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93 Cards in this Set
- Front
- Back
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Describe innate IS receptors.
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Cells surface ptns, soluble ptns in body fluids and also cytoplasmic ptns that sense viral infection
May have several binding sites with dif ligands specificities Polymeric: several binding sites for the same ligand Recognize microbes through PAMPs by multivalent binding |
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What are soluble receptors for common foreign material?
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C1q
MBL SP-A/D Ficolins CRP |
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What is C1q?
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Complement ptn
Needed to bind IgM/G in immune complexes Can bind pathogen surface in absence of Ab |
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What is MBL?
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Mannan binding lectin
Binds patterns of certain carbs Ass't with MASPs |
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What are SP-A/D?
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Pulmonary surfactant ptns (collectins like MBL)
opsonize microbes for alveolar macrophages |
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What are ficolins?
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Like collectins, but not lectins
Bind patterns of acetyl gps Ass't with MASPs |
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What are CRP?
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C-reactive ptns
Pentraxin which binds PAMP via phosphocholine Also triggers complement by binding C1q collagen domain |
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What do phagocyte mb receptors recognize/.
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molec surfaces ass't with normally intracellular molec or molec altered by abnormal conformation, degradation or chemical modification
Also recognize opsonized ptns like Ab, complement and collectins Also have receptors for foreign material |
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What are common mbreceptors?
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Mannose receptor family (MR): have multiple C-type lectin-like Carb binding domains. Can directly phagocytose
DEC205: dendritic cell C-type, multi-lectin receptor Scavenger receptor: diverse ligands, lipoteichoic acid foundin G+ bact wall TLR: important for signalling the presence of foreign material (not uptake of it) t-MLP receptor: signal formyl-methionine at pptd N-terminal |
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What role do TLRs play in efense vs fungal infection in drosophila?
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-Fungal infection causes expression of antimicrobial peptides (AMP)
-AMP genes have binding sites for T activator :dorsal -Activation of dorsal is caused by signals through toll receptor |
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What happens if the toll path is mutated?
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Reduced insect's survival after fungal infection
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What happens in mice that have a mutant TLR-4 genes?
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Hyperesponsive to LPS and are unable to survive infection with G- bacteria
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What happens to TLR-2 KO mice?
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Have impried response to G+ bact cell wall to p/g from S. aureus
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What are the agonists of TLR2?
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Lipoteichoic acid, p/g, lipoptn, zymosan and **HSP70 (released by damaged cells)
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What are the agonists vs TLR-4?
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LPS
**Hyaluronic acid Fragments, **HSP 60/70 |
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Which TLR are on the cell surface?
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TLR:1,2,4,5,6
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Whih TLR are inthe endosomal compartment?
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TLR: 3,7,8,9
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What do the TLR in the endosomal compartment do?
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Make contact with the agonist in the phagolysozome in phagocytic cells
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What does TLR-4 act through?
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MyD88 and a non MyD88 receptor
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How does signalling through the cytoplasmic TLR domains affect signalling cascades?
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TIR adaptors
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What 2 paths does TLR-4 activate?
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-Path through which MyD88 activates NFkB and results in cytokine (TNFa) prod'n
-MyD88 independent path resulting in induction of nitric oxide synthase (iNOS) and type 1 IFN (IFNa/B) |
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How is LPS detected as TLR-4 in a 3 step process?
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1-LPS bound by LPS binding ptn
2-LPS:LBP complex transfers LPS to CD14 on the surface of phagocytes 3-LPS-CD14 complex interacts with and stimulate things on the cytoplasmic side |
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What is TLR activation often ass't with?
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AMP activation
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Howdo bronchial epithelial cells respond to dsRNA do?
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Use TLR3
Produce cytokines and beta-defensins 2 and 3 |
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How do tracheobronchial cells respond to LPS?
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Via T:R2 and TLR4
produce beta-defensin2 (works other way too, beta-defensin 2 in mouse activates dendritic cells via TLR4) |
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What kind of cytokines and inflammatory mediators are released by macrophages upon phagocytosis?
