Innate Immunity: Early Defense against infections Flashcards
Inflammation is not efficient against intracellular pathogens, results from injury and invasion by microorganisms. Normally inflammation - induced damage is repair post inflammation.. what happens when it is not eliminated?
The tissue damage remains and the inflammation can be come chronic
Inflamation cause blood supply to increase to carry immune cells to affected area, this causes the inflamed tissue to swell. Leukocytes/white blood cells release mediators that continue inflammation, which causes..?
Causes nerve stimulation and pain, the body may react by chills fever and muscle aches
Anti-viral innate immune response is mediated by type 1 interferons (alpha/beta IFNs) and natural killer (NK) cells which do what?
IFNs block viral replication within host cells (protecting against infection)
Natural Killer cells kill virus infected cells
Innate immunity is able to discriminate between self and nonself by receptors which recognize pathogen associated molecular patterns (PAMPS). What is special about these? (4)
- PAMPs are indicators of presence of pathogens
- Unique to classes of pathogens
- Required for pathogen survival so cannot be altered suppressed or easily hidden by pathogens
- No structural similarity with self Ags
What is the name for the cell receptors that recognize PAMPs which are expressed on immune cells?
Pattern Recognition Receptors (PRRs)
Whats the difference in the staining between gram negative and positive and why?
Gram - is not stained and Gram + is stained due to the bacteria containing peptidoglycans
Mannose receoptor is a PRR that recognizes glycans with a terminal mannose, however…
There are no glycans with terminal mannose in humans
What toll-like receptors (TLRs) recognize extracellular pathogens?
TLR 1, 2, 4, 5, 6
What toll-like receptors TLRs recognize intracellular pathogens (such as endosomes, only responding to nucleic acids)?
TLR 3, 7, 8, 9
What is the pathway for the signaling of extracellular TLRs?
Ligand will bind to TLRs which will cause a signaling pathway… MyD88 (myeloid differentiation primary response gene 88 adaptor protein) to IRAK (interleulin-1 receptor-associated kinase) to TRAF6 (TNF receptor associated factor 6) to translocate NF-kB to get pro-inflammatory cyotkine secretion
What TLRs use MyD88 to activate transcription factor NF-kB and interferon regulatory factor (IRFs) transcription proteins?
TLRs 1,2,5,6,7,8,9
Which TLR uses TRIF to activate transcription factor NF-kB and IRFs transcription proteins?
TLR 3
Which TLR uses both MyD88 and TRIF to activate NF-kB and IRFS?
TLR 4
What are the functional roles of TLRs? (4)
Cell-mediated immunity by IL-12, bacterial death, apoptosis of host cells, and septic shock
Where are TLRs expressed and what dependent signaling pathways results in transcription of pro-inflammatory genes?
expressed on immune cells like monocytes, neutrophils, macrophages, and DCs and activate NF-kB and IRF
What are the steps for TLR4 LPS signaling in macrophages?
- TLR4, MD2, CD14, and LPS on macrophage
- MyD88 binds TLR4 activating cascade to activate IKK
- IKK adds P to IkB, releasing NF-kB, enters nucleus
- NF-kB activates transcription for inflammatory cytokines, which are made and secreted
What does DAMP stand for and what are three common types?
Damage associated moelcular pattern, HMGB1 (high mobility group box 1), Uric acid, ans HSPs (heat-shock proteins)
What is necrosis and how does it happen?
a passive, catabolic cell death in response to external toxic factors, characterized by swelling and rupture of cell membrane which causes (NFkB) inflammation to other cells
What are the three things a necrotic cell releases that can activate NF-kB to activate inflammation?
- HMGB1: uses rage receptor to activate NFkB
- Uric acid: unknown receptor
- HSP: use CD91 to induce, releasing TNF-A/IL-1B
Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are intracellular proteins. They regulate the host innate immune response. They act as SCAFFOLDING proteins that assemble signaling platforms that trigger what signaling pathways?
Trigger NF-kB and mitogen-activated protein kinase (MAPK) controlling activation of inflammatory caspases
NLRs respond to PAMPs and DAMPs by binding proteins and forming the inflammasome. The inflammasome activates which enzyme and what is its key function?
activates caspase-1 which cleaves the inactive precursors of IL-1B and IL-18
What drives inflammation in NLR?
secreted forms of inflammatory cytokines IL-1B/IL-18
What are the three types of scavenger receptors (SR)?
