Lecture 2 - B Cell Pathology Flashcards Preview

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Flashcards in Lecture 2 - B Cell Pathology Deck (73):
1

How long after vaccination do serum IgG levels stay elevated?

A very long time. Tens of years

2

Another name for isotype switching

Class switch recombination

3

Features of secondary antibody memory response
1)
2)
3)

1) Faster kinetics
2) Greater magnitide
3) Higher affinity

4

Symptoms of CD40 and CD40L deficiency

Normal IgM levels
Very low IgG, IgA levels
No B cell memory response
Normal T cell levels

5

Features of cytophotometry of hyper IgM individuals
1)
2)

1) CD27 absent (top left)
2) Higher than average IgM levels (bottom)

6

Surface marker expressed by memory B cells

CD27

7

On which cells is CD27 expressed?

Memory B cells

8

When do clinical symptoms of hyper IgM normally present?

Between one and two years of age

9

Clinical presentation of hyper IgM syndromes
1)
2)
3)
4)

1) Recurrent URT and LRT bacterial infections
2) Lung infections by cytomegalovirus or cryptococcus fungi
3) GIT problems (malabsorption, diarrhoea) reported in some patients
4) Often enlarged spleen, tonsils, lymph nodes

10

Which part of the spleen is lymphocyte-rich?

White pulp

11

Which cell types are common in white pulp?

Lymphocytes

12

Do lymph nodes contain much red pulp?

No

13

Structure of white pulp
1)
2)
3)
4)
5)

1) Central arteriole
2) Periarteriolar lymphoid sheath
3) Follicle
4) Marginal zone
5) Red pulp (surrounding)

14

Function of the central arteriole in spleen

To bring blood through the white pulp

15

Function of periarteriolar lymphoid sheath in white pulp

Rich in CD4 and CD8 lymphocytes

16

Function of follicle in spleen

Rich in mature B cells and follicular dendritic cells

17

Function of the marginal zone in spleen

Rich in macrophages and B cells
Separated from follicle by marginal sinus

18

Early stages of T and B cell activation

1) Antigen enters into lymphoid organ. Enters intact into B region, is processed and presented at T
2) Antigen-specific T or B cells contact antigen or are presented antigen
3) Chemokine receptor expression is changed. B cells express CCR7. T cells express CXCR5
4) Activated T and B cells move towards boundary between periarteriolar lymphoid sheath and follicle.

19

Outcomes of encounter of activated T and B cells in a lymphoid organ

1) Plasma cell proliferation
2) Germinal centre formation

20

How do B cells become plasma cells or form germinal centres?

Need correct T cell signalling

21

Transcription factor for B cells to become plasma cells

Blimp1

22

Transcription factor for B cells to form germinal centre

Bcl6

23

What does Blimp1 do?

Transcription repressor.
Shuts off B cell program, allows plasma cell program.

24

What does bcl6 do?

Transcription repressor.
Promotes cell cycle
Inhibits response to DNA damage

25

What is a germinal centre?

Where mature B cells proliferate, produce antibodies, undergo somatic hypermutaiton

26

Composition of germinal centres

95% B cells
5% CD4 T cells
1% Follicular dendritic cells

27

Functions within a germinal centre
1)
2)
3)
4)
5)

1) Clonal expansion
2) Isotype switching
3) Somatic hypermutation
4) Affinity maturaiton
5) Memory formation

28

Difference between somatic hypermutation and affinity maturation

Somatic hypermutation is mutations in V region
Affinity maturation is selection of somatically hypermutated V regions with the greatest affinity for antigen

29

Why is IgM the first antibody produced?

Pentameric, so 10 binding sites
High avidity for epitope, despite low affinity

30

Difference between IgM and IgG in terms of affinity and avidity

IgM has greater avidity
IgG has fewer binging sites, but has higher affinity for epitope

31

Which antibodies exist in mucosa?

IgA1, IgA1, IgM (to a lesser extent)

32

Which antibodies can cross the placenta?

IgG1, IgG2, IgG3, IgG4 (kind of)

33

Which antibodies result in complement activation?

IgG1, IgG2, IgG3, IgM

34

Which antibodies can sensitise mast cells?

IgE

35

Most common antibody in the blood

IgG1

36

Least common antibody in the blood

IgE

37

IgG in order of most common to least common

IgG1
IgG2
IgG3
IgG4

38

IgA in order of most common to least common

IgA1
IgA2

39

Does class switch recombination affect binding affinity?

