Block B lecture 1 Flashcards

1
Q

what is the immune system ?

A

this is the tissues, cells and molecules that protect the body from infection.

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2
Q

what is the innate immunity ?

A

the early phase of the host response activated first when exposed to a pathogen

  • Present in all individuals at all times
  • Does not increase with repeated exposure to a pathogen, always the same response.
  • Discriminates between groups of pathogens, rather than closely related individual pathogens.
  • Predates separation of animal and plant lineages
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3
Q

what is the adaptive immunity ?

A

is generated by specific lymphocytes

  • Discriminates between individual pathogens even if they are extremely closely related
  • is associated with “immunological memory”, when exposed to the same pathogen for a second time this provides a quicker response that is more efficient.
  • It appears abruptly in evolution in the cartilaginous fishes such as sharks and sting rays.
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4
Q

what is the first line of defence ?

A

The first is the anatomic barrier provided by the body’s epithelial surfaces which act as a physical barrier to prevent pathogen infection.

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5
Q

2nd ?

A

various chemical and enzymatic systems, including complement, act as an immediate antimicrobial barrier near these epithelia, these will come into effect if the first barrier is breached. C3 is part of the complement system.

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6
Q

if the epithelial are breached then what occurs to provide a rapid cell mediated defence ?

A

nearby various innate lymphoid cells can coordinate a rapid cell-mediated defence. This includes macrophages, granulocytes and NK cells.

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7
Q

inflammatory inducers ?

A

are chemical structures that indicate the presence of invading microbes or the cellular damage produced by them. Bacterial lipopolysaccharides are produced by gram negative bacteria cells, this is a host defence that activates an immune response. When ATP is present this activates the immune response as it is normally found within a cell not out with it.

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8
Q

sensor cells ?

A

include macrophages, dendritic cells and neutrophils which detect these inducers by expressing various innate recognition receptors, and in response produce a variety of mediators that act directly in defence or that further propagate the immune response.

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9
Q

what do the PRR’s of the innate system do ?

A

he pattern recognition receptors (PRRs), detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). The binding of the PAMP to the PRR activates the immune response.

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10
Q

mediators ?

A

include many cytokines, and they act on various target tissues, such as epithelial cells, to induce antimicrobial proteins and resist intracellular viral growth to protect from viral infection; or on other immune cells, such as innate lymphoid cells (ILCs) that produce other cytokines that amplify the immune response.

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11
Q

the response to an initial infection occurs in three phases , what are these ?

A

These are the innate phase, the early induced innate response, and the adaptive immune response.

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12
Q

what do the first 2 phases rely on ?

A

The first two phases rely on the recognition of pathogens via pathogen-associated molecular patterns (PAMPs) by germline-encoded receptors of the innate immune system – pathogen recognition receptors (PRRs).

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13
Q

what does the adaptive immunity rely on ?

A

adaptive immunity uses variable antigen-specific receptors that are produced as a result of gene segment rearrangements.

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14
Q

why does adaptive immunity occur 96 hours after the infection ?

A

because the rare B cells and T cells specific for the invading pathogen must first undergo clonal expansion after recognition of the pathogen before they differentiate into effector cells that migrate to the site of infection and clear the infection. The effector mechanisms that remove the infectious agent are similar or identical in each phase.

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15
Q

what do most antimicrobial agents require to be done before they work ?

A

The innate immune system contains several proteins that are lethal for microorganisms. These are secreted by cells such as epithelial cells and phagocytic cells and are usually made as inactive proproteins that require a proteolytic step to complete their activation, whereupon they become capable of killing microbes by forming pores in the microbial cell membranes.

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16
Q

mucins ?

A

found in mucus that may prevent adhesion to epithelium by microorganisms to prevent receptor binding.

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17
Q

lysozyme

A

glycosidase (sugar cleaving enzyme) that attacks peptidoglycan in bacterial cell wall to degrade it.

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18
Q

defensins

A

disrupt cell membranes of bacteria and fungi via pore formation.

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19
Q

cathelicidns

A

disrupt cell membrane of wide range of microorganisms.

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20
Q

histatins

A

active against pathogenic fungi normally in the oral cavity.

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21
Q

RegIII family

A

C-type lectins which are sugar binding, which target peptidoglycans, promoting pore formation.

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22
Q

describe the structure of beta 1 defensins

A

It is composed of a short segment of an alpha helix (yellow) resting against three strands of antiparallel b sheet (green) generating an amphipathic peptide with charged and hydrophobic residues residing in separate regions.

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23
Q

what does this allow ?

A

allows the defensin to interact with the charged surface of the cell membrane and become inserted in the lipid bilayer (top right panel). A transition in the arrangement of the defensins in the membrane then leads to the formation of pores and a loss of membrane integrity (bottom right panel) in the bacterial cell wall.

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24
Q

there are over 30 different plasma proteins that make up the complement system , where are most of them produced ?

A

mainly the liver

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25
Q

describe complement activation ?