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Protaglandins
leukotrienes others |
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What are some mechanisms of bactericidal agents produced by phagocytes?
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Acidification
Toxic O2 products Toxic Nitrogen-oxides Antimicrobial peptides Enzymes Competitors |
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IL-8 (CXCL8)
Main producer? Acts upon? Effect? |
Macrophages and dendritic cells make it
Acts on Phagocyte chemoattractant for neutrophils |
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TNF-α
Main producer? Acts upon? Effect? |
Macrophages and dendritic cells
Acts on Vasular endothelium Induces change in vascular endothelium: expression of adhesion molec E-/P-selctins, changes in cell-cell jcts with inc fluidloss, local blood clotting |
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What are the benefits of the skin?
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Flxible barrier
Protects from water loss Protects from friction and impact wounds Produces vit D Body T reg'l: sweat |
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What do keratinocytes do?
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In epidermis, structural/nechanical integrity
secrete cytokines that affact immune fct and wound healing |
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What are Langerhans cells?
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APCs
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What do mast cells do?
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Can release regulatory molec
Can stimulate vascular endothelial cells to express adhesion olec (help leukocytes bld-> tissue) |
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What are components of SALT (Skinn ass't lymphoid tissue)?
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Lymphocytes
Langerhans cells |
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What is MALT (mucosa ass't lymphoid tissue)?
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beneath the epithelial layer, has structures that promote Ag presentation
Includes NALT (nasal...): tonsils/adenoids, GALT (gut....): peyers patches and BALT (bronchus....) |
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What happens when microbes penetrate the barrier?
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-Bacteria trigger macrophages to release cytokines and chemokies
-Vasodilation and increased vascular permeability cause redness, heat and swelling -Inflammatory cells migrate into tissues, releasing inflammatory mediators that cause pain |
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Whaare inflammatory mediators? What do they cause?
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Regulatory molec
-Vasodilation: inc local blood flow-> heat, redness -Vascular permeability: fluid and ptns enter tisue-> edema -Expression of adhesion molec;chemotaxis: Recruits neutrophils, monocytes and other leukocytes -Clot formation: helps prevent sprad of infection through blood vessels |
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What are the inflammatory mediators?
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Lipid mediators: prostaglandins, leukotrienes, platelet activating factor
-TNF-α -Histamine -Complement derived polypeptides -Bradykinin |
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What happens following an infection?
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1-Trigger inflammatory mediators
2-Bld vessel endothelial cells and leukocytes express CAMS 3-Bld vessels become permeable 4-Bld clotting |
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What does TNF-α do?
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Released by macrophages to contain local infection
Acts on local bld vessels to inc bld flow and vascular permeability to fluid, ptn and cells -Increase adhesiveness to endothelium for leukocytes and platelets |
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What happens in local release of TNF-α?
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Influx of fluid, cells and ptns into infected tissues
After: blood clots that stop spread of infection Fluidgos to lymph nodes and adaptive is activated |
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What hapens in sysemic infection (sepsis)?
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TNF-α is released into bloodsteam by macrophages, ge to spleen and liver
Clots small vessels Shock, disseminated intravascular with depletin of clotting factors -> bleeding, organ death |
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What happens if there is a mutation in TNF-α?
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No septic shock, but can't control local infection
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What are the 2 groups in the chemokine family?
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CXC: 2 cys residues separated by 1 aa (binds cxc receptor (6))
CC: 2 adj cys near amino end (binds cc receptor (9)) |
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What's a chemokine?
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Chemoattractant for leukocytes (monocytes and neutrophils)
Some are involved in lymphocyte dev'l and migration |
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IL-8 (CXCL8)
Produced by? Receptors? Cells attracted? Major affects? |
Monocytes, mac, fibroblasts, keratinocytes, endo cells
Receptors: CXCR1/2 Attracts: neutrophils and naive T cells Affects:Mobilizes, activates and degranulates neutrophils, angiogenesis |
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What is MCP-1 (CCL2)?
