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Immunology > Week 9 > Flashcards

Week 9 Flashcards

1
Q

LPS is found in Gram positive or Gram-negative bacteria?

A

Gram-negative

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2
Q

What does lysozyme target?

A

B-(1,4) linkage between the two alternating sugars of peptidoglycan in bacterial cell walls. More effective against Gram-positive bacteria.

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3
Q

How does phospholipase A2 work?

A

Highly basic enzyme that can enter the bacterial cell wall and hydrolyze phospholipids in the cell membrane

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4
Q

Three classes of antimicrobial peptides

A

defensins, cathelicidins, and histadins

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5
Q

Defensins structure and function

A

Short peptides that are highly amphipathic, insert themselves into pathogen membranes

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6
Q

How is the lectin pathway of the complement system activated?

A

Recognition of carbohydrate structures on pathogens by mannose binding lectin (MBL) or ficolins. MASPs then cleave the initial complement protein.

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7
Q

C1 structure

A

One recognition protein (C1q) and two proteolytic proteins (C1r and C1s). This is the initial component of the classical activation pathway of the complement system.

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8
Q

C3 convertase

A

Critical component of complement activiation upon which all three activation pathways converge. C3 is cleaved into C3b, the main effector molecule of the pathway and C3a, which is inflammatory.

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9
Q

C3b

A

Forms a covalent bond to microbial surface and is recognized by complement receptors on phagocytes.

Can also bind to C3 convertases of the lectin and classical pathways to create a C5 convertase

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10
Q

C5 convertase

A

Created by the binding of C3b to C3 convertase. Results in the cleaving of C5 into C5a (highly inflammatory) and C5b, which initiates MAC formation.

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11
Q

Differences in glycans in fungi and vertebrates

A

glycans from fungi terminate in a mannose, while vertebrate glycans terminate in sialic acid.

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12
Q

Mannose binding lectin structure

A

Consists of a amino-terminal collagen-like domain and a carboxy-terminal C-type lectin domain.

Trimers are formed by the formation of a triple helix of the collagen-like domains. These further form oligomers of 2-6 trimers in blood, which has very high binding avidity for mannose-containing glycans.

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13
Q

ficolins structure

A

Similar to structure of MBL, although they employ a fibrinogen-like domain rather than a lectin domain. They recognize oligosaccharides containing acetylated sugars

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14
Q

How does MBL activate complement?

A

When in circulation, it is assocaited with zymogens of inactive mannose-assocaited serine proteases (MASPs). Upon binding to pathogen surface, MASP-1 cleaves and activates MASP-2, which can then cleave C4 and C2.

C4b binds covalently to pathogen surface, and binds C2, which is afterwards cleaved by MASP-2. This C4b2a complex is the C3 convertase for the lectin pathway

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15
Q

C4b2a

A

C3 convertase of the lectin and classical pathway. Formed by the cleaving of C4 by MASP-2 of bound MBL or ficolin, from which C4a binds to the pathogen surface. C2 subsequently binds to the bound C4a and is cleaved by MASP-2.

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16
Q

How is C4 activation limited to the pathogen surface?

A

C4 cleavage exposes the thioester bond of C4b, which is rapidly hydrolyzed in the presence of water, so the protein is inactivated if not immediately bound to pathogen surface.

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17
Q

alternative pathway C3 convertase

A

C3bBb, formed when C3b binds to factor B in plasma, which is further cleaved by factor D to form Bb and Ba.

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18
Q

C3 ‘tickover’

A

spontaneous hydrolysis of C3 in plasma that forms C3(H20). This may be subsequently bound to factor B and further cleaved by factor D to form fluid-phase C3 convertase C3(H20)Bb, which can cleave many molecules of C3, although the vast majority of the resulting C3b will be inactivated by hydrolysis.

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19
Q

properdin

A

Also known as factor P. Stabilizes the C3bBb complex on microbial surfaces and is released by neutrophils.

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20
Q

CR1 (CD35)

A

Recognizes C3b and C4bi. Promotes both of their decay if they bind to cell surface. In the presence of C5a, it can stimulate phagocytosis.

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21
Q

CR2 (CD21)

A

Recognizes C3d, iC3b, and C3dg. Enhances B cell response to antigens coated with C3 components.

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22
Q

CR3 (CD11b:CD18) (Mac-1)

A

Recognizes iC3b. stimulates phagocytosis.

