Lecture 4 ((3) - Week 2B) Flashcards Preview

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Flashcards in Lecture 4 ((3) - Week 2B) Deck (74):
1

The immune system must protect us against a wide variety of pathogens

eg bacteria, viruses, parasites, fungi
• which pathogens an individual will encounter is not known in advance
• therefore, immune system must maximize its potential to respond to diverse challenges

2

The immune system must

• recognize and respond to pathogens
(failure = death from infectious disease)
• but not respond to components of our own bodies
(failure = auto-immune disease)
ie must discriminate "non-self" from "self"

3

Antigen

anything that binds to a specific receptor on T or B cells
• generates antibody
• can be bits of bacteria, viruses etc (foreign antigen)
• pathogens can also be bits of our own bodies (self antigen)

4

Epitope

the portion of the antigen that is recognized and bound by a receptor on an immune cell
• structure of antigen that's recognized
• numerous
• antigens contain many epitopes

5

Complex antigens (eg proteins) can contain

multiple different epitopes, each of which can be recognized by different antibodies

6

Epitopes recognized by antibodies are

often shapes formed by the way proteins fold
• different antibodies "fit" different shapes

7

Cells of innate and adaptive immune systems recognize

non-self in different ways

8

Innate immune system

• NK cells
• monocytes/macrophages
• dendritic cells
• granulocytes
• a limited number of common microbial structures can be recognized: PAMPs (toll-like receptors)

9

Adaptive immune system

• T cells
• B cells
• can recognize MANY antigens

10

Overview of antigen recognition

1. receptor binds to Ag
2. signalling cascade initiated (to nucleus, tell cells to start division)
3. gene transcription
4. production of effector molecules (eg antibodies/cytokines)

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Signalling cascade
-->

cell starts dividing

12

B cells

make antibodies

13

Antibody is also known as

immunoglobulin (Ig)

14

Recognition of antigen by B cells

• B cells recognize antigens using the B cell receptor (BCR)
• the BCR is an antibody molecule anchored to the B cell - transmembrane
• antigens are recognized directly (they don't require presentation by other cells)
• epitopes are often conformational (shapes formed by protein folding)

• T cells recognize antigen = complex
• antibody molecules on B cell surface BIND native antigen
--shape and conformation (wrong shape = no binding = no action)

15

In mamamls, B cells develop in

bone marrow
stem cell -->
pro- B cell -->
pre- B cell (start to express antibody on surface)-->
immature naive B cell -->
mature naive B cell

• naive = hasn't seen antigen

16

Each new B cell

has a unique receptor
• recognizes a different antigen

17

Each B cell expresses

only 1 type of receptor
• recognize only 1 antigen

18

Recognition of antigen by B cells

• activated B cells differentiate into plasma cells - secrete a soluble form of the receptor - antibody
• the antibody recognizes the same antigen as the BCR

• B cell divides, loses antibody from surface --> makes a lot of antibody in solution (not on surface)

19

Activated B cells differentiate into

plasma cells that secrete a soluble form of the receptor (antibody)

20

Plasma cells secrete

a soluble form of the receptor (antibody)

21

Each antibody recognizes

a different antigen
• Ag = antigen
• Ab = antibody

22

Structure of a typical antibody

Y shaped
Arms of the Y
• light chain on outside of each arm
• heavy chain on inside of each arm
• variable region is distal and made of a combination of shapes of 2 identical heavy (VH) and 2 identical light (VL)
• antigen binds the variable region

The stem of the Y
• constant region
• controls what the antibody does
• heavy chain = γ α μ ε δ

there are 2 types of light chain and 5 types of heavy

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2 types of light chain

• kappa κ
• lambda λ

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5 types of heavy chain

• mu μ
• gamma γ
• alpha α
• epsilon ε
• delta δ

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Variable domains

contains the sequences that interact with antigen

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Variable regions of H and L chains

combine to form shape that fits that of the antigen

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Fab

arms of the Y
binds antigen

Papain digestion (each separately)
Pepsin digestion ( F(ab')2 both parts separated from Fc)

28

F(ab')2
(2 = subscript)
(unsure)

the arms of the Y together

29

Fc

determines function of antibody
crystallizes

30

V domains contain

areas of hypervariability
• HV regions are also known as complementarity determining regions (CDRs) - 6 combine to form each antibody binding site

31

HV regions

• hypervariable regions
• also known as complementarity determining regions (CDRs)
• 6 combine to form each antibody binding site

32

Antibody classes

determined by the constant region of the heavy chain

• IgG = γ heavy chains
• IgE = ε heavy chains
• IgA = α heavy chains
• IgD = δ heavy chains
• IgM = μ heavy chains

all have 2 heavy and 2 light chains, but IgM has 10 heavy and 10 light chains, IgA can have 4 heavy and 4 light chains

33

IgG =

γ heavy chains
2 heavy 2 light

4 subclasses

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IgE =

ε heavy chains
2 heavy 2 light

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IgA =

α heavy chains
2 heavy 2 light

Or another Y to get 4 heavy and 4 light

2 subclasses

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IgD =

δ heavy chains
2 heavy 2 light

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IgM =

μ heavy chains
10 heavy, 10 light

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Different classes have

different effector functions

39

IgG has

4 subclasses in humans
• IgG1
• IgG2
• IgG3
• IgG4

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IgA has

2 subclasses
• IgA1
• IgA2

41

B cells can produce

different classes of antibodies
• IgM and IgD -->
• IgM
• IgG
• IgA
• IgE

• IgD = recognition
• IgE = allergies
• ER makes protein

42

B cells receptor diversity

• millions of different antigens can be recognized
• each new lymphocyte expresses only 1 type of receptor and recognizes only 1 antigen
• lymphocytes with any given specificity are rare
• an antigen will only activate those lymphocytes with the "right" receptor
• these lymphocytes divide repeatedly - daughter cells express the same receptor
• a large number of useful cells are generated (clonal expansion)

