immunology exam #2

aka natural immunity, the non-specific defenses that protect us from foreign material

what is innate immunity

not affected by prior contact with foreign material

activates immediately upon exposure

response the same with each subsequent encounter with foreign matter, does NOT magnify

characteristics of the innate immunity response

direct = nutrition, physiology, age, and genetics

indirect = personal hygiene, socioeconomics/living conditions

effectiveness of innate immunity is impacted by direct and indirect factors. what is an example of both?

PAMPs (pathogen associated molecular patterns) or DAMPs (danger/damage associated molecular patterns)

innate immunity detects nonself using what?

cell-associated or soluble receptors which trigger immune response upon encountering PAMP or DAMP

what is patter recognition receptors

molecules shared by pathogens that are essential for those organisms and are not found associated with host cells

PAMPs/DAMPs are what type of molecules?

lipopolysaccharides (gram -)

porins

flageelin

lipoteichoic acids

peptidoglycan (part of bacterial cell wall)

bacterial/viral genomes (double stranded RNA)

examples of PAMPs

stressed, injured, infected, or transformed host cells

DAMPs are unique molecules displayed where?

altered membrane phospholipids

heat shock proteins

examples of DAMPs

overresponding

what process can cause more damage to the body than the original foreign material

molecules that activate the immune system but are derived from self (not outside foreign matter) as in tissue death

what are danger signals

uncontrollable form of cell death, can be due to trauma, burns, toxins, etc.

ex. cell membrane ruptures, release cellular components not normally seen outside (healthy) cells/tissue

what is necrosis? give example.

regulated or controlled cell death in an ‘immunologically silent’ manner

what is apoptosis

components of pathogen (ex. carbohydrates, lipids, proteins) not usually seen in host

bacterial proteins (ex. flagellin), dsRNA

changes in host cells due to viral infection of invasive bacterial infection

pattern recognition receptors (PRRs) detect what?

foreign agent

it is opsonized, phagocytize

what do soluble PRRs bind to?

col lagen + lectin = collectin

they are soluble PRR that distingush between foreign and self using surface CHO patterns (affinity to bind sugars allows it ot bind to many G+ and G- bacteria, yeasts, viruses, and parasites

what are collectins

complement lectin pathway

collectins activate what

C-type lectin receptor (CTLR, CLR)

what is soluble counterpart to cell curface in collectins

calcium

collectins are ________ dependent

mannose binding lectin (MBL)

example of collectin

LPS receptor CD14 on tissue macrophages

binds to ligand of pathogen such as bacterial CHO and lipids

binding to PRR triggers messenger proteins (ex. cytokines, chemokines) to be released, mobilize additional components of immune system

cell associated PRRs also bind to infection agent, activation of signal pathways that enhance response, leads to phagocytosis.

give example. (hint LPS receptor CD14)

messenger proteins (cytokines and chemokines)

____________ released, mobilize additional components of immune system, shape or tailor the immune response

IL, TNF, CXCL8

examples of inflammatory cytokines

induce fat and muscle cells to metabolize, generate heat, and raise the temperature in the infected tissue

what does IL-6 induce

recruits and activates natural killer cells to secrete cytokines that strengthen macrophages response to infection

what does IL-12 induce

induc blood vessels to bemore permeable, enabling cells, and soluble effectors to enter infected tissue

what does TNF-a induce

recruits neutrophils from the blood and directs them to the infected tissue

what does CXCL8 recruit

PAMP

• all classes detect infection; each conveys type of infection and its location

different classes of cell associated PRRs, each specific for distinct ____________

pleiotrophic effects

• differing effects on various cells

cytokines have what kind of effects?

guide cells of immune system to site of infection or damage

what are chemokines

CXCL8, CXCL2, CXCL1, CXCL5

example of chemokines

upon PAMP/DAMP recognition, engagement of PRR

PRRs trigger intracellular signaling cascades (cytokiens and chemokines)

expression of a variety of pro-inflammatory molecules results

initiation of host immune response to non-self

subsequent activation and shaping of adaptive immunity

sum up the innate immunity - the immediate response

TLR, CTLR, NLR, RLR, Scavenger Receptors, CDS

PRRs are divided into various groups/families based on structural features. and what are they?

