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BIOM30002 - M2M > Lecture 2 - B cells - Immune Deficiencies 2 > Flashcards

Lecture 2 - B cells - Immune Deficiencies 2 Flashcards

1
Q

What is the phenotype of mice lacking CD40L?

A
  • Unable to undergo isotope switching
  • No memory
  • Low affinity
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2
Q

What is a combined immune deficiency?

A

Spans both humoral and cellular immunity

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3
Q

What is the name for humoral deficiencies (as opposed to combined)?

A

Antibody deficiencies

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4
Q

Describe persistence of B cell immunity

A

Even 60 years after vaccination, there can be protective levels of antibody in the serum

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5
Q

Describe the antibody response after vaccination

A

→ Vaccination
• IgM response
• Later, isotope switching to IgG

→ Booster
• Increased levels of IgG

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6
Q

Compare B memory cells in the healthy people and hyper IgM patients

A

Normal: Many memory cells in serum

HIGM: no memory B cells in their serum

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7
Q

What are the symptoms of Hyper-IgM syndromes?

A
  • Recurrent infections (upper and lower respiratory)
  • GIT dysfunction (malabsorption)
  • Autoimmune disorders
  • Enlarged 2° lymphoid organs
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8
Q

What happens on a cellular level to a B cell when differentiating into a plasma cell?

What brings about this change?

Which other cell mediated this?
Why?

A

Major organelle reorganisation

  1. Expression of BLIMP1
  2. Switching off of B cell program
  3. Change to plasma cell program

Tightly regulation:
• By CD4+ cells (Tfh)
• This is because making Ab is dangerous: once it’s made, it can’t be unmade
• Need to be sure that the Ab being made is not going to cause problems

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9
Q

What are the various areas in the spleen?

Describe the structure

A
  1. Red pulp:
    • Erythrocytes
2. White pulp: 
• Lymphocytes
• Surrounding blood vessels
a. Follicle: B cells
b. PALS: T cells
c. Marginal zone: around follicle
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10
Q

Describe the cell distribution within white pulp

A
  • Mature B lymphocytes: follicle
  • T lymphocytes: periarteriolar sheath (central)
  • Dendritic cells: PALS
  • MZ B lymphocytes: marginal zone
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11
Q

Describe the early and late stages of B and T cell activation in lymphoid organs

A
  1. B cell clonally selected; Ag on follicular DC; T cell stimulated by Ag presented on DC
  2. B cell and T cell migrate to boundary of B cell follicle and paracortex
    a. B cell upregulation of CCR7
    b. T cell upregulation of CXCR5
  3. TFH cell and B cell interaction:
    a. MHC II:peptide – TCR
    b. CD40 – CD40L
  4. B cell forms a germinal centre under the action of Bcl-6 and undergoes maturation events:
    a. CSR
    b. SHM
    c. Affinity maturation
  5. Alternatively, some B cells differentiate immediately into plasma cells under the action of BLIMP1:
    a. BLIMP1: transcription repressor that turns of B cell program
    b. Immediate production of low affinity IgM
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12
Q

What is a germinal centre?

Which cells are present, and in what proportions?

A

An area within a secondary lymphoid organ in which B cells mature and proliferate

Composition:
• B cells: 90%
• T cells: 5%
• Follicular dendritic cells: 1%

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13
Q

What are the outcomes for B cells after interaction with T cells?

A
  1. Initial plasma cells
    • Low affinity IgM
    • Short lived
    • Initial, rapid response
  2. Germinal centre formation
    • Maturation events (SHM, CSR, affinity maturation)
    • Production of memory cells and ‘better’ plasma cells
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14
Q

Which signals are required for Plasma cell development?

Describe the function

A

BLIMP1
• Transcription factor (repressor)
• Expressed in B cells

Brings about:
• Switching off of B cell program
• Switching on of plasma cell program
• Massive intracellular reorganisation

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15
Q

What is the transcription factor vital for B cells to form Germinal centres?

Describe its function

Why is it so vital?

