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MICI 2100 > Lec 20-Immunity To Viral Infection > Flashcards

Lec 20-Immunity To Viral Infection Flashcards

1
Q

Layers of response to viral infection:

A

INNATE:
- Structural protection
- Induceable protection
- Cell-mediated protection

ADAPTIVE:
- CTL (cytotoxic T cell)-mediated protection
- Antibody-mediated protection

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2
Q

When is adaptive immunity activated?

A

Adaptive immunity relies on the innate immune sys. It is activated after innate immune sys has given fast and effective response to mitigate infection

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3
Q

Structural protection to viral infection

A
  • Barrier immunity (first line of defence)
  • Skin protects us from pathogens. Sweat also makes skin surface unfavourable to pathogens
  • GI tract has mucosal barrier to trap bacteria, cilia move pathogens, peristalsis to cause vomiting, acids and enzymes to degrade
  • Vaginal tract has mucous to trap pathogen, urine washes pathogen out of bladder and urinary tract
  • Stomach acid/low pH in stomach is not liked by viruses bc it degrades proteins
  • Respiratory airway has specialized cells to trap pathogens, have cilia that can cause vomiting
  • Eye responds with tears to try to chop lyse virus that may enter thru eye
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4
Q

Innate immunity to viral infection

A
  • Second layer of defense if first is overcome
  • Virus enters epithelial cell membrane and starts to reproduce inside cell. Cell detects virus using PRRs. Detection of virus activates interferon responsive factor (IRF), which are the transcription factors that make IFN. mRNA becomes protein and is secreted, is received by IFN receptors on neighbouring cells so they can start making antiviral proteins before virus tries to infect it
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5
Q

What are interferons?

A

Interferons (IFN): Small cytokine secreted by virally infected cells as soon as they are infected (very quick). IFNs tell other cells that there is a virus!

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6
Q

Examples of ways can we block virus? (3)

A
  • PKR can feel dsRNA virus, and prepares cell to stop translation so virus doesn’t reproduce
  • Oligo-A-synthase can also feel dsRNA virus, promotes degradation of transcript to ensure mRNA from viral genome doesn’t do anything
  • Mx proteins inhibit transcription and virus assembly even if transcription does occur
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7
Q

Overall point of IFN signal…what does it do

A

Overall point: IFN signal mounts response that preps the cell itself to block transcription, translation, and assembly of viral protein

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8
Q

What are NK cells?

A
  • Cytotoxic lymphocytes
  • 5-10% of circulating lymphocytes
  • Part of innate immunity to viral infection
  • Help to eliminate infected host cells or tumour cells
  • Are activated by cytokines and also secrete cytokines
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9
Q

When do NK cells come into play? How fast do they proliferate?

A
  • Comes into play approx 4 days after infection, after IFN response
  • Proliferate fast
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10
Q

Phenotypic characteristics of NK cells

A
  • Don’t come from myeloid progenitor, come from lymphoid progenitor but have no BCR/TCR
  • Thymus is not required for development
  • Do not undergo receptor gene arrangements
  • Have a lot of receptors that can determine whether or not they kill target cell
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11
Q

How do NK cells decide what to kill?

A
  • NK cells decide by looking for MHC1
  • If MHC1 is exposed and empty, NK cells know that they dont have to kill this cell
  • If cell has been infected w/ virus, 2 things could happen: 1. MHC1 is exposing viral antigen, CD8 T-cell will intervene or 2. MHC1 is hidden inside cell, NK cell activates stress protein receptors to promote release of granules from NK cell that contain perforin and granzymes which allow NK cells to kill
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12
Q

What is the NK cell receptor that recognizes MHC1?

A

KIR receptors (killer cell immunoglobulin-like receptors)
- They have an Ig domain
- Many kinds of KIR receptors

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13
Q

KIR receptor map on chromosomes

A
  • KIR receptors sit on chromosome in the same area, meaning that variability of receptors increases with genetic evolution
  • Do not have somatic recomb, so their variability is in their gene copy number
  • Allows us to have a large range of KIR receptors to recognize diff signalling
  • Humans have more possible KIR receptors than less evolved animals i.e. fish bc our immune systems are more sophisticated
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14
Q

How do NK cells kill?

A
  • Via apoptosis
  • Release perforin and granzymes at the junction of the 2 cells once signalling molecs are activated
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15
Q

Granzyme/perforin mediated cytolysis

A
  • Granzyme and perforin are small proteins
  • Perforin forms pore on target cell, granzyme can enter thru pore and degrade protein/initiate apoptosis of target cell
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16
Q

Cytotoxic T-cell mediated protection

A
  • For cell-mediated adaptive immune response
  • Cytotoxic T-cells AKA CD8
  • Virus specific CTLs
  • Most important pathway to fight viral infection
  • Response begins on day 5/6, reaches peak 10 days post-infection. After 10 days is when you usually feel the worst
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17
Q

What if patient has T-cell deficiency?

A

Patients with T cell deficiency will always have overwhelming viral infection

18
Q

Steps of Tc cell activation and killing

A
  1. Virus is killed and taken up/phagocytosed by dendritic cell
  2. Dendritic cell processes antigen and takes it to lymph node
  3. Dendritic cell presents antigen to Tc cells on MHC1
  4. Tc become activated, leave the node, travel to site of infection and recognize infected cells
  5. Tc kills virally infected cells

**this all happens in lymph nodes

19
Q

How does a vaccine cause CD8 memory?