43

A new lymphocyte expresses

only 1 type of receptor and recognizes only 1 antigen

44

Lymphocytes with any given

specificity are rare

45

An antigen will only activate those lymphocytes with

the "right" receptor

46

Lymphocytes divide repeatedly

clonal expansion
• daughter cells express the same receptor
• a large number of useful cells are generated

47

How is receptor diversity generated?

• each developing B cell expresses a distinct receptor
• tens of millions of receptors required - how?
• a gene for each receptor? - no, would require tens of millions of genes
• instead, diversity is generated by "mixing and matching" gene segments within the heavy chain and light chain loci

48

Diversity is generated by

random "mixing and matching" of variable, diversity, and joining segments

49

Diversity is generated by random "mixing and matching" of

variable, diversity, and joining segments

50

Making an immunoglobulin heavy chain

• D-J joining: DNA spliced between diversity and joining regions
• V-DJ joining: DNA spliced out between V and DJ
• transcription
• RNA splicing --> chooses constant part and makes different variants

• mediated by RAG recombinase enzymes

51

Somatic DNA recombination generates

antibody diversity

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... generates antibody diversity

somatic DNA recombination

53

Antibody diversity
2 processes act during B cell development

• combinational diversity
• junctional diversity
~ 5x10^13 antibodies

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Combinational diversity

mixing and matching of V, (D), and J segments
• different combinations of H and L chains

55

Junctional diversity

(CDR3)
• addition of P- and N- nucleotides at joins

56

Antibody responses are dynamic

they evolve DURING immune response
Primary = first time see antigen
• IgM levels in serum up then down
• IgG up

Secondary = second time to see antigen
• IgG down then up

isotype switching and and affinity maturation

57

Antibody responses are dynamic - they evolve during an immune response

1. class (isotype) switching
2. affinity maturation

58

Class switching

• a given B cell starts by making IgM (and IgD) but can switch to making IgG (or IgA or IgE)
• class switch recombination allows a given V-D-J unit to be associated with different constant regions
• antibody specificity remains constant whilst biological effector functions are varied

IgM first, then switches primary
secondary made IgG

59

Class switch recombination

IgM variable (VDJ) followed by constant
• activation induced cytidine deaminase (AID) = DNA chopped out
IgG made
• take out genes that make A and put in genes that make B
• different constant region

60

Affinity maturation

improves the quality of antibodies during an immune response by increasing their affinity for antigen
(ie makes the antigen binding site a better fit for the antigen)
• changes variable regions
• affinity = strength of interaction

61

Affinity maturation mechanism

by somatic hypermutation
• individual nucleotides in variable regions are randomly replaced with alternatives
• "tested" against antigen displayed on follicular dendritic cells (FDC) - many mutations are useless
• B cells with the best fit antibodies survive

occurs during an immune response, not during B cell development`

62

Affinity maturation and class switching occur in

germinal centers (GC) in lymph nodes and spleen
• GC form 3-4 weeks after initial antigen exposure
• rapid initial response is followed by an improved, more effected and diversified, response
• antigen sticks on surface and presents in follicular dendritic cells

63

What do antibodies do to protect us against infections?

five things:
1. agglutination
2. neutralization
3. opsonisation
4. complement activation
5. antibody dependent cellular cytoxicity (ADCC)

64

Agglutination

crosslinking by antibodies creates larger particles that are taken up more efficiently by phagocytes
• esp IgA antibody
• multivalvent antibodies and antigens

65

Neutralization

can block attachment of pathogens to receptor on cells and block the action of bacterial toxins
• keeps shit out
• antibodies bind to pathogens so can't fit into receptor on target cell

66

Opsonization

FcR mediated uptake enhances pathogen clearance by macrophages and neutrophils
• FcR = receptor for Fc part of antibody
-receptor for heavy chain
• constant part of antibodies attaches to receptor on target cell so pathogens/antigens can't get in

67

Complement activation

• "trained spotters"
• proteins in blood
• antibody binds to surface of cell enzyme splits C3 into C3a and C3b
• C3b + C5 into C5 convertase to make MAC (membrane attack complex)
• punches hole in cell --> lysis

• classical, alternative, lectin pathways

68

Antibody dependent cellular cytoxicity (ADCC)

role in killing:
• virally infected cells, helminths, tumour cells
• may be utilized for therapies
• antibody bound to cell
• NK cell or macrophage comes along, recognizes, makes molecules that kill

• viral peptides stick out of target cell surface
• antibodies bind, constant (Fc) region sticks out
• NK cell or macrophage hasFc receptor
• meet up, macrophage/NK cell releases molecules to kill infected cell

69

Antibody classes and subclasses have

different biological properties

70

B cells

make antibodies

71

Each B cell expresses

a single unique receptor for antigen

72

Somatic recombination contributes to

receptor diversity during B cell development in bone marrow

73

During an immune response, antibodies

improve and diversify - affinity maturation an isotype switching

74

Antibodies have 5 main biological activities that

help fight infections