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Infection And Immunity > B cells and antibody production > Flashcards

B cells and antibody production Flashcards

1
Q

whats the basic structure of Ab?

A
  • 2 identical light chains Constant and variable domains (VLCL). Encoded by rearranging variable, joining and constant elements (VLJLCL)
  • 2 identical heavy chains Constant and variable domains (CHVH). Encoded by rearranging variable, joining, diversity and constant elements (VHDHJHCH)
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2
Q

what are antibodies?

A

Soluble plasma proteins
Monomers, dimers or pentamers
ISOTYPE - IgA IgD IgE IgG IgM
Effector functions: fix complement - neutralise - block - opsonise - interact with cells etc.

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3
Q

what are B cell antigen receptors?

A
  • Cell surface-bound Ig of any isotype.
  • Only found on B cells
  • Always a monomer
  • No effector functions
  • Senses the antigenic environment of the B cell
  • Connects the extracellular environment with signalling pathways
  • Activates B cell effector function
  • Only one antigen specificity per B cell
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4
Q

how are Immunoglobulins bifunctional?

A
  • Conserved enough to interact with small number of specialised molecules.
  • Allow changes to interactions during an immune response.
  • Allow extensive variation between antibodies to match the infinite number of potential antigens but retain specificity throughout the immune response
  • requires the protein to be both conserved and infinitely variable
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5
Q

what is the Immunoglobulin fold?

A
  • a β barrel of 7 (CL) or 8 (VL) strands connected by loops and held together with a disulphide bond
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6
Q

The domains all look the same how can domain structure account for bifunctionality?

A

Examine genes encoding VH & VL domains

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7
Q

how does Organisation of Ig VH domain genes Maximise diverse specificity?

A
  1. COMBINATORIAL DIVERSITY - VH1 domains made from any combination of V gene with a D gene and a J gene
  2. JUNCTIONAL DIVERSITY - Imprecise breaking and joining of DNA when V, D and J genes recombine
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8
Q

how is the Ig heavy chain gene rearranged?

A
  • RNA splicing joins the CH domains.
  • Imprecise breaking and rejoining of DNA between the V and D genes and the D and J genes creates diversity of sequence and specificity
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9
Q

How does diversity arise from Ig light chain gene rearrangements (κ and λ)

A
  1. any V gene being able to join to any J gene
  2. deliberate errors in breaking and rejoining DNA
  3. insertion of new nucleotides between the join
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10
Q

what are Hypervariable sequences in Ig?

A
  1. COMPLEMENTARITY DETERMINING REGIONS (CDRs)
    Distinct regions of high variability suggested region of antibody interacted with antigens.
  2. More conserved parts acted as a FRAMEWORK (FR), on to which the hypervariable regions were suspended
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11
Q

how does Organisation of Ig CH chain genes Maximise effector function?

A
  • the ability to switch to, one of several isotype-defining C genes
  • Each CH chain domain is encoded by a separate exon
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12
Q

Summarise Bifunctionality of antibodies explained

by domain structure

A
  • Fc- Structurally conserved end Effector functions
  • Fab- Structurally diverse end Antigen recognition
  • Light chain C domains κ or λ
  • Heavy chain V domain
  • Heavy chain C domains 3 x α, δ, γ, or 4 x μ, ε
  • Papain cleavage sites- 2 x Fab 1 x Fc
  • Domain structure allows diverse specificity with conserved Fc-dependent effector function
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13
Q

Why are they called ‘B’ cells?

A

1954 - Bruce Glick, Ohio State University

Functional studies of the bursa of Fabricius - a lymphoid organ in the cloacal region of birds

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14
Q

what was Bruce Glick’s experiment?

A
  • Bursectomy – no apparent effect
  • Bursectomised chickens re-used to raise anti-Salmonella antibodies
  • Bursectomised chickens did not make anti-Salmonella antibodies
  • The Bursa therefore the organ which antibody producing cells developed
  • No bursa of Fabricius in mammals - bone marrow
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15
Q

how is Bone Marrow a maturation & differentiation microenvironment for B cells

A
  • Regulates construction of antigen receptors
  • Ensures each cell has one specificity
  • Checks and disposes of self-reactive B cells
  • Exports useful cells to the periphery
  • Is a site of antibody production
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16
Q

how do Stromal cells nurture developing B cells?