Produced by? Receptors? Cells attracted? Major affects? |
Monocytes, macrophages, endo cells and neutrophils
Receptor: CCR28 Attracts: Monocytes, NK, T cells, basophils and dendritic cells Affects: Activates macrophages, basophil histamine release, promotes Th2 immunity |
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What kind of receptors are chemokine receptors?
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GPCR
(.: same fmily as receptros for anaphylatoxin C5a, C3a) |
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What attracts and activates neutrophils?
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f-MLP (small peptide of bacterial origin)
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What are the 3 types of adhesion molec?
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Selectins
Integrins Ig superfamily |
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What do selectins do?
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Bind carbs, initiate leukocyte endothelial interaction
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Where is P selectin?
E selectin? |
P: Activated endothelium and platelets
E: Activated endothelium |
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What do integrins do?
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Bind cell-adhesion molecules and extracellular matrix
Strong adhesion |
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What drives activation of endothelial cells?
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Interaction with macrophage cytokines (TNF-α)-> rapid externalzation of Palade bodies
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What is a Palade body?
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Granules in endo cell
Contain P-selectin After P selctin is expressed, make E-selectin |
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What do naive lymphocytes have that is important to their trafficking throufh high endothelial venulaes into the lymph nodes?
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L-selectin
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What are the 3 selectins involved in extravasatio of leukocytes into infected tissue?
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L, P and E
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What induces these selectins on the blood bessel endo cells?
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Inflammatory mediators and exposure to microbial microbes
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What induces P and E selectin?
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P: preformed and stored in vesicles (Palade bodies) and is .: quickly expressed
E: Gene expression is induced (must first synthesize it then express it) |
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What are the 4 steps of extravasation?
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1-Selectins induced and interact with monocytes/neutrophils and adhere to the cell wall
2-Inc interaction due to LFA (integrin) and chemokine makes neutrophils firmly bind 3-Penetrate through cell wall and basement mb (diapedesis) 4-Migration of leukocytes through the tissues under the influence of chemokines |
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What happens during the extravasation process of lymphocytes?
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-LTB4, C5a and histamine exposure causes endothelial cell expression of P-selectin within minutes
-Selectin mediated adhesion to leukocyte sialyl-Lewis is weak and allows leukocytes to roll along the vascular endothelial surface -LPS and TNF-α exposure induces cell expressiokn of E-selctin and ICAM1 within a few hours -IL8 and other chemokines act on leukocytes to increase integrin affinity, promote diapedesis and chemotaxis ->Inc adhesion, stop rolling and bind firmly to endothelium -Leukocyte can squieeze out of the wall btw 2 endo cells -Penetrates basement mb and neutrophil migrates on a [gradient] of chemokines, which were secreted by cells at the site of infection |
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What does TNF-α induce in the extravasation process?
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E-selectin
possibly P-selecin |
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How do the leukocytes interact with the vascular ends of blood vessels in inflammatory cells?
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Inflammatory vessels are dilated, .: the blood flow is slower and leukocytes can move to the side and interact with the vascular ends
(vessels coated with cytokines, and when leukocytes are rolling, E and P selectins bind to the glycoptns on the leukocytes) |
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What does ICAM I bind?
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IL8 (CXCL8) on monocytes and leukocytes
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What kind of binding exists btw the leukocyte and the vascular endothelium?
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Reversible binding through the interactions btw selctins on the endo and the sialyl-Lewis moiety on the carb ligand on the leukocyte
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What is the necessity of ICAM and integrins?
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Need chemokine to inc interaction to anchor the cell vs blood flow (uses integrin LFA-1)
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What stops the rolling?
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Interaction btw ICAM and integrin
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How are local dendritic cells activated?
