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Mechanism of Disease > Regulation of the Immune System > Flashcards

Regulation of the Immune System Flashcards

1
Q

How does the adaptive immune response start?

A

antigen presenting cell presents antigen to naive t-cell

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2
Q

what is the initial event in the adaptive immune response?

A

naive t-cell activation

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3
Q

what does naive t-cell activation lead to?

A

b-cell activation or cytotoxic t-cell response or both

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4
Q

when do a lot of regulatory mechanisms apply”

A

to naive t-cell activation

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5
Q

antibodies do the same as what?

A

t-cell receptors

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6
Q

how were antibodies discovered?

A

100 yrs ago, people immunized animals w/bacteria antigen. In serum from animals there was activity - if they put bacterial toxin in serum it formed precipitation. If they then injected this serum into naive mice, they were protected from bacterial infection (how antibody came from) - neutralizing activity that neutralizes bacterial toxin. nobody knew nature of the antibody; protein, DNA or what?

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7
Q

How did they discover what antibodies actually were?

A

electrophoeisis - you can see immunoglobins between 150 and 900 kd. But they still didn’t know structure of antibody (huge molecular weight)

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8
Q

How did they figure out structure of antibody

A

disassembled them & tried to figure out the pieces - 1950’s Porter and Edelman won nobel prize figuring out structure

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9
Q

Porter’s lab - what did it do?

A

used papain to digest antibody protein - found 3 fragments, two were identical - Fab (fragment of antigen binding), the other one was Fc - fragment of crystallizable - also the constant region of the antibody

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10
Q

what is the function of the two identical parts of the antibody?

A

antigen binding part of the antibody - 2 of them -means antibody can bind to 2 antigens - divalent (antibodies are divalent)

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11
Q

What did Edelman’s lab do?

A

did similar experiment to Porters, but used stronger reducing agent & broke disulfide bonds between light chains & heavy chains, so they got 4 fragments - two light chains & 2 heavy chains

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12
Q

Where is the constant region of an antibody?

A

in both light & heavy chains

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13
Q

what is the most important part of the antibody?

A

FAB, the variable region that recognizes the antigen (both heavy & light chains have variable regions)

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14
Q

Is the variability of an antibody homogeneous?

A

Nope. - there are areas within variable region that are hyper-variable - complementary determining regions

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15
Q

What is CDR?

A

Complementary determining regions of the variable region on the antibody - most important part of the antibody - this is where the antigen binds

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16
Q

what does complementary mean?

A

the amino acids in the complementary determining region are complimentary to the amino acids of the antigen (the epitope)

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17
Q

Where does the antigen bind?

A

only to the CDR region of the antibody (between the light chain and the heavy chain of the variable region)

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18
Q

Why is there a precipitate in the serum of an immunized animal that has the bacterial toxin introduced?

A

the antibodies bind to two antigens each - makes huge complex which is not soluble - precipitates out

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19
Q

What does specificity mean

A

Goodness of fit - fit between ligand and receptor - measured by affinity between antigen determinant (epitope - the binding part of the antigen) with the antibody

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20
Q

how do you quantify the specificity of ligand and antigen?

A

association constant of a good antibody that binds to its counterpart antigen is 10to the 15th L/mole - if you dilute antigen to 10 to the -15th molar, still half of the antibodies are bound to the antigen - very very diluted
doesn’t disassociate very easily

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21
Q

How many antibodies can one species make?

A

100,000 million antibodies

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22
Q

How many antibodies does one individual make?

A

100 million

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23
Q

Do we have to have 100 million genes to encode for each antibody we have?

A

Nope

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24
Q

How many total genes do we have?

A

30 million

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25
Q

How do we have the capacity to make so many different antibodies? What are the 2 theories?

A

2 theories:

  1. instruction theory - we don’t need to have anything ready, we just wait until antigen comes along & depending on the structure of the antigen, we make the corresponding antibody or t-cells
  2. clonal selection theory - means we have all of these antibodies & t-cells & b-cells already there, we don’t wait until antigen comes along
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26
Q

Which theory makes more sense for antibody capacity?