A
  1. Contact between stromal cells and developing B cells

2. Secrete CYTOKINES at each stage of differentiation

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17
Q

how do Cytokines and cell-cell interactions regulate differentiation?

A

Different cytokines and cell-cell contacts are required at each stage of differentiation

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18
Q

how is The stage of differentiation is defined by Ig gene rearrangement

A

Stem cell- Germline unrearranged
Early pro-B- DH to JH
Late pro-B- VH to DHJH
Large pre-B- VHDHJH, PRE-B CELL RECEPTOR expressed

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19
Q

what are the Consequences of pre-B cell receptor ligation?

A
  1. Suppresses further H chain rearrangement
  2. Triggers entry into cell cycle
  3. Ensures only one specificty of Ab expressed per cell
  4. Expands only the pre-B cells with in frame VHDHJH joins
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20
Q

what is ALLELIC EXCLUSION

A

Expression of a gene on one chromosome prevents expression of the allele on the second chromosome

21
Q

what is the Evidence for allelic exclusion of Ig genes?

A
  1. one allotype is inherited from each parent
  2. Allotypes identified by staining B cell surface Ig with antibodies
  3. Suppression of IgH gene rearrangement after pre-B cell receptor ligation prevents two specificities of antibody per B cell
22
Q

why is Allelic exclusion important?

A

prevents autoimmunity
Suppression of IgH gene rearrangement ensures only one specificity of Ab per cell –may prevent pathogens provoking undesirable responses

23
Q

why is allelic exclusion needed to prevent ‘holes in the repertoire?

A
  1. Two specificities of Ag receptor per cell – anti-brain Ig AND anti S. aureus
  2. Infection with S. aureus due to self tolerance
  3. ‘Hole’ in the repertoire of B cell specificities allows infection to proceed unchecked.
24
Q

what are the Consequences of pre-B cell receptor ligation?

A
  1. Suppresses further H chain rearrangement
  2. Triggers entry into cell cycle
  3. Ensures only one specificty of Ab exparessed per cell
  4. Expands only the pre-B cells with in frame VHDHJH joins
25
Q

why are Large pre-B cells need in frame VHDHJH joins to mature?

A

Only B cells with potential to make a B cell receptor can pass this stage

26
Q

why is Heavy and light chain rearrangement wasteful?

A
  • Two “random” joins – only a 1:9 chance of a rearrangement being in frame
  • One “random” join only a 1:3 chance of a rearrangement being of frame
  • Only a 1:27 chance of an in frame rearrangement per B cell
  • Out of frame rearrangements arrest further B cell maturation
27
Q

how do B cells have more than one chance to

rearrange heavy chains

A
  1. DH-JH or VH-DJH On first chromosome 14

2. DH-JH or VH-DJH On second chromosome 14

28
Q

why is Heavy and light chain rearrangement wasteful?

A
  • Only a 1:27 chance of an in frame rearrangement per B cell

- Out of frame rearrangements arrest further B cell maturation

29
Q

what are Lymph nodes

A

A secondary lymphoid organ in which lymphocytes and antigens encounter each other

30
Q

describe Lymphocyte recirculation through 2° lymphoid tissue

A

Non-lymphoid cells
Pass through the blood vessels in the lymph node and continue arterio-venous circulation
Lymphoid cells
Adhere to and squeeze between HIGH ENDOTHELIAL VENULES (HEV), then percolate through the lymph node and exit via the efferent lymphatic vessel

31
Q

how do Cells with antigen receptors check for recognition of self antigens

A 
EXPORT
DELETION
ANERGY
STALLED MATURATION
RECEPTOR EDITING
32
Q

explain Germinal Centre formation

A
  1. Antigen drains in lymph and on cells into afferent lymphatic.
  2. Ag activated B cells increase CCR7 expression and move to CCL19/21 rich T/B zone border
  3. GERMINAL CENTRE forms – a transient structure of intense proliferation
  4. B cells released by germinal centre differentiate into plasma & memory cells
  5. Mature B cells leave blood via
    HEV and home to the B cell follicles - CXCL13/CXCR5 dependent
33
Q

whats the difference between Follicular dendritic cells

and DCs?

