lecture 1 immunology (week 1)

Question 1

describe innate immunity

Answer 1

the early phase of the host response

present in all individuals at all times

does not increase with repeated exposure

discriminates between groups of pathogens

predates separation of animal and plant lineages

Question 2

describe adaptive immunity

Answer 2

is generated by specific lymphocytes

discriminates between individual pathogens
is associated with “memory”

appears abruptly in evolution in the cartilaginous fishes

Question 3

what are the anatomic barriers

Answer 3

skin, oral mucosa, respirator epithelium, intestine

Question 4

what are the complement/antimicrobial proteins

Answer 4

C3, defensins, reg III - gamma

Question 5

what are the innate immune cells?

Answer 5

macrophages, granulocytes, NK cells

Question 6

what are the adaptive immune cells?

Answer 6

B cells/antibodies, T cells

Question 7

how does the immune system recognize pathogens?

Answer 7

PAMPs

Question 8

what are the germline encoded receptors of the innate immune system

Answer 8

PRRs

Question 9

what are the soluble mediators

Answer 9

mucins: may prevent adhesion to epithelium by microorganisms

lysozyme: glycosidase that attacks peptidoglycan in bacterial cell wall

defensins: disrupt cell membranes of bacteria and fungi via pore formation

cathelicidins: disrupt cell membrane of wide range of microorganisms

histatins: active against pathogenic fungi

regIII family: C-type lectins, which target peptidoglycans, promoting pore formation

Question 10

what are the complement activation molecules?

Answer 10

mannose-binding lectin - recognize sugars, eg. mannose; fucose

ficolin - recognizes oligosaccharides containing acetylated sugars

c-reactive proteins - recognizes phosphorylcholine

Question 11

what do the complement activation molecules require for activation?

Answer 11

proteolysis

Question 12

what is proteolysis?

Answer 12

proteolysis is the breakdown of proteins into smaller peptides or amino acids and occurs through hydrolysis of a peptide bond by enzymes called proteolytic enzymes, proteinases, proteases, or peptidases.

Question 13

describe the C-type lectin family

Answer 13

recognises b-1,3 linked glucans, common component in fungal cell walls; mannose receptor, recognises mannose containing structures and also plays a role in clearance of host proteins

Question 14

describe scavenger receptors

Answer 14

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

Question 15

what does complement and the Fc receptor do?

Answer 15

recognise complement coated and antibody coated organisms

Question 16

describe the TLRs

Answer 16

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

Question 17

where was the Toll receptor protein first found?

Answer 17

in the fruit fly (drosophila melanogaster

Question 18

how was the Toll receptor discovered?

Answer 18

flies deficient in the Toll receptor are dramatically more susceptible to fungal infection – leading to uncontrolled hyphal growth (arrow) of aspergillus fumigatus.

it was later found that humans and other mammals use these receptors to detect infections, kick-starting the innate immune response

Question 19

what does TLRs and IL-1R both contain?

Answer 19

a conserved intracellular signalling domain - TIR domain

Question 20

what is the TIR domain needed for?

Answer 20

critical for downstream signalling in innate immune responses

both activate similar signalling cascades - MAPK and NFxB

both recruit adaptor proteins -mainly MyD88

both receptors play a role in inflammatory responses - TLRs recognise PAMPs and IL-1R binds to the pro-inflammatory cytokine IL-1

Question 21

what are the locations of TLRs

Answer 21

extracellular - 18-25 copies of leucine rich repeats (LRRs)

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

Question 22

describe the heterodimer in toll like receptors

Answer 22

tlr-1 and tlr-2 are located on cell surfaces

they can directly recognise triacyl lipoproteins

dimerization of the two tlr subunits brings their cytoplasmic toll-IL-1 receptor (TIR) domains together to initiate cell signalling

Question 23

describe the homodimers

Answer 23

tlr-4 recognises lps in association with the accessory protein md2

stabilisation leads to signal transduction

Question 24

describe the pathway of adaptor recruitment

Answer 24

lps binding - tlr4 requires coreceptor md2 = dimerization

tlr4 signal transduction : signalling downstream of tlr4 divided into two main pathways

adaptor recruitment

Question 25

describe the myd88 pathway - not mandatory

Answer 25

myd88 dependent (proinflammatory cytokines) - primarily leads to the production of pro inflammatory cytokines like tnf alpha, il-6, il1 beta

Question 26

describe the trif dependant pathway - not mandatory

Answer 26

trif dependent (type 1 interferons) leads to the production of type 1 interferons (ifn-alpha and ifn-beta) and late phase NF-kB activation

Question 27

describe the adaptor recruitment step of the pathway - not mandatory

Answer 27

myd88 + tirap - triggers a series of reactions inside the cell that lead to the activation of NF-κB. Once activated, NF-κB moves into the cell’s nucleus and leads to production of cytokines

trif + tram - triggers a chain of events that leads to the production of type I interferons (antiviral proteins). This pathway also activates NF-κB, but slower than MyD88

Question 28

what are the key outcomes of tlr4 siganlling?

Answer 28

pro inflammatory cytokines (TNF-a, IL-6, IL-1b) via NF-kB activation

type 1 interferons (ifn-a, ifn-b) through the activation of irf3 in the trif dependant pathway

activation of mapk pathways (erk, jnk, and p38) which contribute to inflammation, cell survival and apoptosis

anti microbial defence by promoting phagocytosis and recruitment of immune cells like macrophages and neutrophils to the site of infection

Question 29

describe the detection of cytoplasmic microbial products

Answer 29

nod like receptors

cytoplasmic receptor proteins - 22 identified in humans

intracellular sensors of bacterial infection and cell damage

centrally located nucleotide binding oligomerizaton domain and other variable domains that detect microbial products or cell damage

some nlrs activate NFkB to initiate the same inflammatory responses as the tlrs, other nlrs trigger a distinct pathway that induces cell death and the production of pro inflammtory cytokines

the physiological importance of nlrs is underscored by a high incidence of genetic mutations that are associated with chronic inflammatory or autoimmune disorders

Question 30

what is the card domain

Answer 30

allows subfamilies of nlrs to be detected

amino terminase caspase recruitment domain (card)

structurally related to the tir death domain in myd88 and can dimerize with card domains on other proteins to induce signalling

nod2 recognizes muramyl dipeptide which is present in the peptidoglycans of most bacteria

nod1 senses ie dap, a breakdown product of gram neg bacteria (salmonella) and some gram pos (listeria)

Question 31

what are pyrin containing nlrs

Answer 31

aka inflammasomes

strutcurally related to card and tir domains and interact with other pyrin domains

humans have 14 nlrs containing the pyrin domain - two well described as nlpr1 and nlpr3

contribute to a multiprotein complex (inflammasome)

drives pro inflammatory cytokine production and induces cell death

detected and response to PAMPs and DAMPs

inflammasome activation is crucial for host defence to pathogens

also a role in pathogenesis of inflammatory diseases; ibd, arthritis, atherosclerosis

Question 32

describe nlpr3

Answer 32

activation –> forms inflammasome complex that induces the adaptor protein ASC ( apoptosis associated speck like protein containing a CARD)

ASC helps recruit and activate caspase 1 –> caspase 1 activates il-1b and il-18

these cytokines are crucial for inflammation and recruiting other immune cells

pathway essential for protective immune responses –> overactivation leads to autoimmune and chronic inflammatory diseases