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Microbiology And Immunology > Humoral Immunity; Antibodies and the life cycle of B cells > Flashcards

Humoral Immunity; Antibodies and the life cycle of B cells Flashcards

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1
Q

State the types of antibodies?

A
  • Membrane bound (B-cell receptor BC) OR secreted antibody
  • Secreted antibody is released by plasma cells
  • Membrane bound / BCR is found on activated B cells
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2
Q

Describe the difference between membrane and secreted Ig in terms of its structure?

A
  • Both have same constant and variable region (if same clas)
  • Difference between secreted + membrane Ig structure
  • Secreted Ig -> Tail piece
  • Membrane Ig -> Hydrophobic transmembrane region + Cytoplasmic tail
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3
Q

Describe the complete structure of an antibody in terms of general bonding?

A
  • General bonding:
  • String of AA ( NH3+ + COO- ends) -> Chains joined via disulphide bonds
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4
Q

Describe the complete structure of an antibody in terms of regions

A
  • Regions/fragments:
  • Variable region: Different -> Contains complementarity determining regions/ antigen binding site (Fab) (VH + VL)
  • Constant region -> biological activity + Same for all Ab of same class
    • Hinge -> flexibility
    • Glycosylation (CHO bond) on CH2 domain -> interaction to other immune cells
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5
Q

Describe the complete structure of an antibody in terms of chains?

A
  • Chains:
  • Light (2 chains/4 domains): k or \ chain
  • Heavy (2 chains 4 domains):
  • u,s,v, a or & chain (9 different HCs) (VD)
  • y1, y2, y3, y4
  • a1, a2
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6
Q

State the major antibody effector functions once antigen binded? (3) (PART 1)

A
  1. Virus & toxin neutralisation: Prevents pathogen-host binding
  2. Opsonization (tagging of pathogen -> increased visibility for immunity)
    a. ADCP (antibody-dependent cellular phagocytosis)
    I. Recruits Macrophages via FC binding on M
    II. Phagocytosis -> smaller pathogens
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7
Q

State the major antibody effector functions once antigen binded? (3) (PART 2)

A

b. ADCC (antibody-dependent cellular cytotoxicity)
I. Recruits NK cells
II. NK-induced apoptosis -> infected or cancerous cells
3. Complement fixing/ MAC formation (CDC)
a. MAC = Membrane attack complex -> complement-dependent cytotoxicity (CDC)
b. Binds to complements (c1q, c1s, c1r) -> Causes phagocytosis or lysis

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8
Q

State the 5 different classes of antibodies describing its differences

A
  • IgG: Main AB of secondary response
  • IgD: Indicates mature B cells: only AB not secreted
  • IgE: Allergy/ anti-parasites
  • IgA: Secreted into mucous, tears, saliva
  • IgM: Main AB of primary response
  • All differ in HC constant region + function
  • IgA and IgM both have J chains, but IgA has secretory components
  • BCR = B-cell receptor
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9
Q

Describe heavy chain class switching, its purpose and the 2 types?

A
  • Only affects heavy chain CONSTANT region
  • Allows for Different effector functions - deal with different pathogens
  • Minor: Differential splicing (mRNA level) -> Doesn’t affect DNA: IgM and IgD (last lecture)
  • Major: DNA recombination: IgM to IgG, IgA, IgE. IgG to IgA, IgE
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10
Q

Describe the two factors required for class switching to occur?

A
  • CD40L on T cell interacts with CD40 on B cells + cytokine signalling -> signals what Ig to convert to depending on what cytokines are signalled
  • VD
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11
Q

Describe the mechanism behind major recombination of class switching

A
  • Known as class switch recombination
  • Factors required: 1. Cytokine signal 2. Switch regions 3. AID and DSB (double strand break) repair proteins
  • Recombination occurs between switch regions
  • Switching only proceeds downstream: IgM to IgG, IgA, IgE. IgG to IgA, Ig
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12
Q

Provide a summary for this section

A
  • Antibodies - secreted by B cells to neutralize pathogens; B-cell receptor
  • Structure - 2 HC, 2LC: domain vs fragment. membrane-bound vs secreted
  • VH and VL CDRs bind to antigen
  • 5 classes of antibodies - different effector functions to deal with different pathogens
  • Class switching: Heavy chain constant region change, the rest stays the same
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13
Q

Life cycle of B cells

A

VD

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14
Q

Generation of B cells (life cycle)
What’s the Difference between somatic recombination vs differential splicing?

