Innate Immunity (part 1) Flashcards by Colt Moller

in most cases, the initial innate immune response to pathogens is

prevents, controls, or eliminates infection without an engagement of adaptive immunity

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if the impact (pathogen load) is signifiant, innate immunity

keeps the infection in check until more specialized adaptive immune responses are activated
directs adaptive immunity towards either Ab-mediated or cell-mediated response

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innate immunity eliminates host damaged cells and initiates the process of tissue repair that include:

recognition of host molecules related by stressed, damaged, and/or dead host cells
phagocytosis and clearance of cell debris
stimulation and control of tissue remodeling

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physical barriers of innate immunity

epithelial layers of skin and mocosal/glandular tissues

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chemical barriers of innate immunity

acidic pH of skin (5.5) and anti-microbial proteins and peptides

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if intracellular pathogen is present, what innate immune cell takes action

NK cell will kill cell –> releasing pathogens –> that are picked up by phagocytes

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activated innate immune cells (e.g. macrophages) produce

antimicrobial substances (peptides, interferons)
cytokines and chemokines –> systemic effects (fever); inflammation (recruitment of other cells); and activation of adaptive immune responses

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if pathogens overwhelm macrophages, what becomes active

dendritic cells which can then activate adaptive immune responses

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opsonization

process by which the pathogen is marked for elimination

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neutrophils

polymorphonuclear leukocytes (PMNs)

most abundant of circulating white blood cells

early phagocytosis and killing of microbes

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natural killer (NK) cells

lysis of infected cells, activation of macrophages

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TNF, IL-1, chemokines

inflammation

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IFN-alpha-beta

resistance to viral infection

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IFN-gamma

macrophages activation

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IL-12

IFN-gamma production by NK cells and T cells

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IL-15

proliferation of NK cells

Proliferation of T cells

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IL-10, TFT-beta

control on inflammation

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innate immunity have the ability to discriminate between _____ and _____

self

nonself

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innate immunity discriminate between self and nonself by the mechanism involving _______ and their receptors called ______

pathogen-associated molecular patterns (PAMPs)

Pattern Recognition Receptors (PRRs)

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PAMPs (pathogen-associated molecular patterns) have no structural similarity with

self Ags

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general properties of PRRs (pattern recognition receptors)

recognize broad classes of pathogens

are encoded in germline (limited diversity)

can discriminate between self and nonself

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mannose-tailed glycans are essential surface molecules of

bacteria and viruses

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types of PRRs

mannose receptors

N-formyl methionyl receptor

toll-like receptor

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general properties of PRRs (pattern recognition receptors)

specificity

receptors

distribution of receptors

discrimination of self and nonself

specificity: for structures shared by classes of microbes (‘molecular patterns’)
receptors: encoded in germline; limited diversity

distribution of receptors: nonclonal; identical receptors on all cells of the same lineage

discrimination of self and nonself: yes; host cells are not recognized or they may express molecules that prevent innate immune rxns

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phagocytes use PRRs to help distinguish

self from nonself

PRR-triggered responses of phagocytes: N-formyl methionyl peptide (fMet) is present in ______ but not in ______

prokaryotes eukaryotes

polymorphonuclear cells (neutrophils) can bind proteins starting with fMet, and use them to control ______ and initiate ______

motility phagocytosis

phagocytosis without activation, results in ______ infection

chronic

role of PRRs in phagocytosis

1. microbes bind to phagocyte receptors 2. phagocyte membrane zips up around microbe 3. microbe ingested in phagosome 4. fusion of phagosome with lysosome 5. killing of microbes by lysosomal enzymes in phagolysosomes and killing by reactive oxidative species and nitric oxide synthase

Pattern Recognition Receptors (PRRs) groups

Toll-Like receptors intracellular NOD-like receptors scavenger receptors lectin family of PRRs

some toll-like receptors (TLRs) are present on the cell surface of innate immune cells where they recognize products of ______ while other TLRs are located in endosomes that recognize which respond only to ______

extracellular microbes nucleic acids

toll-like receptors that recognize extracellular pathogens

1, 2, 4, 5, 6

toll-like receptors that recognize intracellular pathogens

3, 7, 8, 9

toll-like receptor 2 recognizes

gram-positive bacteria | peptidoglycan

toll-like receptor 4 recognizes

gram-negative bacteria | lipopolysaccaride

toll-like receptors recognize pathogens and actviate

inflammation

each pathogen can be recognized by ______ TLRs

several

TLR1 : TLR2 heterodimer ligands: cells carrying receptors: cellular location of receptor:

ligands: lipopeptides; GPI cells carrying receptors: monocytes, DC, eosinophils, basophils, mast cells cellular location of receptor: plasma membrane

TLR2 : TLR6 heterodimer ligands: cells carrying receptors: cellular location of receptor:

ligands: lipoteichoic acid; zymosan cells carrying receptors: monocytes, DC, eosinophils, basophils, mast cells cellular location of receptor: plasma membrane

TLR3 ligands: cells carrying receptors: cellular location of receptor:

ligands: double-stranded viral DNA cells carrying receptors: NK cells cellular location of receptor: endosomes