A

In the presence of pathogens (or antibodies bound to pathogens) the complement system becomes activated. Complement activation results in inflammation, phagocytosis and microbe destruction via membrane attack and pore formation. Activation follows interaction of complement proteins with soluble receptors (shown in red above) that recognize molecules/structures on microbial surfaces.

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26
Q

mannose binding lectin ?

A

recognise sugars, such as mannose; fructose which are expressed on the surface of a pathogen.

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27
Q

ficolin ?

A

recognises oligosaccharides containing acetylated sugars

28
Q

C reactive proteins

A

recognises phosphorylcholine.

29
Q

what does Mannose binding lectin and ficolins form complexes with ?

A

form complexes with serine proteases and recognize particular carbohydrates on microbial surfaces. Three MBL monomers associate to form a trimer (top left panel) and between two and six trimers assemble to form a mature MBL molecule (bottom left panel). An MBL molecule associates with MBL-associated serine proteases (MASPs), which are involved in the complement activation process, and recognizes mannose or fucose residues in a particular spatial arrangement found on microorganisms. The ficolin’s (right hand panels) have similar structure and function but recognize different sugars.

30
Q

what is the distribution of antigen receptors in the adaptive and innate immunity ?

A

Antigen receptors of the adaptive immune system are clonally distributed on individual lymphocytes and their progeny. Typically, receptors of the innate immune system are expressed non-clonally, that is, they are expressed on all the cells of a given cell type.

31
Q

what is the exception of NK cells ?

A

NK cells express various combinations of NK receptors from several families, making individual NK cells different from one another. A particular NK receptor may not be expressed on all NK cells.

32
Q

explain the Tol like receptors ?

A

The Toll-like receptors (TLRs) are an important family of PRRs present on macrophages, dendritic cells, and other immune cells. TLRs recognize different microbial components; for example, a heterodimer of TLR-1 and TLR-2 binds certain lipopeptides from pathogens such as Gram-positive bacteria, while TLR-4 binds both lipopolysaccharides from Gram-negative and lipoteichoic acids from Gram-positive bacteria.

33
Q

C type lectin family for example Dectin -1 ?

A

recognises beta-1,3-linked glucans, common components of fungal cell walls.

34
Q

mannose receptor ?

A

may recognise mannose-containing structures on pathogens but also plays a role in clearance of host proteins.

35
Q

scavenger receptor

A

structurally heterogenous, recognise various anionic polymers and acetylated low-density lipoproteins; may bind pathogen (e.g., bacterial cell wall) or host products.

36
Q

complement and Fc receptor

A

Complement recognise Complement-coated and Fc antibody-coated organisms.

37
Q

Toll like receptors

A

family of PRRs recognising molecular patterns not found in healthy vertebrate cells.

38
Q

how was the toll like receptor discovered ?

A

The receptor protein Toll was identified initially as a gene controlling the correct dorsal-ventral patterning embryo of the fruit fly Drosophila melanogaster. The role of Toll receptor in immunity was also discovered first in the fly.

39
Q

what TLR are heterodimer proteins ?

A

TLR-1:TLR-2 and TLR-6:TLR-2

40
Q

what allows ligand binding ?

A

TL-4 , MD-2 and CD14

41
Q

explain the lueicine rich repeats on TLR ?

A

TLRs are transmembrane proteins whose extracellular region contains 18–25 copies of a leucine-rich repeat (LRR) sequence.

42
Q

describe extracellular TLR

A

Some TLRs are located on the cell surface of dendritic cells, macrophages, and other cells, where they can detect extracellular pathogen molecules. TLRs are thought to act as dimers.

43
Q

TLR located intracellularly?

A

in the walls of endosomes, can recognize microbial components, such as DNA, that are accessible only after the microbe has been broken down or RNA, which is not usually present in endosomes in healthy mammalian cells.

44
Q

what does TLR 4 recognise ?

A

Lipopolysaccarhides in association with the accessory protein MD-2`

45
Q

cell signalling in mammalian TLR require 4 adaptor molecules , what are they?

A

MyD88
MAL ( TIRAP)
TRIF
TRAM

46
Q

what is the exception of TL-3 ?

A

All TLRs interact with MyD88, except TLR-3, which interacts only with TRIF

47
Q

what transcription factors does TLR signalling activate ?

A

transcription factor NF-kB, which induces the expression of pro-inflammatory cytokines. These cytokines require activation be enzyme caspase 1 in the cytoplasm

AP-1 which leads to cell proliferation and differentiation

IRF which is interferon regulation factor leading to interferons being produced.

48
Q

describe MyD88 ?

A

The MyD88 death domain is an adaptor protein that is associated with TLR. upon recognition of an antigen from a pathogen , the TLR will dimerise and the MyD88 adaptor protein recruits serine threonine kinases IRAK 1 and 4.

49
Q

TRAF 6 cooperation ?