A

FDC- Probably develop from mesenchymal precursors
DC- Bone marrow derived
DC are the only antigen presenting cell that can present antigen to naïve (as opposed to memory) T cells.
DC are crucial to establishing the primary immune response

34
Q

explain Germinal Centre formation

A
  1. Antigen drains in lymph and on cells into afferent lymphatic.
  2. Ag activated B cells increase CCR7 expression and move to CCL19/21 rich T/B zone border
  3. GERMINAL CENTRE forms
  4. B cells released by germinal centre differentiate into plasma & memory cells
  5. Mature B cells leave blood via HEV and home to the B cell follicles - CXCL13/CXCR5 dependent
35
Q

describe FDC bead formation & release

A
  • Veils on antigen-bearing DC surround the FDC beads.
  • Immune complexes transferred from DC to FDC beads.
  • B cells also involved in transport of immune complexes to FDC
  • Immune complexes bind to and are taken up by B cell
    surface immunoglobulin
36
Q

explain Germinal Centre formation

A
  1. Antigen drains in lymph
  2. Ag activated B cells and move to T/B zone border
  3. GERMINAL CENTRE forms
  4. B cells released by germinal centre differentiate into plasma & memory cells
  5. Mature B cells leave blood via HEV and home to the B cell follicles
37
Q

describe FDC bead formation & release

A
  • antigen-bearing DC surround FDC beads.
  • Immune complexes transferred from DC to FDC beads.
  • B cells also involved in transport of immune complexes to FDC
  • Immune complexes bind to and are taken up by B cell
    surface immunoglobulin
38
Q

how do T cells help B cells survive?

A
  1. Signal 1 antigen & antigen receptor
    Signal 2 delivered via CD40 and cytokines in the germinal centre
  2. B cells are inherently prone to die by apoptosis
  3. Signals 1 & 2 upregulate Bcl-XL, which rescues B cells from apoptosis
  4. Signal 2 from T cells allows the B cell to survive
  5. T cells control the CLONAL SELECTION of B cells
39
Q

where do T cells control B cell clonal selection?

A

germinal centre

40
Q

what is affinity maturation?

A
  1. Cells accumulate mutations in their CDR
  2. are selected or neglected on the basis of antigen binding affinity
  3. affinity ‘matures’ throughout the response
41
Q

how do T helper cells control affinity maturation?

A
  1. if a cell has a higher affinity for antigen, it will
    - bind more antigen (receive more signal 1)
    - present more antigen to T cells (solicit and receive more signal 2)
    - express more CD40 (receive more signal 2)
    - express more cytokine receptors (receive more signal 2)
  2. Receipt of more signal 1 and 2 gives the cell a selective advantage i.e. it is rescued from apoptosis and is clonally selected.
  3. Cells with lower affinity receptors are neglected and die by apoptosis
42
Q

how do T cells help B cells survive?

A

T cells control CLONAL SELECTION of B cells
1. Signal 1 antigen & antigen receptor
Signal 2 delivered via CD40 and cytokines in the germinal centre

  1. B cells are inherently prone to die by apoptosis
  2. Signals 1 & 2 upregulate Bcl-XL, which rescues B cells from apoptosis
  3. Signal 2 from T cells allows the B cell to survive
43
Q

how do T helper cells control antibody isotype switching in the germinal centre?

A
  1. Diverse effector function arises from ability to switch isotype-defining C genes
  2. Class Switch Recombination (CSR) is T cell dependent and takes place in the germinal centre
44
Q

what are Switch regions?

A

Repetitive regions of DNA upstream of C regions

45
Q

how do switch regions work?

A
  1. Switching similar to V(D)J recombination.

2. Occurs after B cell activation by antigen and help from T cells in germinal centres

46
Q

what is Switch recombination?

A

At each recombination constant regions are deleted from the genome
An IgE - secreting B cell will never be able to switch to IgM, IgD, IgG1-4 or IgA1

47
Q

what is an ALLOTyPE?

A

a polymorphism in a conserved region of Ig

48
Q

what are High endothelial venules?

A

specialised properties to allow lymphocytes and no other types of cells into the lymph node

49
Q

what is the GERMINAL CENTRE?

A

a transient structure of intense proliferation

Infection And Immunity (16 decks)

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