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Immature dend cells live in peripheral tissues
Dend cells migrate via lymphatc vessels to regional lymph nodes Mature dend cells activate naive T cells in lumphoid organs (lymph nodes) |
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Where are lymphocytes found?
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Blood
Lymph Lymphoid organs |
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What are the peripheral lymphoid organs used for in immunity?
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Trap Ag-carrying dendritic cells and help start adaptive
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What happens when infection occur?
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Ag and Ag-bound dendritic cells go from ste of infection-> afferent lymph vessels-> drain lymph nodes, activates specific lymphocytes-> leave lymph nodes as effector cells, through the efferent vessels-> blood stream
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What does the lymphatic system do?
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Collects all the extracellular fluid from tissues and returns it to the blood
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What are the components of the lymph node?
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HEV (high endotheliar areas): special bld region through which lymphocytes enter lymph nodes
Follicles: where B cells are localized Outer cortex: made up of follicles Pararcortical areas: Where T cells are distributed, mmigrating lymphocytes end up here |
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How do lymphocytes migrate fro bld to lymph node?
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Through high endothelial venules (postcapillary venules)
->adhere ->sqieeze btw endothelial cells |
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What do the durface adhesion molec on naive T cells bind?
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Vascular addressins on vascular endo cells n the lymphoid tissues
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What does L selectin on the T cell bind to?
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CD34 and GlyCAM1 on LN HEV
MAdCAM-1 on endothelium in the mucosa |
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What produces the secondary lymphoid tissue chemokine (SLC)?
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High vascular endothelium
Stromal cells Dendritic cells |
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What do SLC do?
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Increases the affinity of T ell integrin LFA-1 for its ligands on the endothelial cells and promotes migration into the lymphoid organ
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How do lymphocyte enter the lymph nodes through HEV?
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-Lymphocyte enters HEV
-Binding of L-selectin to Gly-CAM-1 and CD34 allows rolling interaction -LFA-1 is activated by chemokines bound to he extracellular matrix -Activated LFA-1 binds tightly to ICAM-1 -Lymphocytes migrate into the LN by diapedesis |
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Where does the spleen collect Ag?
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Blood (not peripheral lymph nodes like the lymphatic sys)
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What happens in the Red pulp in the spleen? White?
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Red: site of RBC disposal
White: where spleen arterioles are surrounded by lymphocyes |
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What is PALS?
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Periarterioles lymphoid sheath (sheath of lymphocytes around arteriole, has mostly T cells)
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What are Peyer's patches?
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Part of GALT
Ag collected from M cells Where lymphocytes enter by the blood |
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What's transcytosis?
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When Ag taken up by M cells and are carried across the epithelial barrier
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How do NK cells recognize a target cell?
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NK cells have many receptors that rec'z ligand on many cells
this recognition would stimulate the NK to kill the cell but there are also INHIBITORY receptors Killer inhib recep (KIRs) interact with class I MHC |
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What kind of cells do NK attack?
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Cells with reduced MHC expression
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How do normal cells protect themselves form NK cells?
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Express MHC I that's rec'z by KIR or lectinlike CD94:NKG2 on NK cells, which inhibits activation of the activating receptors
(abnormal cells don't express enough MHC I, can't stimulate negative signal, NK cell triggered by signals from activating receptors: causes apoptosis of the cell) |
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What inc NK activity?
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IFN-α and β
IL-12 |
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What does the combination of IL12 and TFN-α do to NK cells?
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Synergize to promote secretion of IFN-γ
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What can IFN-γ do?
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Help activated macrophage
Tip balance of CD4 T cell differentiation towards Th1 type (Th1 are a source of IFN-γ themselves) |
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What role do Th1 cells play in bacterial infection?
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Help macrophages clear mycobacterium
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Why would NK cells secrete IFN-γ?
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Stimulates normal, uninfected cells to upregulate MHC 1, making them resistant to killing by the activated NK cells
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What is the point of NK cells?
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Control infection before CD8 Tcyt can come and secrete IFN-γ and kill infected cells
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