Innate Immunity Flashcards
sort these into intrinsic or innate immunity:
a. autophagy
b. NK cells
c. apoptosis
d. complement system
e. microRNAs
f. APC
g. neutrophils
h. cytokines
intrinsic immunity (always present): autophagy, apoptosis, microRNAs
innate immunity (rapidly induced): NK cells, complement system, APCs, neutrophils, cytokines
what are used to recognize pathogens in innate immunity?
PAMPs: pathogen-associated molecular patterns
or
DAMPs: damage-associated molecular patterns
recognized by PRR (pattern recognition receptors)
identify the microbe type associated with the following PAMPs:
a. ssRNA
b. CpG (dinucleotide)
c. pilin
d. LPS (lipopolysaccharide)
e. mannan
f. dsRNA
g. flagellin
h. lipoteichoic acid
a. ssRNA - virus
f. dsRNA - virus
b. CpG - virus, bacteria
c. pilin - bacteria
g. flagellin - bacteria
d. LPS - gram NEG bacteria
h. lipoteichoic acid - gram POS bacteria
e. mannan - fungi, bacteria
heat-shock proteins (HSPs) are an example of ____
stress-induced proteins, type of DAMP (damage associated molecular pattern) that is recognized by innate immunity
what kinds of pathogens are recognized by the following families of PRR (pattern recognition receptors)?
a. TLR (toll-like receptor)
b. C-type Lectin Receptor (CLR)
c. RIG-like receptors (RLR)
d. NOD-like receptors (NLR)
membrane:
a. TLR - diverse
b. CLR - fungi, bacteria (polysaccharides)
cytoplasm:
c. RLR - virus RNA
d. NLR - bacteria (peptidoglycans, toxins)
what type of pattern recognition receptor family recognizes viral RNA and where are they found
RIG-like receptors (RLR), found in cytoplasm
(Rig for Rna)
what family of pattern recognition receptors recognize fungi and where are they found?
C-type Lectin Receptors (CLR), found on membrane (also recognize bacteria)
what family of pattern recognition receptors recognize gram +/- bacterial peptidoglycans and toxins, and where are they found?
NOD-like receptors (NLR), found in cytoplasm
what are the circulating effector cells of innate immunity? (4)
- neutrophils
- macrophages (also cytokine secretion)
- NK cells (also macrophage activation) - exteacellular killing
- dendritic cells (also cytokine secretion)
*all partake in phagocytosis or cell killing, plus added functions in parenthesis
what are the circulating effector proteins? (2)
- complement - microbe killing, opsonization, leukocyte activation
- mannose-binding lectin (collectins) - opsonization, complement activation
what do TLRs on the plasma membrane vs in the endosome recognize? (use your reasoning)
TLRs on PM recognize bacterial components (lipopeptides, LPS, flagellin)
TLRs in endosome recognize viral components (dsRNA, ssRNA, CpG DNA) - viruses infect cells from the inside
TLR activation leads to a signaling/phosphorylation cascade and activation of transcription factors. Two of these are IRFs and NF-kB - contrast the effect of these
IRFs (interferon response factors) —> expression of Type I and III interferon genes (main antiviral genes) —> secretion of IFN (interferons) —> antiviral state and stimulation of adaptive immunity
NF-kB —> expression of pro-inflammatory genes (cytokines, chemokines, endothelial adhesion molecules) —> acute inflammation and stimulation of adaptive immunity
what is the effect of NF-kB (transcription factor)
expression of pro-inflammatory genes:
- cytokines (IL-1, TNF, IL-6)
- chemokines
- endothelial adhesion molecules
leading to acute inflammation and stimulation of adaptive immunity
what is the effect of active IRF transcription factors
IRF = interferon response factors
—> expression of Type I and III interferon genes, secretion of interferons (IFNs)
—> antiviral state and stimulation of adaptive immunity
_____ are responsible for inducing antiviral state
_____ is responsible for causing acute inflammation
*both stimulate adaptive immunity
IRFs (interferon response factors) - induce antiviral state
NF-kB - causes acute inflammation
these proteins bind specific cell-surface receptors of target cells, and can cause a variety of effects including proliferation, differentiation, activation, chemotaxis, inactivation
what are?
cytokines
categorize the following cytokines as pro inflammatory, chemotactic, or antiviral:
a. IL-1
b. IL-8
c. Type I IFN-alpha/beta
d. Type III IFNs
e. IL-6
f. TNF-alpha
pro inflammatory: IL-1, IL-6, TNF-alpha
chemotactic: IL-8
antiviral: Type I and III IFNs
name 3 important pro inflammatory cytokines
IL-1, IL-6, TNF-alpha
what are the important antiviral cytokines?