Scavenger receptor class A type I Scavenger receptor class A type II MARCO- macrophage receptor with collagenous structure
What are the scavenger receptors 3 distinct extracellular structural domains?
- SR cyteine rich (SRCR) domain not in SRAII
- Collagenlike domain binds polyanionic ligands
- A-helical coiled coil domain not in MARCO
SRs are receptors that mediate uptake of oxidized lipoproteins. SR-A is expressed on Mø and mediate phagocytosis of microorganisms.. SRs bind bateria based on negative charges of the bacterias….
LPS, lipoteichoic acid, nucleic acids, Bglucagon, and proteins
Without SRs, what would happen?
An increased susceptibility to infection of microbial pathogens
C type lectin family bind carbohydrates, they all have a carb recognition domain for recognition of ?
Microbial mannose, N-acetylglucosamine and B glucans
Some lectins are soluble proteins found in the blood or extracellular fluids while others are what?
integral membran proteins found on surfaces of Mø and DCs
What are the main functions of the lectin receptors?
facilitate phagocytosis, triggers secretion of cyotkines that promote ADAPTIVE immune response
The mannose receptor is a well studied Ctype lectin on microbial surface which helps with phagocytosis. Which protein is involved in complement activation via the lectin pathway?
mannan binding protein (MBP)
What does the epithelial barriers (skin) do for the innate immune system?
Provides physical barrier, produce antimicrobial substances, and harbor intraepithelial lymphocytes that kill microbes/infected cells
Defensins are produced by epithelial cells, neutrophils, NK cells, and CTLs. Synthesis is stimulated by cytokines and by microbial products via…?
pattern recognizing receptors PRR
Defensins have direct toxicity to microbes, kill microbes, and regulate activation of immune cells involved in?
inflammatory response to microbes
Cathelicidins are antimicrobial peptides (AMP) like defensins, produced by epithelial cells and neutrophils, stimulated by cytokines, and have mechanisms including direct toxicity and activation of leukocytes… What do they bind and neutralize?
LPS
What is important of cathelicidins?
some play an anti-inflammatory role by binding to DNA and blocking inflammasome activation
Neutrophils are first response to tissue damage, release granules, macrophages engulf organisms and release inflammatory mediators. What are the last two cells involved?
Eosinophils contain cationic granule proteins which fight helminthes and parasites and NK cells kill infect host cells by mediators perforin and granzymes
In neutrophils and macrophages, N-formylmethionyl peptide (fMet) is present in P but not eukaryocytes. Phagocytes use it to help distinguish self from non self. Polymorphouclear cells can bind proteins with fMet and will do what?
Use them to initiate phagocytosis (migration)
What TLRs activate macrophages?
TLR 1,2,3,4,5,6,9
What are the different types of dendritic cells from the myeloid lineage (3) and what are they all directly from?
Classical DCs from stem cells, myeloid DCs (mDCs) from monocytes, plasmacytoid DCs (pDC) from stem cells
What do DCs do?
DCs expresse reeptors that recognize Ags made by microbes and not mammaian cells, secret cytokines
What is the function of classical DCs (langerhans)?
migrate to LNs where they display microbial protein Ags to t cells
What is the function of plasmacytoid DCs?
they recognize nucleic acids of intracellular viruses and produce solube interferons aka IFN-A/B (have antiviral activities)
Mast cells are close to blood vessels which allows them to?
contribute to many events including angiogenesis, wound healing and the exacerbation of inflammation
Mast cells respond during hypersensitivity reactions where they are activated by crosslinking of IgE receptor (FceRi). IgE crosslinking results in?
the release of effector molecules stored in mast cell granules such as histamine, serotonin, tryptase, chymase, PGD2 and LTB4
What is unique of natural killer cells?
Generated from lymphoid progenitor (tcell precursor) but functions as innate immune cells
What are the main functions of NK cells? (3)
recognize ligans on infected cell
kill infected or stressed host cells
eliminate reservoirs of infection and release pathogens for phagocytosis
Activating receptors of NK cells recognize ligans and activate protein tyorsine kinases PTKs. The NK cell activating receptors are called?
killer cell immunoglobulin (Ig) -like receptors KIRs
The inhibitory receptors that recognize class I MHC molecules and activate protein tyrosine phophatases PTP inhibits activation signal, therefore NK cells…
Do not kill class I MHC expressing healthy cells ….. SO NO MHC CLASS 1 = DEATH BY NK
When there is a virus that inactivates the class 1 MHC on a infected cell, there will no longer be a inhibitory receptor causing?
causing activation of the NK cell, killling the cell. Active NKs also produce cytokine IFN-gamma which activates phagocytosis in macrophages
What are the four steps in how a NK cell kills an infected cell?