A

problem with instruction theory, is that when we are born it means we don’t have antibodies for anything. When we are infected with something, we then make a gene out of nowhere & that gene encodes for antibody - means that the outside world will determine our genome (that’s what instruction theory entails) - that hasn’t happened in biology.
Scientist from CU & another scientist from Australia put forth clonal selection theory - now that is the accepted hypothesis - each b-cell & t-cell in our immune system is programmed to make one antibody or one t-cell or b-cell receptor. Choice of which antibody the cell can make is random. Entire b-cell population is already there when we are born. Antigen causes activation of one clone of t-cell or b-cell, so we get immunity against that antigen

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27
Q

What is the N-terminal?

A

End of the antibody where light chain and heavy chain has different sequences between other antibodies of different specifications - the variable domain (V)

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28
Q

Describe the clonal selection theory

A

(1950’s posed by David Talmage & MacFarlane Burnet) - proposed that each Bcell of the immune system is programmed to make only one antibody; that the choice of which antibody the cell will make is random, not dependent on outside information; and that the entire population preexists in a normal individual, even before contact with any antigens. When a new antigen is introduced into the body, it comes into contact with a huge number of B lymphocytes and when it encounters one to whose receptors it binds with sufficient affinity, it activates that cell, resulting in expansion of that clone of b cells and production of antibody. The best fitting clones are selected by the antigen

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29
Q

How do we get so much antibody diversity with fewer genes?

A
  1. Multiple genes that create the v domain
  2. genes are organized into segments that can be rearranged to give diversity
  3. combinatorial diversity - creates more diversity & flexibility & randomness
  4. somatic mutation
  5. pairing of heavy and light chains (each antibody has 2 heavy & 2 light chains) 1000 heavy chains + 1000 light chains gives you 1,000,000 different antibodies with just 2000 genes
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30
Q

What are the gene segments that code for heavy chains?

A

V, D and J

31
Q

What are the gene segments that code for light chains?

A

V and J

32
Q

How many genes encode for each segment on an antibody?

A 
For heavy chains:
65 - V
27 - D
6 - J
=10,500 different antibodies by using only 98 genes
for light chain
35 v-segment
5-J
=175 antibodies by only 40 genes

only one gene encodes for constant region for each antibody

33
Q

How many genes for constant region?

A 
5
(5 flavors) - each one encodes for a different kind 
IgG gamma
IgM Mu
IgA alpha
IgD delta
IgE epsilon
34
Q

What accounts for the majority of the complexity of the variable region of antibodies?

A

recombination
in developing B cell making antibody
genes in D region come closer to genes in J regin - intervening DNA in between is removed & D & J region are joined
same thing happens for V - genes in V region then come into the D and J and the DNA’s in between are removed, then we have VDJ recombined variable region

35
Q

What enzyme does the V-D-J recombination?

A

RAG 1 & RAG 2 recombinase

without these two enzymes, we wouldn’t have any b-cells or t-cells

36
Q

How does RAG recombinase work?

A

recognizes splicing signal to right of D segment, and splicing signal to left of J segment, brings the two together, cut everything in between & then join the two segments
then recognizes splicing signal to right of V segment, brings it to the D & cuts the intervening DNA & joins the V and D - how we get VDJ recombination - then transcribed to mRNA & we get the antibody

37
Q

What mechanism adds unpredictability or randomness to the antibodies we make?

A

recombinational inaccuracy:
during joining, two ends of each segment, there are nucleotides that can be removed or added before the two segments are joined

38
Q

What enzyme removes or adds nucleotides to the ends of the V,J & D segments before they are joined to each other?

A

terminal deoxynucleotide (TDT) transferase - doesn’t need a template - that’s why there’s randomness - can’t predict what’s going to happen based on the genome

39
Q

Which kind of cell recognizes antigen on its own?

A

B-cells recognize antigen on its own. T-cells do NOT.