TLR4 : TLR4 homodimer ligands: cells carrying receptors: cellular location of receptor:

ligands: lipopolysaccharide cells carrying receptors: macrophages, DC, mast cells, eosinophils cellular location of receptor: plasma membrane

TLR5 ligands: cells carrying receptors: cellular location of receptor:

ligands: flagellin cells carrying receptors: intestinal epithelium cellular location of receptor: plasma membrane

TLR7 ligands: cells carrying receptors: cellular location of receptor:

ligands: single-stranded viral RNAs cells carrying receptors: plasmacytoid DC, NK cells, eosinophils, B cells cellular location of receptor: endosomes

TLR8 ligands: cells carrying receptors: cellular location of receptor:

ligands: single-stranded viral RNAs cells carrying receptors: NK cells cellular location of receptor: endosomes

TLR9 ligands: cells carrying receptors: cellular location of receptor:

ligands: unmethylated CpG-rich DNA cells carrying receptors: plasmacytoid DC, B cells, eosinoophils, basophils cellular location of receptor: endosomes

signaling of extracellular TLRs always results in activation of transcriptional factor

NF-kB | nuclear factor - kappa light chain enhancer of B cells

what TLR uses TRIF dependent signaling? what is downstream effect?

TLR3 activates NF-kB and Interferon regulatory factors (IRFs)

what TLR uses MyD88/TRIF dependent signaling? what is downstream effect?

TLR4 activates NF-kB and Interferon regulatory factors (IRFs)

what TLR uses MyD88 dependent signaling? what is downstream effect?

TLRs 1, 2, 5, 6, 7, 8, 9 activates NF-kB and Interferon Regulatory factors

broad outcomes of TLR-signaling

influence adaptive response direct antimicrobial response (bacterial death) tissue injury (host) - apoptosis of host cells; septic shock

TLR-dependent signaling pathways activate _______ and _______ which results in transcription of _______

NF-kB IRF pro-inflammatory genes

cytokine IL-12 produced by DCs (after phagocytosis of intracellular pathogen) controls

cell-mediated immunity via stimulating T cell response (activates T cells)

cytokine IL-12 is not produced by DCs (after phgocytosis of extracellular pathogen), and stimulates the development of

humoral adaptive immunity

activation of TLRs can also be detrimental to host: they can contribute to tissue injury by _______ they can lead to life threatening symptoms of ______

inducing apoptosis in host cells septic shock

TLR4 signaling pathway in macrophages

1. complex of TLR4, MD2, CD14, and LPS is assembled at the macrophage surface (LBP delivers LPS to cell surface and MD2 and CD14 deliver LPS to TLR4) 2. MyD88 binds TLR4 --> activates IRAK4 to phosphorylate TRAF6 --> phosphorylation and activation of IKK 3. IKK phosphorylates IkB/NF-kB complex which leads to IkB degradation --> release of NFkB which then enters the nucleus 4. NFkB activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted via the ER

nucleotide oligomerization domain (NOD)- like receptors (NLRs) are a specialized group of Pattern Recognition Receptors (PRRs) that recognize ______ proteins

intracellular

NOD like receptors (NLRs) act as scaffolding proteins that assemble signaling platforms that trigger_______ and _______ signaling pathways.

NF-kB mitogen-activated protein kinase (MAPK)

NLRs respond to cytosolic PAMPs and DAMPs by binding other proteins and forming signaling complexes called

inflammasomes

these pathways control the activation of inflammatory ______

caspases

by recruitment to the complex, inflammasomes activate

caspase-1

main function of caspase-1 is to cleave the inactive cytosolic precursor forms of two homologous cytokines called

IL-1b and IL-18

secreted forms of proinflammatory cytokines IL-1b and IL-18 drive

inflammation

inflammasome activation (NLR activation) is induced by a wide variety of cytoplasmic stimuli that are often associated with infections and cell stress, including

microbial products (bacterial products) environmentally or endogenously derived crystals reduction in cytosolic potassium concentrations reactive oxygen species

NLRP3 senses many DAMPs and PAMPs, including

uric acid crystals, aluminum hydroxide crystals used in vaccines, ATP released from mitochondria, silica, bacterial products, bacterial DNA-RNA hybrids, and the influenza virus

prolonged activation of NLRP3 inflammasome also causes _______ of macrophages and DCs called pyroptosis which releases inflammatory mediators including: IL-1b, IL-18, TNF, IL-6, and IL-8

programmed cell death

scavenger receptors are important in tissue remodeling after collateral damage due to

inflammation and infections

3 types of scavenger receptor (SR) family

Class A type I Class A type II MARCO (macrophage receptor with collagenous structure) (are organized as trimeric complexes)

scavenger receptors have 3 distinct extracellular structural domains

1. scavenger receptor cysteine-rich (SRCR) domain 2. the collagen-domain (responsible for binding of polyanionic ligands) 3. the alpha-helical coiled-coil domain