A

Bcl6

Function:
• Transcription repressor
• Promotes cell cycling

Vital:
• Inhibition of the DNA damage response to SHM and CSR

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16
Q

List the processes occurring in the germinal centre

A
  • Clonal expansion
  • Isotope switching
  • Somatic hypermutation
  • Affinity maturation
  • Memory formation
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17
Q

Describe the mechanism of somatic hypermutation

A
  1. AID converts Cystosine to Uracil in variable region
  2. Induction of error prone DNA repair
  3. Random mutation in the V region of the heavy and light chains
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18
Q

Describe affinity maturation

A

Cells with mutations in Ig with increased affinity are selected, others are discarded

(Evolution on a microscale)

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19
Q

Describe memory formation

A

High affinity GC B cells differentiate into either:
• Plasma cells
• Memory cells

Memory cells persist after primary infection in secondary lymphoid organs, as well as the BM

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20
Q

What is the difference between the plasma cells derived from the GC and those originally derived from the B cell that was yet to undergo maturation events?

A

GC derived plasma cells have much higher affinity, and are class switched

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21
Q

Which class of immunoglobulin is made first?

What would be the benefit of this?

A

IgM

Initially, the immunoglobulins have low affinity, so the pentamer IgM, which confers higher avidity, compensates for this fact

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22
Q 
Compare the effector functions of the following:
• IgG
• IgM
• IgA
• IgE
A

IgG
• Complement activation
• Placental transfer

IgM
• Complement activation
• Little bit of mucosal protection

IgA
• Mucosal protection

IgE
• Sensitising of Mast cells

IgD
• Present on mature B cells (naïve)

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23
Q 
Compare the location of the following:
• IgG
• IgM
• IgA
• IgE
A

IgG
• Serum

IgM
• Serum

IgA
• Secretions

IgE
• Bound to mast cells

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24
Q

Describe the regions on the Ig molecule that are changed through CSR

What is the significance of this?

A

Constant region: changes
Variable region: no change

This ensures the antibody still has the same affinity after isotype switching

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25
Q

Describe the process of CSR

Which enzyme is required?

A
  1. AID introduces nicks into ‘S’ region (upstream from each constant region segment) of heavy chain
    • By converting C to U, and then U is removed
  2. Formation of loop, cleaved out, deletion intervening sequences
  3. Ligation of ends

IgM → IgG → IgE → IgA

26
Q

Describe the likely events after helminth infection

A
  1. DC recognition and migration to lymph node
  2. DC presentation to Th cell; 3 signals
  3. Th cell releases cytokines and presents antigen to B cell
  4. B cell undergoes CSR differentiation and starts producing antibody against helminth
27
Q

Describe DC and Th cell interaction

A

Signal 1:
• TCR binds to MHC-peptide complex

Signal 2:
Costimulation: CD28 and CD80/CD86

Signal 3:
• Release of cytokines from DC that act on IL-R on T cell
• Drives differentiation into various Th cell subtypes

28
Q

Describe T cell help for B cells

A
  1. Interaction between TCR on Tfh and MHC-peptide complex on B cell
  2. Interaction between CD40 and CD40L on B cell and T cell respectively
  3. Release of cytokines from Tfh cell (IL-21) onto B cell
4. B cell forms a GC
Undergoes:
• CSR
•  SHM
• Affinity maturation
• Memory formation
29
Q

What is AID?

Where is it expressed?

Describe its function and mechanism of this function

A

Activation induced deaminase

Expressed in the germinal centre

Role in:
• CSR
• SHM

Mechanism
• Converts Cytosines to urasils
• Error prone DNA repair is then induced → SHM

30
Q

By which process do the variable portions of Ig’s change?

A

SHM: Somatic hyper mutation

31
Q

Where does B and T cell interaction occur?

A

At Marginal zone; the border of the B cell follicle

32
Q

What are some of the molecular bases of HIGM?

A
  • CD40 mutation
  • CD40L mutation (X linked)
  • AID mutation
  • UNG mutation
33
Q

Which processes is AID important for?

A
  • CSR (class switch recombination)

* SHM (somatic hypermutation)

34
Q

What happens on AID deficiency?

A

GC form, but there is no:
• CSR
• High affinity Ig

35
Q

What happens in CD40L deficiency?

A

• Defective B cell proliferation

No GC formation:
• No memory
• No CSR
• No SHM and Affinity maturation

36
Q

What are some therapies for HIGM?

A

Intragam (intravenous immunoglobulin)

Bone marrow transplantation

37
Q

What is CVID?

What are the manifestations?

A

Common variable immune deficiency

Individuals unable to produce one or two of the isotypes

More common than XLA and HIGM (1 / 25 000)

Less severe than those as well

38
Q

What are symptoms of CVID?

A

Recurrent pyogenic infections from encapsulated bacteria

39
Q

List some mutations that can cause CVID

A
  • TACI (most common)
  • ICOS
  • CD19
  • STAT3
40
Q

How many binding sites on the IgM pentamer?