toll like receptors (TLR)

this receptor is named for its similarity in a specific gene in Drosophila

PAMP

humans have 10 different TLRs, all act as sensors for what

dimerize

two TLR’s may __________ to recognize a particular pattern

TLR2/TLR6

which complex detect diacylated lipoprotein found in G+ bacteria

TLR2/TLR1

which complex detect triacylated lipoproteins found in G- bacteria

TLR4 + co-receptor MD-2

which complex detect LPS of G- bacteria cell walls, specifically the lipid A region of LPS

cell surface or endosomal membrane

where do TLRs reside

intracellular domain: conserved region, TIR for signaling

extracellular domain: LRR, pathogen recogniton

how are TLRs cell membrane spanning?

Activation

TLRs + Ag/PAMP = what?

adapter proteins

TLRs recruit __________ to propagate Ag-induced signal transduction pathway

MyD88, TRIF, TRAF6

TIR domain adapter proteins utilized to help bring signaling components together to facilitate gene expression. what are these proteins

protein kinases (IKK, IRAK4, TBK1)

adapter proteins responsible for subsequent activation of other downstream proteins including ___________, that further amplify signal

nuclear factor kB (NFkB) and/or interferon regulating factor (IRF)

signal pathway activates _____________ which direct expression of genes for various antimicrobial factors

septic shock

X-linked hypohidrotic ectodermal dysplasia

excessive inflammation

autoimmunity

malignancy

genetic variation in TLR associated with resistance, susceptibility to disease. give examples.

C-type lectin receptors (CTLRs)

calcium dependent transmembrane proteins

collectins

what is the soluble part of CTLRs

CHO on surface of bacteria and fungi

what do CTLRs recognize

intracellular activation or phagocytosis

CTLD (C-type lectin domain) engagment signals what

NOD-like receptors

soluble proteins in cytoplasm, recognize bacterial degradation products in cytoplasm

detect infection, products of degradation, phagocytosis

NF-kB

what does NOD-like receptors trigger to control the activation of inflammatory caspases

inflammasome

NOD-like receptors play a role in the formation of what

inflammasomes

protein complex formed in response to infection, enable releaase of IL-1B (regulates inflammation)

PRR/NLR

adapter protein

pro-caspase 1

what is in the multi-protein cytoplasmic complex that make up the inflammasome

recognition of PAMP activates macrophage, which then secretes cytokines to recruit cells to promote inflammatory response, due to production of IL-1B

IL-1 is cleaved by caspase-1 to form activated IL-1B

macrophages activated by release of IL-1B

what occurs in the in an inflammasome when there is a recognition of a PAMP

a variety of inflammatory diseases

mutations in NLR are linked to what?

nucleotide oligomerization domain (NOD) - like receptors

what does NOD-like receptors stand for

RIG1 (retinoic acid inducible gene 1) like helicase receptors

what does RLRs stand for

DSRNA to intiate transcription of antiviral genes

RLRs detect viral infections and are activated by what

type I interferons (IFNs)

RIG-1 activation in virus infected cells leads to the production and release of cytokines, particularly what?

interferes w viral replication

signals neighboring (uninfected) cells to beware

signals cells of immune system of viral infection

what do IFNs interfere with and/or signal

interferon induces changes in virus-infected cells that make them more susceptible to attack by NK cells

what occurs during the interferon response after RLR activation

scavenger receptors (SR)

phagocytic receptors found on myeloid cells, particularly macrophages, scavenge damaged molecules

have the ability to partner with various co-receptors

what do SRs have the ability to do that makes their responsiveness extremely versatile

homeostasis

apoptosis

inflammatory diseases

pathogen clearance

SR also involved in a wide range of processes such as…

SR (scavenger receptors)

which receptors can detect LPS of G- bacteria

kupffer cells in the liver

where are SRs rich

bacterial or viral DNA presence in cytoplasm binds to cGAS

GMP-AMP (c-GAMP) is generated

CGAMP binds to STING (stimulator for interferon genes), IFN produced

what occurs when CDSs are activated

a form of endocytosis whereby cells ingest large particles (>0.5 micrometers) into membrane bound vesicles (phagosomes)

