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Molecule to Malady > Lecture 2 - B Cell Pathology > Flashcards

Lecture 2 - B Cell Pathology Flashcards

1
Q

How long after vaccination do serum IgG levels stay elevated?

A

A very long time. Tens of years

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2
Q

Another name for isotype switching

A

Class switch recombination

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3
Q

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

A

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

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4
Q

Symptoms of CD40 and CD40L deficiency

A

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

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5
Q

Features of cytophotometry of hyper IgM individuals
1)
2)

A

1) CD27 absent (top left)

2) Higher than average IgM levels (bottom)

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6
Q

Surface marker expressed by memory B cells

A

CD27

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7
Q

On which cells is CD27 expressed?

A

Memory B cells

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8
Q

When do clinical symptoms of hyper IgM normally present?

A

Between one and two years of age

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9
Q 
Clinical presentation of hyper IgM syndromes
1)
2)
3)
4)
A

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

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10
Q

Which part of the spleen is lymphocyte-rich?

A

White pulp

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11
Q

Which cell types are common in white pulp?

A

Lymphocytes

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12
Q

Do lymph nodes contain much red pulp?

A

No

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13
Q 
Structure of white pulp
1)
2)
3)
4)
5)
A

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

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14
Q

Function of the central arteriole in spleen

A

To bring blood through the white pulp

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15
Q

Function of periarteriolar lymphoid sheath in white pulp

A

Rich in CD4 and CD8 lymphocytes

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16
Q

Function of follicle in spleen

A

Rich in mature B cells and follicular dendritic cells

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17
Q

Function of the marginal zone in spleen

A

Rich in macrophages and B cells

Separated from follicle by marginal sinus

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18
Q

Early stages of T and B cell activation

A

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.

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19
Q

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

A

1) Plasma cell proliferation

2) Germinal centre formation

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20
Q

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

A

Need correct T cell signalling

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21
Q

Transcription factor for B cells to become plasma cells

A

Blimp1

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22
Q

Transcription factor for B cells to form germinal centre

A

Bcl6

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23
Q

What does Blimp1 do?

A

Transcription repressor.

Shuts off B cell program, allows plasma cell program.

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24
Q

What does bcl6 do?

A

Transcription repressor.
Promotes cell cycle
Inhibits response to DNA damage

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25
Q

What is a germinal centre?

A

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

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26
Q

Composition of germinal centres

A

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

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27
Q 
Functions within a germinal centre
1)
2)
3)
4)
5)
A

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

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28
Q

Difference between somatic hypermutation and affinity maturation

A

Somatic hypermutation is mutations in V region

Affinity maturation is selection of somatically hypermutated V regions with the greatest affinity for antigen

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29
Q

Why is IgM the first antibody produced?

A

Pentameric, so 10 binding sites

High avidity for epitope, despite low affinity

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30
Q

Difference between IgM and IgG in terms of affinity and avidity

A

IgM has greater avidity

IgG has fewer binging sites, but has higher affinity for epitope

31
Q

Which antibodies exist in mucosa?

A

IgA1, IgA1, IgM (to a lesser extent)

32
Q

Which antibodies can cross the placenta?

A

IgG1, IgG2, IgG3, IgG4 (kind of)

33
Q

Which antibodies result in complement activation?

A

IgG1, IgG2, IgG3, IgM

34
Q

Which antibodies can sensitise mast cells?

A

IgE

35
Q

Most common antibody in the blood

A

IgG1

36
Q

Least common antibody in the blood

A

IgE

37
Q

IgG in order of most common to least common

A

IgG1
IgG2
IgG3
IgG4

38
Q

IgA in order of most common to least common

A

IgA1

IgA2

39
Q

Does class switch recombination affect binding affinity?

A

No

40
Q

How does class switch recombination take place?

A

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
Q

What is class switch recombination?

A

Deletional recombination mediated by S-S recognition

42
Q

Where does class switch recombination take place?

A

Only at the heavy chain locus

43
Q

What is AID?

A

Activation Induced cytidine Deaminase

44
Q

How does activation induced cytidine deaminase work?

A

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
Q

How is DNA repaired after cutting by AID?

A

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

46
Q

Role of AID in somatic hypermutation

A

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

47
Q

Stages of affinity maturation
1)
2)
3)

A

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
Q

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

A

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

49
Q

Effect of CD40-CD40L interaction

A

1) Within B cell, NEMO activates NFkappaB

2) NFkappaB activates AID

50
Q

Is CD40L deficiency autosomal or sex-linked?

A

X-linked

51
Q

Is CD40 deficiency autosomal or sex-linked?

A

Autosomal recessive

52
Q

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

A

Issues with either NEMO or NFkappaB

53
Q

What do issues with NEMO or NFkappaB result in?

A

X-linked hyper IgM syndrome with anhydroptic ectodermal dysplasia

54
Q

What causes autosomal recessive AID deficiency?

A

Lack of functional AID

55
Q 
Effect of CD40L deficiency
1)
2)
3)
4)
A

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

56
Q

Effect of CD40 deficiency
1)
2)
3)

A

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

57
Q

Effect of AID deficiency
1)
2)
3)

A

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

58
Q

Effect of defective NFkappaB signalling

A

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

59
Q

Mode of NFkappaB inheritance

A

X-linked

Autosomal dominant

60
Q

Therapy for hyper IgM syndrome

A

1) Intravenous Ig infusion

2) For X-linked HIGM, bone marrow transplant

61
Q

Common variable immune deficiencies
1)
2)
3)

A

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

62
Q

Definition of hypogammaglobulinaemia

A

IgG under 3g/L

IgA under 0.05g/L

63
Q

Frequency of common variable immune deficiencies

A

1/25,000

64
Q

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

A

~20%

65
Q

What occurs in the germinal centre?

A

Isotype switching, affinity maturation

66
Q

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

A

10,000 times

67
Q 
How does somatic hypermutation occur?
1)
2)
a)
b)
c)
A

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
Q

Where do somatic hypermutation mutations cluster?

A

At CDR1, CDR2 or CDR3

69
Q

Which T cells express ICOS and CD40L?

A

Activated T cells

70
Q

Which B cells express ICOSL and CD40?

A

All B cells

71
Q

What are two proteins involved in DNA repair?

A

PMS2

UNG

72
Q

What does UNG do?

A

Removes urasil form DNA

73
Q

Which enzyme removes urasil from DNA?

A

UNG

Molecule to Malady (35 decks)

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