Compare this with IgG and IgA

A

IgM: 10
IgG: 2
IgA: 4

41
Q

Which classes of Ig can be transferred to the placenta?

A

IgG only

NB IgA present in milk

42
Q

How do B cells ‘know’ how to produce the appropriate Immunoglobulin?

A

The helper T cell releases a certain program of cytokines that bring the CSR about.

43
Q

Which PID is most important?

A

(Primary immune deficiency)
CVID (common variable immunodeficiency)
It has the highest incidence

44
Q

Which antibody deficiency is the most severe?

Why?

A 
Order of severity:
• Agammaglobulinaemia: no B cells or Ig
• HIGM: only IgM
• CVID: missing only one or two isotopes
• SAD: missing Ab against certain polysaccharide antigens
45
Q

What is the treatment for HIGM?

A

IVIg

Bone marrow transplantation (in more serious cases)

46
Q

In which types of HIGM will a GC form?

When won’t a GC form?

A 
GC:
• UNG mutation
• AID mutation
• TACI
• STAT3
No GC:
• CD40L mutation
• CD40 mutation
• ICOS
• CD19
47
Q

What is the therapy for CVID?

A

IVIg

48
Q

Where are the CD40L and CD40 molecules located?

A

CD40L: Th cell
CD40: B cell

49
Q

Where is white pulp found?

A

In the spleen

50
Q

Which sort of infections is one more susceptible to in XLA?

Why?

A

Extracellular bacteria

Can’t make Ab, which is most important in protection against bacterial infections

T cell compartment, which mediated viral immunity, is still intact

51
Q

Which type of B cells are seen in HIGM patients?
Which are lacking?
Why is so?

A
  • Naïve cells present
  • Lacking memory B cells

This is because there is a mutation (CD40L, CD40, AID, UNG) that means that CSR and affinity maturation can not occur

52
Q

Compare the location of erythrocytes in the lymph nodes and the spleen

A

Spleen: red pulp

Lymph nodes: not found here

53
Q

Compare location of the genes for CD40L and CD40

A

CD40L: X-chromosome
CD40: Autosomal chromosome

54
Q

What is the driver of clonal expansion of B cells in GC?

A

T cells stimulate the clonal population of B cells to proliferate to produce a robust response through IL-21 signalling

55
Q

Describe the germ line configuration of constant regions at the heavy chain locus

A 
Downstream of VDJ mini gene segments:
• Cμ
• Cδ
• Cγ3
• Cγ1
• Cγ2b
• Cγ2a
• Cε
• Cα
56
Q

What happens to B cells in the absence of Blimp1?

A

The B cell can never be a plasma cell

57
Q

Compare the effect of the following on B cells:
• Bcl6
• Blimp1

A

B cell expression of

Blimp1 → plasma cell

Bcl6 → Maturation events in GC

58
Q

What is the function of UNG?

In which cells is it found?

A

Enzyme that removes uracils that AID inserted during SHM or CSR

Ubiquitous throughout the body

59
Q

What determines which class of Ig is made through CSR?

A

Depending on the infection, the DC will induce different Th cell subsets

These Th cell subsets will release specific cytokines that induce CSR to a specific isotype

60
Q 
When do the following mutations affect B cells:
• CD40L
• AID
• ICOS
• UNG
• CD40
• CD19
• TACI
• STAT3

In which cases would a germinal centre form?

Which disorder results?

A
  1. CD40L
    • B-T cell interaction at MZ
    • No germinal centre
    • HIGM
  2. AID
    • Maturation events in GC
    • GC still forms
    • HIGM
  3. ICOS
    • B-T cell interaction
    • No germinal centre
    • CVID
  4. UNG
    • Maturation events in GC
    • GC still forms
    • HIGM
  5. CD40
    • B-T cell interaction
    • No germinal centre
    • HIGM
  6. CD19
    • B-T cell interaction
    • No GC
    • CVID
  7. TACI
    • Maturation events in GC
    • GC still forms
    • CVID
  8. STAT3
    • Defective B cell response to cytokines
    • GC still forms
    • Hyper-IgE
61
Q

Compare cellular expression of the following:
• AID
• UNG

A

AID: only in B cells

UNG: all cells

62
Q

Which PID (of the ones spoken about) is less severe?

A

CVID

BIOM30002 - M2M (36 decks)

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