokines
What cytokines do basophils mostly release? How are they different from mast cells?
IL-4 and IL-13; they don’t produce heparin or hydrolases
Other than IgE receptors, what ligands/receptors do basophils express?
CD40 ligand (for B cells) and CCR3 (eotaxin receptor)
What stimulates differentiation of neutrophils?
Cytokines (IL-1, TNF, IL-3) and growth factors (G-CSF)
What do neutrophils have receptors for?
CXCL8 (IL-8)
What do band neutrophils have that other neutrophils don’t?
Tertiary granules with MMP-9
What is the most important product released by eosinophils? What else do they release?
Major basic protein; cytokines, chemokines, proteases, GFs, ROS
What is chemoattractant for eosinophils?
Histamine, C5a, IL-4, IL-5, IL-13, CCL11 (eotaxin), CCL5 (RANTES)
What is another name for NK cells?
Large granular lymphocytes
What cells do NK cells kill?
Tumor cells, viral infected cells
What receptors do all NK cells express?
CD16, Fc receptor for ADCC
CD161, c-type lectin
What receptor do type I NK cells express? What do they produce?
CD56+, IFN gamma to support Th1 response
Most NK cells are this type
What is different about type II NK cells
Don’t express CD56, produce IL-4, 5, and 13 to support Th2
What regulates differentiation of NK cells? What else does it do?
IL-21; Upregulates CD16 expression, release of IFN gamma, and apoptosis of the NK cell
Most important cause of differentiation and survival of monocytes?
CSF1
What receptors do macrophages express?
Receptors for opsonins- IgG Fc, C3b, MBL, collectins
Free macrophages
Histiocytes, alveolar, serous fluids, some in LN, some in spleen
Fixed macrophages
Some in lymph node, some in spleen, Kupffer cells, IV, microglial, skin, BM
Positive acute phase proteins
C-reactive protein
Haptoglobin
Ceruloplasmin
SAA
Fibrinogen
Hepcidin
Thrombopoietin
What does c-reactive protein do
Activates complement
What does haptoglobin do?
Bind hemoglobin
What does Hepcidin do?
Reduces iron availability by internalizing ferroportin
What does thrombopoietin do?
GF for megakaryocytes
What are the negative acute phase proteins?
Albumin
Transferrin
What cells have pattern recognition receptors?
All cells involved in innate immunity- endothelial, epithelial, phagocytes, ILCs
What are the three categories of PRRs?
Transmembrane, Cytosolic, and Secreted
What is the link between innate and adaptive immunity?
TLRs
End result of LPS binding TLR4
Cytokine and inflammasome responses
Generally, TLR pathway
PRR-PAMP complex activates TIR, forms complex with MyD88 protein, IRAK, and TRAF6, which activates MAPK (p38) signaling, activating NF-kappaB
How is MyD88 independent pathway different?
Results in formation of IFNs by TLR4 signaling via TRIF to activate IRF
What facilitates the binding of LPS to the cell? What initiates LPS induced cell signaling?
LPS Binding Protein binds LPS to CD14, then leaves; LPS-CD14 then binds TLR4, then MD2 complexes and results in signaling to TIR
What do TLRs 1, 2, and 6 recognize? What pathway?
Bacterial lipoprotein; MyD88–>NF-kappaB
What does TLR 4 recognize? What pathway?
LPS, lipotechoic acid; CD14, MyD88–>NF-kappaB or or TRIF–>IFNs
What does TLR 5 recognize?
Flagellin
What does TLR 11 recognize?
Uropathogenic bacteria
Which TLRs recognize bacterial PAMPs?
1, 2, 4, 6
Which TLRs recognize viral PAMPs?
3, 7. 8, 9 (all endosomal)
What do C-type lectin receptors recognize?
Fungal and mycobacterial glucans, mannose/fructose residues
What does TLR 3 recognize? Pathway?
dsRNA; TRIF/IRF3–>Type I IFNs
What does TLR 7 and 8 recognize? Pathway?
ssRNA; MyD88 and IRF7–>IFNs
What does TLR 9 recognize? Pathway
unmethylated CpG DNA; MyD88 and IRF7–>IFNs
What are the two intracellular PRRs?
NOD-like receptors and RIG-like receptors
What do NLRs recognize? Result?
Bacteria, stress signals, urate crystals; inflammasome–>caspase 1–>IL-1beta and IL-18, also cleaves gasdermin D to cause pyroptosis
What do RIG like receptors recognize? Result?
dsRNA; production of type I IFNs via IRF3 (no TRIF)
What are the two categories of secreted PRRs?
Collectins- MBLs and pulmonary surfactants A and D
Pentraxins- C reactive protein
What do MBLs bind? What is the result?
Terminal mannose residues on yeast; Opsonization and activation of lectin complement pathway
What do C-reactive proteins bind? What is the result?
Microbial membranes; opsonization and classical complement pathway activation
What does NFkappaB do?
TF, for inflammatory cytokines
NFkappaB pathway
Bound by IkappaBalpha, which has to be phosphorylated by IkappaBkinase (IKK), which results in free NFkappaB that translocates to nucleus