Type I and III interferons (IFNs)
how are neutrophils activated
neutrophils: predominant WBC (short lifespan), phagocytic (via enzymes), first cell to enter site of acute inflammation
respond to chemotaxis, activated by pro-inflammatory cytokines - TNF-alpha, IL-1 produced by macrophages or endothelial cells
[neutropenia (neutrophil deficiency) can accompany infections, cancer treatment, etc]
how are macrophages activated?
in response to inflammation - IFN-y (gamma) and T cell cytokines, PAMPs and complement receptors on macrophage cell surface
functions: phagocytosis, cytokine production, APC
note that monocytes (immature macrophages) can be phagocytic themselves
how are NK cells activated (2)? what is their response (2)?
activated by:
1. Type I and III IFNs (antiviral cytokines) from virus-infected cells
2. LPS (bacteria)
response:
1. cytokine production: IFN-y (gamma) —> macrophages activation
2. cell apoptosis (Fas/FasL or perforin/granzyme system)
These cells, referred to as “large granular lymphocytes,” have receptors that are gene-encoded without rearrangement. What are?
Natural killer (NK) cells
activated by Type I and III IFNs (viral) and LPS (bacterial)
leave blood to infection site (chemotactic)
what are the 2 responses of activated NK cells? (be specific with molecules involved)
- cytokine production: IFN-y (gamma) —> macrophage activation
- apoptosis via:
a. Fas (target) / FasL/ligand (NK) interaction
b. perforin/granzyme system
describe the balance of inhibitory/ activating signaling to NK cells
inhibitory receptors: recognize normal MHC expression on healthy cells (viral-infected or cancer cells may be deficient in MHC I)
activating: recognizing stress molecules (carbs or proteins)
most effective APC
dendritic cells
2 classes: myeloid (bone marrow, tissue resident), plasmacytoid (periphery, spleen)
*some DC cells can be immunosuppressive rather than immunoactivating - prevents immune response from getting out of control
differentiate between myeloid DC (mDC) and plasmacytoid DC (pDC)
mDC: bone marrow/tissue resident, produce IL-12, express TLR2/4, effective in APC, mostly for bacteria/fungi
pDC: periphery/spleen, express TLR7/9, produce antiviral IFNs (Type I and III) —> critical for antiviral response!
what type of DC cells are critical for antiviral response?
plasmacytoid DC (pDC): periphery/spleen, express TLR7/9 (HIGH levels), produce Type I and III IFNs (antiviral)
complement proteins are produced primarily in the ___
liver
present in high concentrations in blood
synthesis begins in 1st trimester of embryo
what are the outcomes of macrophage activation (give 4)?
- cytokine production (TNF, IL-1, IL-6, IL-12) —> inflammation and increased MHC/HLA II expression (induces adaptive immunity)
- ROS —> kill microbe
- nitric oxide —> kill microbe
- phagocytosis —> kill microbe
how do macrophages induce the adaptive immune system?
cytokine secretion (TNF, IL-1, IL-6, IL-12) increases inflammation and causes increased expression of MHC/HLA II —> activates adaptive immunity
what type of DC cell is important for bacterial and fungal response, and is very effective in acting as an APC?
myeloid DC (mDC): produce IL-12, express TLR2/4
found in bone marrow, tissues
opsonization
“tagging” bacteria for other elements of immune system
occurs via complement system
what are the 3 pathways of the complement system
- alternative: spontaneous C3 activation and binding to pathogen
- mannose-binding lectin pathway: binging MBL to mannose on pathogen
- classical: antibody binds pathogen, complement binds Ab
*all lead to proteolytic cascade, activation of C3–>C3b + C3a
leading to opsonization, MAC assembly, chemotactic fragment release
where do the 3 complement pathways (alternative, mannose-binding lectin, and classical) converge?
and what are the 3 outcomes of this?
3 pathways cause proteolytic cascade leading to C3 being cleaved into C3b (large fragment) and C3a (small fragment)
C3b binds pathogen, C3a is chemotactic (attracts WBC)
outcomes:
1. opsonization
2. MAC (membrane attack complex) assembly
3. release of chemotactic fragments
contrast roles of C3b and C3a fragments in complement pathway
3 pathways (alternative, mannose-binding lectin, and classical) converge on proteolytic cascade that cleaves C3 into C3b and C3a
C3b binds pathogen, C3a is chemotactic
downstream effects:
1. opsonization
2. MAC assembly (C5-C9)
3. chemotactic fragments (C3a, C5a)
the 3 pathways of the complement system converge on C3–> C3b + C3a cleavage
what are the 3 effects of this and ultimate outcome of these?