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23
Q

CD88

A

C5a receptor. Activates neutrophils, macrophages, etc.

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24
Q

C1 inhibitor (C1INH)

A

Binds C1 complex or MBL and dissociates the proenzymes (C1r/s or MASPs) from the complex.

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25
Q

C4-binding protein

A

Displaces C2a from C4 and promotes the inactivation of C4 by factor I.

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26
Q

Carboxypeptidase N

A

Inactivates C3a and C5a (inflammatory components of the complement system)

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27
Q

Factor I

A

Serine protease that cleaves C3b and C4b into inactive forms.

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28
Q

Main transcription factors downstream of TLR signaling

A

IRFs, NFkB, AP-1

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29
Q

Why is TLR4 unique in TLR signaling?

A

It uses both TRIF and MyD88 to signal. This allows for two phases of signaling - MyD88 dependent on cell surface and the second is dependent on TRIF. MyD88 will give you NFkB dependent IL6, but TRIF will give you a type I interferon response as well

30
Q

What are four properties of PAMPs?

A

Produced by pathogens but not by self
Evolutionarily conserved molecular patterns
Shared by large groups of microorganisms
Often represent a ‘class’ of invading pathogen.

31
Q

What engages the production of ‘second signal’ for DCs?

A

Engagement of PRRs (like TLRs) by PAMPs

32
Q

How was the first TLR discovered?

A

First discovered by Janeway in 1997, a homolog Toll was found in Drosophila to be important in protection against pathogenic fungi - production of AMP called Drosomycin

33
Q

How was the signaling function of TLRs worked out?

A

Receptor was created that was extracellularlly CD4, but intracellularly had the signaling domain from TLR4. anti-CD4 antibodies were used to cross-link them and looked for expression of proinflammatory genes via PCR (Janeway) (IL-1, IL-8, IL-6, and B7.1). Also used a NFkB reporter cell line.

34
Q

What do TLR2 heterodimers recognize?

A

TLR2:TLR-6 recognizes diacyl lipopeptides
TLR2:TLR1 recognizes triacyl lipopeptides

35
Q

What are the cell membrane TLRs?

A

TLR2:TLR6, TLR2:TLR1, TLR-5, TLR-4

36
Q

What are the endosomal TLRs and what are they specific for?

A

TLR-3 (dsRNA), TLR-7 (ssRNA), TLR-8 (ssRNA), TLR9 (CpG DNA)

37
Q

What are the three groups of transcription factors that TLR signaling converges on?

A

Interferon regulatory factors (IRF3/IRF7), NFkB, AP-1

38
Q

What are upstream of IRFs, NFkB and AP-1?

A

MAPK upstream of AP-1
IKKB and NEMO upstream of NFkB
IKKe and TBK1 upstream of IRFs (downstream of TRIF (mostly))

39
Q

Which TLRs use TRIF adaptor protein?

A

TLR3 and endosomal TLR4

40
Q

What are the differences mostly for MyD88 and TRIF signaling?

A

MyD88 mostly leads to proinflammatory (IL1B, IL6);

TRIF leads to IFNB (type 1 interferon)

41
Q

What are the two sorting adaptors for TLRs and what do they do?

A

TIRAP/MAL (for MyD88) and TRAM (for TRIF).

The sorting adaptors recruit the signaling adaptors

Sorting adaptors are mostly used by cell surface TLRs, we are not sure why

42
Q

What part of LPS is recognized by TLR4?

A

Lipid A portion that has six repetitive acyl chains. These fit into MD2 adaptor as a burger into a bun

Some bacteria can become tetra-acylated to avoid TLR4 stimulation

43
Q

How does TLR-2 signaling work?

A

TLR-2 will dimerize with either TLR-6 or TLR-1 upon binding to diacyl or triacyl lipoproteins. This binding leads to their dimerization and the bringing together of their signaling domains.

44
Q

What is the most critical amino acid for TIR signaling?

A

A proline at position 712. This is highly conserved. It is mutated to a histidine in C3H mice, which is basically a TLR4 KO

45
Q

Where does the dimerization of TLR TIR domains occur

A

in the “BB” loop

46
Q

How do TIR domains work?

A

TIR domains bind to one another through the BB loop. For example, the TIR domain of a TLR will recognize the TIR domain of MyD88 to associate the signaling adaptor with the intracellular portion of the TLR.