what is phagocytosis

lysosomes

contents of phagosomes are targeted to ___________ for enzymatic degradation

macrophages, neutrophils, dendritic cells

what are dedicated ‘professional’ phagocytes

begin in bone marrow, mature to pro-monocytes that differentiate to monocytes

monocytes different into macrophages in tissues, are distributed throughout the body

where do macrophages begin in and mature

both pro-inflammatory and antimicrobial mediators

what do macrophages secrete

programmed cell death and combat pathogens that invade host cells

macrophages are long-lived cells, eliminate diseased and damaged cells through what

begin in bone marrow as myeloid progenitor cell, develops into mature neturophil in blood

where do neutrophils begin and mature

TNF-a

IL-6

IL-12

IL-1Beta

CXCL8

what cytokines, chemokines are released during the inflammatory response

increased vascular permeability, enhanced phagocytosis, increase in temperature, immune cells recruited

what occurs after release of inflammatory cytokines and chemokines

neutrophils (presence in immune response is critical) and

antimicrobial plasma proteins

during inflammation, the increase in vascular permeability draws in what

macrophage

when called upon by ____________, neutrophils leave blood stream and enter infected tissue

arrival of neutrophils

what is the beginning of the inflammatory response

neutrophils move from the blood into tissues, infiltrate into infected tissues

neutrophils accumulate at sites of infection where they phagocytose microbes within minutes

large pathogens require additional efforts

what occurs during neutrophil migration

swarm-like migration patterns of neutrophils have been detected in tissues

intercellular communication among neutrophils amplifies their recruitment; they are able to self-organize into a swarm

what occurs during neutrophil swarming

large fungi or clusters of bacteria

when neutrophils encounter ____________ that are too large for individual neutrophils to kill, a process known as swarming occurs

scouting/initiation

recruitment amplification

added amplification via intracellular signaling

stabilization/equilibrium

resolution

neutrophil swarming occurs in phases. what are they?

neutrophils activated by a signal (PAMP/DAMP) during random migrations

initially (5-15 min after injury/infection) only few individual neutrophils close to the damage site respond

these pioneer cells switch from random motility to directed migration toward the injury

what occurs during scouting/initiation

exponential growth of the swarm

activated neutrophils release cytokines, chemokines that direct the migration of additional neutrophils

what occurs during recruitment/amplification

neutrophils release secondary amplified intracellular signal to bring more distant neutrophils to the swarm

population keeps moving towards the center

what occurs during added amplification via intracellular signaling

crowding neutrophils congregate tightly to form stable, protective seal over the damaged/infected area

pathogen removal and tissue reconstruction

what occurs during stabilization/equilibrium

cellular debris is being cleared away, inflammatory chemokines degraded

immune cells undergo apoptosis or migrate away

what occurs during resolution

these join the swarm along its exterior

they clear away cell debris including dead, spent neutrophils

monocytes, macrophages inolved in initiating neutrophil clustering do what?

dead neutrophils

____________ contribute to the formation of pus in wounds/infections

extravasation

how do neutrophils get from the bloodstream to the site of infection

drawing out of neutrophils from circulation to site of infection

rolling adhesion, tight binding, diapedesis, migration

what is extravasation, what processes are involved

• macrophages, mast cells activated and release cytokines (IL-8)

• TNFalpha and IL-beta also released by activated macrophages increase adhesiveness of endothelial cell lining blood vessel closest to infection site

• selectins allow neutrophils to slow down, roll along endothelial cell walls

• integrins allow neutrophils to stop so they can squeeze through endothelium, travel to infection site (diapedesis)

what are the steps in extravasation

monocyte chemotactic protein 1/monocyte chemoattractant protein (MCP-1, CCL2)

what protein(s) intiates monocyte movement from bloodstream to tissue (monocyte recruitment)

remove battle weary neutrophils and tissue debris

macrophages pathogen as well as ____________ - to promote wound healing

to induce inflammation

what is the overall effect of the innate response

accumulation of fluid, plasma proteins, WBC

what accumulates at or near site of infection or injury