- opsonization —> phagocytosis
- MAC assembly (macrophage attack complex) —> lysis
- chemotactic factor release (C3a, C5a) —> WBC recruitment, degranulation of mast cells
in the alternative complement pathway (spontaneous C3 activation and C3b binding to pathogen), fill in the following:
1. recruit ___ and cleave it to ___
2. _____ acts as a more efficient protease and amplifies breakdown of C3 into C3b
3. complex of C3bBb3b is now termed ___ and is broken down by _____
4. large and small fragment, ____ fragment is chemotactic
….
5. downstream effects (opsonization, MAC, chemotactic fragments)
in the alternative complement pathway :
1. recruit B and cleave it to Bb
2. C3 CONVERTASE acts as a more efficient protease and amplifies breakdown of C3 into C3b
3. complex of C3bBb3b is now termed C5 and is broken down by C5 CONVERTASE
4. large and small fragment, C5a fragment is chemotactic (more so than C3a)
….
5. downstream effects (opsonization, MAC, chemotactic fragments)
during late steps of the complement pathway, opsonization of pathogens occurs largely via coating by ____
C3b is very important for coating pathogens in opsonization
which chemotactic fragment of the complement system is more effective, C3a or C5a?
C5a
in both the mannose-binding lectin pathway and classical pathway of the complement system, fill in the blank:
1. recruit and cleave _____, then _____
2. ____ acts as a more efficient protease, amplifying cleavage of C3 to C3b + C3a
3. ____ forms, and is cleaved by _____
4. large and small fragment, ____ is chemotactic
…
5. downstream effects (opsonization, MAC, chemotactic fragments)
in both mannose-binding lectin pathway and classical pathway of the complement system:
1. recruit and cleave C4–>C4b, then C2->C2a
2. C3 CONVERTASE acts as a more efficient protease, amplifying cleavage of C3 to C3b + C3a
3. C5 forms, and is cleaved by C5 CONVERTASE
4. large and small fragment, C5b is chemotactic (more so than C3a)
…
5. downstream effects (opsonization, MAC, chemotactic fragments)
How do the following 4 plasma proteins protect self against the complement system:
A. C1-INH
B. Factor I
C. Factor H
D. C4BP
- C1 inhibitor (C1-INH): inhibits C1 protease
- Factor I (FI): cleaves, inactivates C3b and C4b
- Factor H (FH): causes disassociation of C3 convertase of alternative pathway
- C4 binding protein (C4BP): causes dissociation of C3 convertase in classical pathway
why are Factor I and Factor H important? What do they do?
prevent self cells being killed by complement system
Factor I: cleave, inactivate C3b, C4b
Factor H: dissociates alternative pathway C3 convertase
what two plasma proteins are needed to cause dissociation of C3 convertase from the classic and alternative complement pathways, respectively?
C4 binding protein (C4BP): dissociation of classical pathway C3 convertase (C4 = Classical)
Factor H: dissociation of alternative pathway C3 convertase
what are the purposes of the following proteins?
a. MCP/CD46
b. DAF/CD55
c. CD59
d. CR1, CD35
all are membrane proteins that protect self from complement system
a. MCP/CD46: membrane cofactor protein, cofactor for Factor I (plasma protein) mediated cleavage of C3b and C4b
b. DAF/CD55: decay accelerating factor, blocks formation of C3 convertase
c. CD59: prevents C9 binding and formation of MAC
d. CR1, CD35: Type I complement receptor, dissociates C3 convertase
what combination of plasma protein and membrane protein is required for cleavage and inactivation of C3b and C4b, in order to prevent self harm from complement system?
Factor I (plasma protein) and MCP/CD46 (membrane protein)
this membrane protein prevents C9 binding to and formation of MACs, helping prevent self harm from complement system. what is?
CD59
which of these pathways of the complement system are at default OFF?
a. alternative
b. mannose-binding lectin
mannose-binding lectin pathway is OFF by default, requires activation
alternative system is on/active by default [Alternative = Active]
what occurs from a C3 deficiency?
predisposition to severe infections (pneumococcal pneumonia, meningococcal meningitis)
*remember that C3 is a protein of the complement systems that gets proteolytically cleaved into C3b + C3a
what occurs from a C5-C8 deficiency? Why?
infections from Neisseria baceteremia, among other infections
C5-C8 are needed for MAC formation (complement system direct killing of pathogens), which is not used often, but especially important against Neisseria bacteria because it has thin walls and no glycocalyx
A patient presents with a Neisseria bacteria infection. Their PMHx reveals frequent infections by the same bacteria. What proteins in their complement immune system may be deficient?