No

40

How does class switch recombination take place?

1) Each C region has a Switch region upstream of it. All S regions are homologous
2) AID enzyme recognises Switch regions, makes a nick in dsDNA
3) Double strand breaks are brought together. DNA between S-S forms a loop
4) Loop is excised

41

What is class switch recombination?

Deletional recombination mediated by S-S recognition

42

Where does class switch recombination take place?

Only at the heavy chain locus

43

What is AID?

Activation Induced cytidine Deaminase

44

How does activation induced cytidine deaminase work?

1) Recognises Switch region
2) Deaminates cytosine to urasil
3) Urasil is removed from DNA, leaving a staggered double stranded break
4) Staggered double stranded break is homologous with all other S regions cut by AID

45

How is DNA repaired after cutting by AID?

Using similar DNA repair enzymes to V(D)J recombination

46

Role of AID in somatic hypermutation

1) Replaces C with U
2) Error-prone DNA repair enzymes recruited
3) Mistakes that improve affinity are selected for

47

Stages of affinity maturation
1)
2)
3)

1) In early germinal centre. No somatic hypermutation taking place. Isotype switching
2) SHM gene activated, leads to somatic hypermutation
3) Selective proliferation of B cells with greater affinity. Rest of B cells die

48

Surface proteins On B and T cells involved in isotype switching and somatic hypermutaiton

1) CD40L (T cell), CD40 (B cell)
2) TCR (T cell), MHCII (B cell)
3) ICOS (T cell), ICOSL (B cell)

49

Effect of CD40-CD40L interaction

1) Within B cell, NEMO activates NFkappaB
2) NFkappaB activates AID

50

Is CD40L deficiency autosomal or sex-linked?

X-linked

51

Is CD40 deficiency autosomal or sex-linked?

Autosomal recessive

52

What causes X-linked hyper IgM syndrome with anhydrotic ectodermal dysplasia?

Issues with either NEMO or NFkappaB

53

What do issues with NEMO or NFkappaB result in?

X-linked hyper IgM syndrome with anhydroptic ectodermal dysplasia

54

What causes autosomal recessive AID deficiency?

Lack of functional AID

55

Effect of CD40L deficiency
1)
2)
3)
4)

1) Defective B cell production
2) No germinal centres
3) No memory
4) Defective dendritic cell activation

56

Effect of CD40 deficiency
1)
2)
3)

1) Defective humoral immunity
2) No germinal centres
3) No memory

57

Effect of AID deficiency
1)
2)
3)

1) Germinal centre formation
2) No isotype switching
3) No switched memory

58

Effect of defective NFkappaB signalling

1) Abrogates signals from CD40
2) No germinal centres
3) No somatic hypermutation
4) No isotype switching

59

Mode of NFkappaB inheritance

X-linked
Autosomal dominant

60

Therapy for hyper IgM syndrome

1) Intravenous Ig infusion
2) For X-linked HIGM, bone marrow transplant

61

Common variable immune deficiencies
1)
2)
3)

1) Characterised by hypogammaglobulinaemia
2) Recurrent pyogenic infections by capsulated bacteria
3) Normally manifests in early adulthood

62

Definition of hypogammaglobulinaemia

IgG under 3g/L
IgA under 0.05g/L

63

Frequency of common variable immune deficiencies

1/25,000

64

Number of common variable immune deficiencies that have an identified genetic basis

~20%

65

What occurs in the germinal centre?

Isotype switching, affinity maturation

66

How much can affinity maturation increase the affinity of an antibody for an antigen?

10,000 times

67

How does somatic hypermutation occur?
1)
2)
a)
b)
c)

1) AID replaces C with U in variable region
2) One of three things can happen
a) U is converted to T. Adjacent G is converted to A
b) Excision repair
c) Mismatch repair

There is a chance in excision and mismatch repair that a mistake will be made. This is a mutation

68

Where do somatic hypermutation mutations cluster?

At CDR1, CDR2 or CDR3

69

Which T cells express ICOS and CD40L?

Activated T cells

70

Which B cells express ICOSL and CD40?

All B cells

71

What are two proteins involved in DNA repair?

PMS2
UNG

72

What does UNG do?

Removes urasil form DNA

73

Which enzyme removes urasil from DNA?

UNG