47
Q

How do sorting adaptors work?

A

They sense changes in the composition of the plasma membrane that occur as a result of TLR activation (PIP2-rich regions) and bind and recruits MyD88, all through TIR domains.

48
Q

How does CD14 work?

A

When membrane-bound, CD14 will take LPS bound to LBP from the EC environment and transfer it to MD-2 on TLR4. It has no intracellular signaling domain.

49
Q

How is PIP2 enriched in the plasma membrane in TLR4 signaling?

A

CD14 engagement leads to PIP2 in the plasma membrae

50
Q

What are the two waves of TLR4 signaling?

A

First wave is at the cell membrane, signals through MyD88 and leads to endocytosis. The second wave is in an endosome and signals through TRIF, leading to IFNB production.

51
Q

What are the general steps of TLR activation signaling?

A

1) Dimerization of TLR upon ligand recognition
2) TIR domain interactions (MyD88, sorting adaptors)
3) Kinase activation
4) Kinase will then phosphorylate a transcription factor

52
Q

What is downstream of MyD88?

A

IRAK1 and IRAK4 (kinases) (phosphorylates IRF7)

53
Q

What is downstream of TRIF?

A

TRAF3

54
Q

How does Rheumatoid factor lead to inflammation?

A

RF is an autoantibody against self DNA/histones. These bind as immune complexes to Fc receptors and are endocytosed, leading to TLR7 signaling.

55
Q

How is TLR7/9 prevented from recognizing self-nucleic acids?

A

They require the acidic environment of the endolysosome to be activated by proteases

56
Q

What are the four types of intracellular signaling domains used by C-type lectin receptors?

A

hemi-ITAMs, ITAM-coupled, ITIMs, and ITAM-ITIM independent

57
Q

What kinase is recruited to ITAM and ITIM domains?

A

Syk

58
Q

What are cytosolic sensors (PRRs), Adaptors, and Effectors?

A

Sensors: AIM2, IFI16/p204, NLRs (NLRP3,6,7,1, and NAIP)
Adaptors: ASC (PYD-CARD) and NLRC4
Effectors: Caspases (1/4/5/11)

59
Q

Caspase 1

A

Cysteine protease.

60
Q

How does ASC work?

A

ASC has a PYD domain and a CARD domain. It interacts with the PYD domain on activated Nlrp3/1, and recruits caspase-1 through it’s CARD domain. Thus, it is a PYD-CARD bridge between the PYD-containing Nlrp3/1 and the CARD-containing Caspase-1.

This also works for signaling through the PYD domain of AIM2, which recognizes DNA

61
Q

Why is nlrp4 considered a sensor and an adaptor protein?

A

NLRP4 has its own CARD domain, and thus does not require ASC to engage caspase-1 (ASC-independent)

62
Q

What is the noncanonical caspase?

A

Caspase-11 (mouse). Can be directly activated by cytosolic components (cytoplasmic LPS)

63
Q

What does NLRP3 sense?

A

Potassium influx

64
Q

What does NLRP4 sense?

A

Lethal toxin of anthrax

65
Q

What does NLRC4 sense?

A

Flagellin or T3/4SS

66
Q

What does AIM3 sense?

A

DNA in the cyotosol

67
Q

What sensors recognize RNA in the cytosol?

A

MDA5 recognizes longer dsRNA, and RIG-I recognizes 5’triphosphate capped dsRNA. MAVs is the adaptor for both of these receptor, which leads to IRF3/7 and T1 interferons (alpha and beta)

68
Q

cGAS

A

cyclic GMP AMP synthase. Senses cytosolic DNA. Adaptor for cGAS is STING.

69
Q

Adaptors for cytosolic nucleic acid sensors

A

cGAS - STING
AIM2 - ASC
MDA5/RIG-1 - MAVs

70
Q

What is the general pathway for cGAS activation?

A

Sensing of dsDNA leads to cGAS-production of cGAMP from ATP and GTP. cGAMP binds to STING dimer present on ER membrane activate its signaling. STING activates the kinase TBK1 to phosphorylate IRF3, which enters the nucleus, TADA!

71
Q

Domains of NLRP1

A

amino-terminal PYD, a NOD, LRRs, a FIIND, and a carboxy-terminal CARD.

Immunology (17 decks)

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