Lecture 2 - B Cell Pathology

Question 1

How long after vaccination do serum IgG levels stay elevated?

Answer 1

A very long time. Tens of years

Question 2

Another name for isotype switching

Answer 2

Class switch recombination

Question 3

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

Answer 3

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

Question 4

Symptoms of CD40 and CD40L deficiency

Answer 4

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

Question 5

Features of cytophotometry of hyper IgM individuals
1)
2)

Answer 5

1) CD27 absent (top left)

2) Higher than average IgM levels (bottom)

Question 6

Surface marker expressed by memory B cells

Answer 6

CD27

Question 7

On which cells is CD27 expressed?

Answer 7

Memory B cells

Question 8

When do clinical symptoms of hyper IgM normally present?

Answer 8

Between one and two years of age

Question 9

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

Answer 9

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

Question 10

Which part of the spleen is lymphocyte-rich?

Answer 10

White pulp

Question 11

Which cell types are common in white pulp?

Answer 11

Lymphocytes

Question 12

Do lymph nodes contain much red pulp?

Answer 12

No

Question 13

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

Answer 13

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

Question 14

Function of the central arteriole in spleen

Answer 14

To bring blood through the white pulp

Question 15

Function of periarteriolar lymphoid sheath in white pulp

Answer 15

Rich in CD4 and CD8 lymphocytes

Question 16

Function of follicle in spleen

Answer 16

Rich in mature B cells and follicular dendritic cells

Question 17

Function of the marginal zone in spleen

Answer 17

Rich in macrophages and B cells

Separated from follicle by marginal sinus

Question 18

Early stages of T and B cell activation

Answer 18

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.

Question 19

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

Answer 19

1) Plasma cell proliferation

2) Germinal centre formation

Question 20

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

Answer 20

Need correct T cell signalling

Question 21

Transcription factor for B cells to become plasma cells

Answer 21

Blimp1

Question 22

Transcription factor for B cells to form germinal centre

Answer 22

Bcl6

Question 23

What does Blimp1 do?

Answer 23

Transcription repressor.

Shuts off B cell program, allows plasma cell program.

Question 24

What does bcl6 do?

Answer 24

Transcription repressor.
Promotes cell cycle
Inhibits response to DNA damage

Question 25

What is a germinal centre?

Answer 25

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

Question 26

Composition of germinal centres

Answer 26

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

Question 27

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

Answer 27

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

Question 28

Difference between somatic hypermutation and affinity maturation

Answer 28

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

Question 29

Why is IgM the first antibody produced?

Answer 29

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

Question 30

Difference between IgM and IgG in terms of affinity and avidity

Answer 30

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

Question 31

Which antibodies exist in mucosa?

Answer 31

IgA1, IgA1, IgM (to a lesser extent)

Question 32

Which antibodies can cross the placenta?

Answer 32

IgG1, IgG2, IgG3, IgG4 (kind of)

Question 33

Which antibodies result in complement activation?

Answer 33

IgG1, IgG2, IgG3, IgM

Question 34

Which antibodies can sensitise mast cells?

Answer 34

IgE

Question 35

Most common antibody in the blood

Answer 35

IgG1

Question 36

Least common antibody in the blood

Answer 36

IgE

Question 37

IgG in order of most common to least common

Answer 37

IgG1 IgG2 IgG3 IgG4

Question 38

IgA in order of most common to least common

Answer 38

IgA1 | IgA2

Question 39

Does class switch recombination affect binding affinity?

Answer 39

No

Question 40

How does class switch recombination take place?

Answer 40

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

Question 41

What is class switch recombination?

Answer 41

Deletional recombination mediated by S-S recognition

Question 42

Where does class switch recombination take place?

Answer 42

Only at the heavy chain locus

Question 43

What is AID?

Answer 43

Activation Induced cytidine Deaminase

Question 44

How does activation induced cytidine deaminase work?

Answer 44

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

Question 45

How is DNA repaired after cutting by AID?

Answer 45

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

Question 46

Role of AID in somatic hypermutation

Answer 46

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

Question 47

Stages of affinity maturation 1) 2) 3)

Answer 47

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

Question 48

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

Answer 48

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

Question 49

Effect of CD40-CD40L interaction

Answer 49

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

Question 50

Is CD40L deficiency autosomal or sex-linked?

Answer 50

X-linked

Question 51

Is CD40 deficiency autosomal or sex-linked?

Answer 51

Autosomal recessive

Question 52

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

Answer 52

Issues with either NEMO or NFkappaB

Question 53

What do issues with NEMO or NFkappaB result in?

Answer 53

X-linked hyper IgM syndrome with anhydroptic ectodermal dysplasia

Question 54

What causes autosomal recessive AID deficiency?

Answer 54

Lack of functional AID

Question 55

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

Answer 55

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

Question 56

Effect of CD40 deficiency 1) 2) 3)

Answer 56

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

Question 57

Effect of AID deficiency 1) 2) 3)

Answer 57

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

Question 58

Effect of defective NFkappaB signalling

Answer 58

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

Question 59

Mode of NFkappaB inheritance

Answer 59

X-linked | Autosomal dominant

Question 60

Therapy for hyper IgM syndrome

Answer 60

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

Question 61

Common variable immune deficiencies 1) 2) 3)

Answer 61

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

Question 62

Definition of hypogammaglobulinaemia

Answer 62

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

Question 63

Frequency of common variable immune deficiencies

Answer 63

1/25,000

Question 64

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

Answer 64

~20%

Question 65

What occurs in the germinal centre?

Answer 65

Isotype switching, affinity maturation

Question 66

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

Answer 66

10,000 times

Question 67

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

Answer 67

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

Question 68

Where do somatic hypermutation mutations cluster?

Answer 68

At CDR1, CDR2 or CDR3

Question 69

Which T cells express ICOS and CD40L?

Answer 69

Activated T cells

Question 70

Which B cells express ICOSL and CD40?

Answer 70

All B cells

Question 71

What are two proteins involved in DNA repair?

Answer 71

PMS2 | UNG

Question 72

What does UNG do?

Answer 72

Removes urasil form DNA

Question 73

Which enzyme removes urasil from DNA?

Answer 73

UNG