40
Q

How do t-cells recognize antigen?

A

MHC restricted recognition of antigen
discovered with experiment
took cytotoxic t-cells from inbred strain A mice infected with virus V - found t-cells kill v virus infected cells, but don’t kill e-virus infected cell (makes sense -antigen specificity)
cytotoxic t-cells taken from strain a mice did not recognize infected v cells from strain b mice, even though they were infected with the same virus. that suggests that t-cells don’t just recognize antigen - it recognizes something else that has to be self (recognize antigen plus something identical that is self-protein)

41
Q

What can t-cells “see”?

A

only antigen presented to them on the surface of a genetically identical cell to themselves

42
Q

What is the self molecule important for t-cell antigen recognition?

A

major histocompatibility complex

or human leukocyte antigen (MHC, HLC)

43
Q

how many classes of MHC are there?

A 
2
class 1 - ABC
class 2 - DP, DQ and DR
44
Q

Where do you find MHC’s?

A 
Class one - all nucleated cells in our body
class 2 - only on antigen presenting cells macrophages &dendritic cells & b-cells
45
Q

What kind of t-cells recognize what kind of MHCs?

A

CD8 T- cells (cytotoxic T-cells) recognize MHC class 1, CD4 T-cells recognize MHC class 2

46
Q

What are cytotoxic t-cells?

A

CD-8 t-cells, killer t-cells

47
Q

What do CD-4 cells become?

A

t-helper cells - after they recognize antigens presented by dendritic cells, macrophages & sometimes b-cells - they then release cytokines to help b-cells or cytotoxic t-cells

48
Q

What is the structure of an MHC receptor?

A

alpha beta chains, antigen sits in the groove (beta barrel forms groove, & sides are alpha helices), t-cell receptor recognizes antigen but also binds to regions on the sides of MHC molecule - that’s why it is MHC restricted recognition

49
Q

What is meant by MHC restricted recognition?

A

The t-cell recognizes the antigen that sits in the groove of the MHC molecule - so the t-cell also has to recognize the side of the MHC molecule where the antigen binds

50
Q

What are the requirements in the thymus for a successful t-cell?

A

it should not recognize self peptide (derived from self protein) or the self MHC - they do need to recognize self MHC molecule when bound to antigen, but they cannot respond to MHC too strongly (MHC alone, or MHC loaded with self peptide)
should recognize antigenic peptide plus self MHC
should not recognize free antigen

51
Q

How many selections to t-cells go through in the thymus?

A

2 - negative selection, and positive selection

52
Q

what is negative selection?

A

cells that respond to self are removed - go through apoptosis
If t-cell responds to self-peptide loaded onto MHC with high affinity, they apoptose
if the t-cell receptor doesn’t recognize anything - not even MHC with low affinity - those cells are also destroyed by apoptosis - only those that recognize self-MHC or self-MHC + self peptide with low affinity
The AFFINITY is what makes the difference - high affinity makes them self-reactive. If they don’t respond at all, they won’t recognize pathogens. have to recognize with low affinity - not enough to cause t-cell activation, but when self-peptide is exchanged with pathogenic peptide, the hope is it will have high affinity

53
Q

What is positive selection?

A

If they recognize MHC class II, they become CD4 cells, if they recognize MHC class I cells, they become CD8 cells

54
Q

What is central tolerance?

A

education process of t-cells in the thymus - the most important part of central tolerance is negative selection
positive selection determines what kind of t-cells they will become

55
Q

How do you define low affinity?

A

ambiguous - in the thymus, even though we do our best & we get the right t-cells, but when they get out we need to have more regulations to make sure we respond to infection & we don’t respond to self

56
Q

What are the three regulatory mechanisms in the periphery for t-cells?

A
  1. anergy
  2. activation-induced cell death
  3. suppression by regulatory t-cells
57
Q

How is a naive t-cell activated?