A

Dendritic cells can uptake, present, and build strong clonal response to pathogen

20
Q

What are cytotoxic T-cells also called?

A

CD8

21
Q

How does dendritic cell know if to do MHC1 or 2?

A

Depends on how DC uptakes pathogenic material:
- Bacteria: uptake by phagocytosis—MHC2—presents to CD4
- Virus: uptake by endocytosis—MHC1—presents to CD8

22
Q

CD8 vs CD4 activation

A

CD8 activation:
- Same mechanism of CD4 activation
- TCR feels viral particle on MHC1, starts intracellular signalling, divides T-cell into effector and memory cells
- Virus is inside cytoplasm, therefore can be on MHC1 on ER

CD4 activation:
- Need larger antigen bc it needs to be engulfed by phagocytosis to be exposed on MHC2

23
Q

What is cross-presentation?

A
  • DCs can also uptake antigens from outside the cell, and present them on MHC1
  • ONLY DCs do this
  • Cross-pres is mechanism by which vaccines work
24
Q

When do CD4 and CD8 interact?

A

CD4 and CD8 interact when there is immunological synapses for antigen presentation

25
Q

What happens once effector cells exit node?

A
  • They exit the lymph node via blood, follow cytokine/chemokine gradient to infection site
  • Recognize viral particles from MHC1
  • Tc cell granules with granzyme and perforin—MHC1 and TCR tight rxn causes granzyme release, perforin forms pore in target. Granzyme passes thru pore and initiates apoptosis in target cell
26
Q

CTL-mediated killing

A
  • CTLs recognize and kill infected tumour cells via TCR activation
  • When CD8 recognized tumour cells it will release perforin and granzymes, destroying the tumour cell
27
Q

2 ways of activation of killing mechanism from CD8 cell

A

happen thru recognition of loaded MHC1 or Fas/FADD interaction

28
Q

Fas/FasL pathway

A
  • FasL’s on CD8 bind to Fas receptors on target cell
  • Fas recruits FADD (death domain) and binding of procaspase-8 (initiator), making a DISC
  • Leads to activation of procaspace-3 (effector) which causes apoptosis of target pathogenic cell
29
Q

Methods of viral antigen presentation

A
  • Most cells (i.e. dendritic) present pathogen to CD8 on MHC1
  • Antigen-presenting cells present pathogen to CD4 on MHC2
  • Dendritic cells can also do cross presentation—taking up antigen from outside cell and presenting it on MHC1—this is how vaccines work
30
Q

MHC genetic diversity

A
  • 2 genes to make MHC1, one maternal and one paternal
  • Makes everyone present virus differently
  • Diff genes encode for diff parts of MHC1, allow us to adapt to diff viruses
  • MHC alleles are polymorphic—many variant forms of DNA sequence for diff ppl. Proteins with slightly different nucleotide patterns do the same function
  • MHC receptors are also polygenic—influenced by 2+ genes
31
Q

Why are MHC receptors so polymorphic

A

Have to accommodate viruses. Viruses change/adapt a lot themselves, so they have to be able to adapt their groove to accommodate all the foreign pathogens we meet

32
Q

What receptors are the most polymorphic?

A
  • MHC and KIR
33
Q

Dominance of MHC allele expression

A
  • Expression of MHC alleles is codominant
  • Codominance: 2 alleles of the same gene are expressed seperately to get diff traits
  • Mom will have diff alleles for MHC1 than dad, all kids will get diff assortment as we get 1 copy from each parent
34
Q

What are the 2 things that contribute to MHC diversity

A

Polymorphism and polygeny contribute to diversity of MHC molecs expressed

35
Q

What happens if you don’t have an MHC complex

A

You would have no adaptive immune response—you lose CD4 and B cell efficiency, without MHC1 there would be no CD8 adaptive immune response

36
Q

What subunits of MHC1 and 2 have the most genomic variability?

A

MHC1 has alpha 1, 2, and 3 chains. A1 and A2 chains contribute to groove, so they have the most genomic variability
MHC2 has beta 1, 2 and alpha 1,2 chains. B1 chains contribute to groove, so they have the most genomic variability

37
Q

How long after infection does antibody response come into play?

A

Begins around day 5, peaks at day 10…last response

38
Q

What do antibodies do?

A
  • Block attachment: binds to virus and prevents viral penetration, antibodies are neutralizing
  • Aggregate for phagocytosis: viral particles are clustered together and removed from circulation via phagocytosis
  • Activate complement for MAC attack: if complement is forming on infected cell, antibody stabilizes complement and makes MAC attack more efficient
39
Q

Virus strategy to strike back

A
  • Downregulates MHC1 expression
  • Can avoid expression of viral proteins that are searching for them on MHC1
  • Allows them to hide from CTL
  • But: NK cells recognize cells with low level of MHC1 expression and will kill them anyway with perforin/granzyme or FasL
40
Q

Viral infections of immune system

A
  • Human T lymphotrophic virus 1 and 2: attack T lymphocytes
  • HIV: attacks immune cells
  • We need drugs to try to combat these viruses
  • Worst is virus that kills CD4 cells bc they produce cytokines and also instruct CD8

MICI 2100 (11 decks)

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