A

IRAK 1 and IRAK 4 then leads to the recruitment of the E3 ubiquitin ligase called TRAF 6 . IRAK undergoes polyubiquitination , and leads to the phosphorylation of TRAF6 to activate the ligase activity. TRAF 6 then cooperates with E2 ligase and this recruits kinase TAK1.

50
Q

IKK gamma subunit ?

A

Tak1 then assocaites with the Ikk , this causes phosphorylation of IKKbeta and Ikbeta. This causes Ikb being degraded and NFkappaB is produced. This is a transcription factor that enters the nucleas , resulting in the generation of an RNA molecule , that once translated at the ribosomes result in pro inflammatory cytokines being released.

51
Q

TLR-3 and signalling ?

A

TLR-3 is found in the endosome of cells,such as dendritic cells and macrophages. It senses double- stranded viral RNA .

TLR-3 signalling uses the adaptor protein TRIF, which recruits the E3 ligase TRAF3 to generate K63-linked polyubiquitin chains. This scaffold recruits NEMO and TANK. These associate with the serine–threonine kinases IKKε (IκB kinase ε) and TBK1 (TANK-binding kinase 1). TBK1 phosphorylates (red dot) the transcription factor IRF3, and IRF3 then enters the nucleus and induces expression of type I interferon genes.

52
Q

TLR-7 ?

A

LR-7, expressed by plasmacytoid dendritic cells, detects single-stranded RNA (ssRNA) and signals through MyD88.

Here, IRAK1 directly recruits and phosphorylates IRF7, which is also highly expressed in plasmacytoid dendritic cells. IRF7 then enters the nucleus to induce expression of type I interferons.

53
Q

NOD like receptors ?

A

intracellular sensors of bacterial infection and cellular damage found in the cytoplasm

54
Q

CARD containing NOD like receptors ?

A

CARD (caspase recruitment domain) containing family members recognise bacterial cell-wall peptidoglycan fragments.

55
Q

NOD 1 sense ?

A

gamma -glutamyl diaminopimelic acid;

56
Q

NOD 2 sense ?

A

muramyl dipeptide

57
Q

what can occur to the CARD on NOD proteins to induce cell signalling ?

A

CARD on NOD proteins can dimerise with CARD on other proteins to induce cell signalling. The pyrine domain on the NLR wil bind to the pyrine of the adaptor protien

58
Q

once the intracellular NOD proteins sense bacteria what occurs ?

A

Intracellular NOD proteins sense the presence of bacteria by recognising bacterial peptidoglycan and activate NFkB to induce the expression of pro-inflammatory genes.

59
Q

what are the pyrin domains structurally related ?

A

related to CARD and TIR domains and interact with other pyrin domains.

60
Q

what is NLRP3?

A

Humans have 14 NLRs containing the pyrin domain and the best characterised is NLRP3.

61
Q

when are the NLRP members activated and what forms ?

A

response to pathogen or host-driven cellular damage.

They contribute to a multiprotein complex – “inflammasome” -that drives pro-inflammatory cytokine production and induces cell death

62
Q

describe the stages of inflammasome ?

A

Cellular damage activates the NLRP3 inflammasome to produce pro-inflammatory cytokines. The LRR domain of NLRP3 associates with chaperones (HSP90 and SGT1) that prevent NLRP3 activation. Damage to cells caused by bacterial pore-forming toxins or activation of the P2X7 receptor by extracellular ATP allows efflux of K+ ions from the cell; this may dissociate these chaperones from NLRP3 and induce multiple NLRP3 molecules to aggregate through interactions of their NOD domains (also called the NACHT domain)

63
Q

pro caspase 1 and NLRP3 ?

A

Reactive oxygen intermediates (ROS) and disruption of lysosomes also can activate NLRP3. The aggregated NLRP3 conformation brings multiple NLRP3 pyrin domains into proximity, which then interact with the pyrin domains of the adaptor protein ASC (PYCARD). This conformation aggregates the ASC CARD domains, which in turn aggregate the CARD domains of pro-caspase 1. This aggregation of pro-caspase 1 induces proteolytic cleavage of itself to form the active caspase 1, which cleaves the immature forms of pro-inflammatory cytokines, releasing the mature cytokines that are then secreted.

64
Q

what does the production of inflammasome require ?

A

PRODUCTION OF INFLAMMATORY CYTOKINES BY THE INFLAMMASOME REQUIRES A PRIMING STEP.

For cytokine production, cells must produce and translate the mRNAs that encode the pro-forms of IL-1b and IL-18.

The priming step can result from TLR signalling, which may help ensure that inflammasome activation proceeds primarily during infections.

65
Q

RIG I like receptors ?

A

sense viral RNAs produced within cells as opposed to those that enter cells from the endocytic pathway that are recognised by TLRs.

Activation of RIG-I-like receptors results in type I interferon production.

66
Q

cytosolic DNA sensors ?

A

multi-component pathway, incorporating cGAS (cyclic GAMP synthase) and STING, which acts as an innate sensor of pathogen cytoplasmic DNA.

Activation of pathway results in type I interferon production.