A

t-cell receptor recognizes antigen presented by MHC molecule is signal 1 (not enough)
also needs signal 2 - provided by co-stimulatory molecules
CD4 molecule plays as an anchor to make sure interaction lasts long enough
adhesion molecules make sure they interact for 9-12 hours, these molecules are signal 2

58
Q

What molecules are signal 2 for naive t-cell activation?

A

t-cells express CD40Ligand and CD28, bind to CD40 and B7 on antigen presenting cells - those provide the signal 2. (costimulatory molecules)

59
Q

what does anergy mean?

A

t-cells see antigen but don’t respond - they only see signal one but not signal 2 - they are anergized.

60
Q

When do our antigen presenting cells have B7 molecules?

A

when we have an infection

61
Q

Why do we get b7 when we have infection?

A

toll-like receptor recognizes PAMPs - transcription factor - NFkB, a lot of functions of innate immune cells (or antigen presenting cells) are made possible by activation of NFkB, toll-like receptor recognition of PAMPs leads to NFkB activation
upregulates MHC molecule - normally in resting state there aren’t enough MHC molecules to present antigen, B7 and CD40 are induced (not expressed on naive APC’s)

62
Q

What is CTLA-4?

A

When t-cell gets activated, start to express
cytotoxic t-lymphocyte associate molecule - 4
this molecule also binds to B7-1 and B7-2, when it binds it causes inhibition (shut down T-cell activation)
part of anergy (peripheral tolerance)- a way to regulate t-cells

63
Q

What is the difference between CD28 and CTLA-4

A

When CD28 binds to b7, t-cell gets activated, when CTLA-4 binds to B7, the t-cell gets shut down

64
Q

What is the importance of CTLA-4

A

way of controlling t-cells so we don’t have t-cell activation for a long time - especially when pathogen has already been irradiated. T-cells need to be inhibited. CTLA-4 molecule is unregulated when T-cells are already activated

65
Q

How is CTLA-4 used clinically?

A

in tumor immunity - used in clinic to boost immune response against cancer cells - when t-cells are activated, they express CTLA-4 which inhibits t-cells, in immunity against tumor, we want t-cells to be activated - especially cytotoxic t-cells that recognize the tumor antigen - so we block CTLA-4 - CTLA-4 blockade is used in clinics - inhibits anergy
opposite - autoimmune diseases t-cells are over-activated, so we want to have CTLA-4

66
Q

What happens to the majority of t-cells once pathogen is eliminated?

A

they die, a few become memory cells

67
Q

What mechanism controls apoptosis of t-cells once they are activated?

A

They up regulate Fas and FasLigand - transduce signal to the cells & activates extrinsic apoptosis pathway either autocrine or paracrine fashion

68
Q

What is another molecule expressed on t-cells when they are activated other than Fas and FasL?

A

PD1 - programmed death

69
Q

how is PD1 related to cancer?

A

PD1 on t-cells will bind to PDL-1 on cancer cells
a lot of cancer cells express PDL - will cause t-cell death
cancer therapy, you want to inhibit interaction between PDL and PD1 so that t-cells don’t die

70
Q

how is Fas related to autoimmune diseases?

A

If you delete gene for Fas or FasLigand in mice, they develop lupus. Demonstrates how important activation induced cell death mechanism is to make sure we don’t develop auto-immune diseases

71
Q

What is Active Suppression by regulatory t-cells and how does it work?

A

regulatory t-cells suppress effector cells
when they get signal 1 and signal 2, t-cells will proliferate. IL-2 is important growth factor for c-cell proliferation. Regulatory t-cells suppress effector t-cells several ways:
act as IL-2 sync - neutralize IL-2 so effector cells won’t have enough IL-2 to proliferate
2. regulatory t-cells produce immunosuppressive cytokines (most potent are IL-10 and TGF-beta & those will suppress effector t-cells.

72
Q

What are the most potent cytokines that regulatory t-cells produce?

A

TGF-beta and IL-10

73
Q

What happens if you don’t have regulatory t-cells?

A

develop autoimmune diseases

Mechanism of Disease (4 decks)

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