- NK releases perforins forming a hole in infected cell
- Granzymes from NK enter hole, activates cell apoptosis
- Cell dies by apoptosis, NK releases IFN-gamma
- Most powerful activator of macrophages
What is a general overview of the complement system?
30 proteins, activation initiated in 3 ways, all lead to production of C3b, which initiates activation of C5, creating holes in plasma membranes and kill pathogens
Acute phase proteins (APP) are apart of the systemic acute phase response, produced by hepatocytes, accompany inflammation, and its production is regulated by?
CYTOKINES IL-6
What are the 4 major roles of acute phase proteins?
C reactive protein/mannose binding protein: fixes complement & opsonizes
A1- acid glycoprotein : trasnport protein
serum amyloid P component: amyloid component precursor
Cytokines are small proteins secreted by immune cells to mediate inflammation, imunnity and hematopoiesis. For innate immunity, they are divided into two classes…
Pro-inflammatory and Anti-inflammatory
What are chemokines?
Small protein chemoattractants important for trafficking of immune cells
What is the only cytokine of the innate immune system that is not expressed by macrophages?
Interferon gamma (IFN)
What are the two anti-inflammatory cytokines of the innate immune system?
interleukin 10 (IL-10) and TGF-B
What is the local effect of IL-1B, and what happens systemically?
Activates vascular endothelium and lymphocytes.
Fever and produces IL6 systemically
Which cytokine leads to increased entry of IgG complement and cells to tissues and increased fluid drainage?
TNF-A
Which cytokine activates lymphocytes and increases antibody production?
IL6
Which cytokine has a chemotactic factor that recruits neutrophils, basophils, and t cells to the site?
IL8
Which cytokine activates NK cells and induces differentiation of CD4 cells into Th1 cells?
IL12
Lymphocyte activation requires two signals, what are they and what is the possible third signal?
An antigen is the first signal, substances produced in response to microbes is second signal, which will then signal for T cells
(cytokines are the 3rd signal)
What are costimulators?
T cells that fucntion together with antigens to stimulate the cell
What are the four steps for how neutrophils come to the tissue?
Neutrophils slow down and roll along endothelium
Tight binding to integrins occur
Diapedesis (transmigration through endothelium)
Chemoattractant (interleukin 8) controls migration of N to inflammatory sites
What do inflammation activated endothelial cells (activated by cytokines histamine and chemokines produced by activated mast cells and Mø) increase the expression of?
E selectrin (ES) and P selectin (PS) adhesion molecules
What do leukocytes and neutrophils express?
Leukocytes express integrin LFA-1 (activated by chemokines expressed on the surface of activated endothelial cells)
and neutrophils express ligands for ES and PS
How are integrins activated for leukocyte uptake?
Integrin LFA-1 is usually in low affinity state until chemokines on edothelial surface bind to chemokine receptors on leukocyte, increasing the affinity (to extended position)
Transmigration for monocytes are the same for steps 1-3 (rolling adhesion and diapedesis). The chemoattractants for monnocytes are..?
macrophage inflammatory protein 1A (MIP-1A and MIP 1B)
What are the steps for phagocytosis of microbes?
- MIcrobes bind to phagocyte receptor
- Phagocyte membrane zips up around it
- Lysosomes fuse with phagosome to kill microbes by lysosomal enzymes
- Killing is done by ROS and NO (iNOS= inducible nitric oxide synthase)
What do type I IFNS do in antiviral innate immune reponse?
induce expression of proteins that interfere with virus replication
What does PKR protein kinase RNA-activated do in antiviral innate immune reponse?
prevents recycling of guanidine diphosphate which blocks viral RNA translation
How are innate and adaptive responses linked?
PRRs cause activation and maturation of antigen presenting cells (APCs), which is presented to naive T cells, and secrete cytokines that assist development and maturation of Tcell (IL12)