SR-AI and SR-AII mediate the uptake of _______ into cells which lead to atherosclerosis

oxidized lipoproteins

all SRs bind various bacterial constituents based on ______ charges on bacterial LPS, lipoteichoic acid, nucleic acids, beta-glucan, and proteins

negative

SRs are expressed on on macrophages and mediate ______ of microorganisms via recognition of PAMPs leading to clearance of pathogens

recognition/phagocytosis

SRs KO mice have an increased susceptibility to ______ with several microbial pathogens

infections

lectin family of PRRs are receptors for what macromolecule

carbohydrates

all lectin PRRs contain a conserved carbohydrate recognition domain for recognition of

microbial mannose, N-acetylglucosamine, and beta-glucans

some lectins are soluble proteins found

in the blood and ECF

some lectins are not soluble and are membrane proteins found on what cells

macrophages, DCs, and some tissue cells

eukaryotic cell carbohydrates are most often terminated by mannose or galactose and sialic acid

galactose and sialic acid

lectin receptors facilitate

phagocytosis of various microbes

activation of lectin receptors triggers the secretion of

cytokines that promote inflammation and adaptive immune responses

mannose receptor on phagocytes is involved in ______ of microbes

phagocytosis

soluble mannose-binding lectin (MBL) also known as mannan-binding protein (MBP) is involved in _______ activation via the lectin pathway

complement

PAMPs and DAMPs trigger

inflammation

necrosis

a passive, catabolic cell death in response to external toxic factors dirty form of cell death characterized by swelling and rupture of cell membrane (cell lyse) which may cause inflammation or harm neighboring cells

what generates DAMPs

necrosis

inflammation

a response of the innate immunity that involves activation of leukocytes and release of inflammatory mediators

inflammation is innate reaction caused by: 1. an increased blood supply to the affected area resulting in _____ and _____ 2. an increased capillary permeabilty resulting in leaking from the blood vessels, resulting in _____ and ______ 3. a massive influx of ______ into the tissue 4. an arrival of _______ (16-48 hours) 5. distortion of the homeostasis and ______ of function

1. redness and heat 2. swelling and pain 3. neutrophils 4. monocytes/macrophages 5. loss

T/F DAMPS act through same receptors and PAMPs

True

DAMPs activate

NF-kB

necrotic cells release what DAMPs

HMGB1: activates NF-kB pathway; RAGE is receptor for HMGB1 Uric acid: activates NF-kB pathway HSP (heat shock proteins): activate NF-kB pathway and release of inflammatory cytokines (TNF-alpha and IL-1beta)

epithelia at the portals of entry of microbes provide physical barriers, kill microbes by producing _______ , and harbor intraepithelial ______ that kill microbes and infected cells

antibiotics (defensins and cathelicidins) lymphocytes

the rapid movement of intestinal contents through peristalsis, secretion of mucus by _______ cells, and release of extensive antimicrobial products into the lumen by _______ cells all function to limit the invasion of pathogenic organisms

goblet paneth

defensins (antimicrobial peptides) are small cationic peptides that contain both _____ and _____ regions

cationic hydrophobic

defensins are produced by ______ cells of mucosal surfaces and by granule-containing leukocytes including ______

epithelial neutrophils, NKcells, and CTLs

synthesis of defensins are stimulated by ______ and microbial products via ______

cytokines (cytokine receptors) PRRs

defensins have direct toxicity to microbes, including:

bacteria, fungi, and enveloped viruses

defensins kill microbes by

inserting into and disrupting functions of the microbial membranes

cathe'licidins (antimicrobial peptides) are produced by ______ and barrier ______ cells in the skin, gastrointestinal tract, and respiratory tract

neutrophils epithelial

synthesis of cathe'licidins may be stimulated by _____ and microbial products

cytokines

cathe'licidins have multiple mechanisms, including ______ to microorganisms and the activation of ______

direct toxicity (disrupting plasma membrane) leukocytes

some cathe'licidins can bind and neutralize

LPS

some cathe'licidins play an anti-inflammatory role by binding to DNA and blocking

inflammasome activation

NK cells recognize ligands on

infected cells or stressed cells

NK cells eliminate reservoirs of infection and thus release intracellular pathogens for

phagocytosis

NK cells kills host cells by _____ releasing pathogens for phagocytes

apoptosis

NK cells respond to _____ produced by macrophages (with phagocytosed microbes) and secrete _____ that activates the macrophages to kill phagocytized microbes

IL-12 IFN-gamma

NK cell Activating Receptors (KARs) are called killer cell immunoglobulin (Ig)-like receptors that recognize stress-associated molecules ( _____ and _____ ) on the surface of abnormal host cells

MICA and MICB

activating receptors of NK cells trigger activation of what kinases?

protein tyrosine kinases

NK cell Inhibitory Receptors (KIRs) recognize _____ and activate protein tyrosine phosphatases (PTP) and inhibit an activation signal

class I MHC

if insufficient KIR-MHC I binding occurs, the NK cell will proceed to

kill the target host cell

sufficient binding by KIRs will override the KAR kill signal and

spare the life of the host cell

how do NK cells kill enemy cells

1. NK cell releases perforins, which polymerize and form a hole in the enemy cell membrane 2. Granzymes from NK cell enter perforin hole and degrade enemy cell enzymes 3. enemy cell dies by apoptosis 4. macrophage engulfs and digests dying cell