C5-C8, because these are important for MAC (membrane attack complex) formation, which is not utilized often but very important against Neisseria bacteria, which have thin walls and no glycocalyx
can deficiencies in the complement system be associated with autoimmune disease?
yes! because the complement system is also important for recognizing products of cellular damage, which it tags for degradation by macrophages
in absence, can get a buildup of self cellular products which can overwhelm immune system and cause autoimmunity
what do TLR7/9 on pDC and monocytes, and RIG-1 receptors (widespread) have in common?
(what is their purpose)
virus PRRs (pattern recognition receptors)
what is the primary antiviral response? what 2 classes of proteins are involved? contrast their purpose/role
primary antiviral response: antiviral cytokines
- Type I IFNs: produced by virus-infected cells and pDCs, global/systemic defense (act on almost all nucleated cells - widespread receptor expression)
- Type III IFNs: produced by many cell types including pDCs, targeted/specialized defense for mucosal/barrier surfaces (restricted expression of IFN-lambda receptor)
describe Type I IFNs as part of the primary antiviral response
Type I IFNs:
- 17 species (mostly IFN-alpha/beta)
- produced by viral infected cells, pDCs
- global/systemic defense - widespread receptor expression for Type I IFNs
describe Type III IFNs as part of the primary antiviral response
Type III IFNs:
- 4 types (IFN-lambda 1-4)
- produced by many cells, including pDCs
- targeted response - IFN-lambda receptor expression restricted to epithelial and mucosal cells
*note that Type III IFNs can be PRODUCED by many cell types but only ACT ON epithelial/mucosal cells
Type I and III IFNs are important for the primary antiviral response. Match each of these features with either Type I or Type III IFNs:
a. more types, mostly IFN-alpha/beta
b. targeted/specialized defense
c. global/systemic defense
d. receptor expression restricted to epithelial and mucosal cells
Type I IFNs:
a. more types, mostly IFN-alpha/beta
c. global/systemic defense
Type III IFNs:
b. targeted/specialized defense
d. receptor expression restricted to epithelial/mucosal cells (IFN-lambda)
name 4 effects of interferons (in general)
- antiviral state induction
- apoptosis of infected cells
- NK cell activation (enhanced detection and killing)
- adaptive immunity activation - MHC induction, DC maturation, Th1 biasing, B-cell class switching
which of these are potential effects of interferons?
a. MHC induction
b. DC maturation
c. Th1 biasing
d. B-cell class switching
all of these !
interferons act as a bridge between innate and adaptive immunity
all of these effects are part of the overall effort to induce adaptive immunity
what are the major outcomes of innate immunity (as a whole) - name 3
- acute inflammation
- antiviral defense
- activate adaptive immunity
cytokine _____ release from macrophages activates NK cells, which produce _____
- macrophages recognize microbe via TLR or other receptors
- macrophage release IL-12, which activates NK cells
- NK cells produce IFN-gamma, which further activates macrophages
- macrophages release TNF-alpha, IL-1, IL-6, and more IL-12
NK cells kill cells which ____
lack MHC
cytokine that decreases inflammation:
a. IL-1
b. IL-8
c. TGF-b
TGF-b (transforming growth factor beta): down regulation of immune response
In a patient, the complement system can be activated by bacterial polysaccharides but not IgG. A molecular defect in this patient could be:
a. C1q
b. C3
c. C9
D. C6
a. C1q - start of classical pathway
(alternative pathway begins with binding microbe surface component like polysaccharides)
which of these can activate alternative pathway of complement system?
a. flagella
b. pili
c. membrane proteins
d. capsular polysaccharides
capsular polysaccharides
which complement protein assembles the MAC?
a. C1qrs
b. C2b (active)
c. C3b (active)
d. C4b (active)
e. C5b (active)
C5b assembles MAC
a patient with viral infection experiences flu symptoms - what process is most responsible?
a. secretion of acute-phase proteins in the liver
b. release of histamines and leukotrienes by mast cells
c. secretion of cytokines by monocytes and T cells
viral infection —> secretion of IFN Type I and III (from monocytes and T cells)