A
  • Somatic recombination: Alteration of DNA level -> irreversible once coded -> e.g. V(D)J recombination, Tdt nucleotide addition, Somatic hypermutation + Class switching
  • Differential splicing -> Changes at mRNA level -> E.g. IgM and IgD, Membrane bound + secreted Ig
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15
Q

Describe key principle behind how unique antibodies are formed?

A

Body -> formation of many resting B cells -> each with unique, random BCR

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16
Q

Antigen-independent phase of B cell life cycle
Describe the antigen-independent phase within the life cycle of B cells?

A

Bone marrow:
- Stem cell -> Pro-B cell -> Pre- B cell -> immature B cell - mature/resting/naive recirculating B cell (IgM OR IgD)
- Pro-B to Pre-B -> 1) D-J recom. 2) V-DJ recom. -> codes HCVR + u constant R
- Pre-B to immature -> placeholder LC expressed + V-J recom. -> LCV + constant
- Immature-mature -> Additional diversity mechanism -> junctional flexibility + P & N nucleotide addition ->random + generates unique B cells
- Mature -> Quality control -> IgM or ID production via differential splicing

17
Q

V(D)J recombination
What is inherited in terms of antibody genes and what does it generate?

A
  • Only Gene segments -> arranged in different combinations -> different lg generated
18
Q

Describe what happens in V(D)J recombination?

A
  • LC (VJC) + HC (VDJC(u)) -> specific segments chosen
  • LC - VJ recombination -> variable region
  • HC - VDJ recombination -> VR
  • J or D/J -> codes CDR3 (most variable region)
19
Q

State the 3 genetic loci + chromosome that codes for lg

A
  • LC -> kappa (к/C2) + lambda (\/C22) -> VJ
  • HC -> C14 -> VDJ
20
Q

Describe VJ recom. of kappa light chain gene + number of segments?

A
  • 40 Variable (V), 5 Joining (J) , Constant region (C)
  • Germline k-chain DNA -> random segment (VJ) chosen -> Rearranged K-chain -> transcription -> Splicing -> translation
21
Q

Describe VDJ recom. of heavy chain gene + number of segments? VD

A

51 Variable (V), 27 Diversity (D), 6 Joining (J), Constant region (C)

22
Q

What are recombination signal sequences and state the 2 types?

A
  • RSS: Conserved sequences upstream or downstream of gene segments
  • Types -> Turn -> heptamer + nonamer + spacer
  • One turn -> 12 op S
  • Two turn -> 23 bp S
23
Q

Describe the one-turn/two-turn rule in V(D)J recombination?

A

Recombination: ONLY between one turn + two turn -> Prevents D/V/J recombination

24
Q

Describe the complete mechanism behind V (D) J recombination? VD

A
  • Diversity generated after minor hairpin formation
  • Enzymes bind turn + pull together -> Major hairpin formed (whole DNA folded in half) -> cleavage at hairpin site (random) via artemis -> Minor hairpin formed (between 2 strands) with overhanging ends -> exonuclease + TdT repair & joining via add or removing nucleotides -> P nucleotides addition to overhang -> N/TDT nucleotide addition via terminal deoxynucleotidiyl transferase (Tdt)
    (mostly HC) -> coding + signal joint formed
25
Q

State 7 mechanisms involved in the generation of antibody diversity?

A
  • Multiple germline V, D and J gene segments
  • Combination V-J and V-D-J joining
  • Junctional flexibility
  • P-nucleotide addition
  • N-nucleotide addition
  • Combinatorial association of HC + LC, Somatic -
  • Hypermutation during affinity maturation
26
Q

Describe the mechanisms involved within junctional diversity stating good + bad points?

A
  • Junctional flexibility during V(D)J recombination, P + N nucleotide additions
  • Good: Antibody diversity
  • Bad: Non-productive rearrangements (incorrect reading frame) - wasteful process
27
Q

Describe junctional diversity?

A
  • Removal of mismatched nucleotides via exonuclease -> between gene segments during V(D)J recombination -> Precise mechanisms unknown -> Signal joint is precise (no removal)
  • Happens at the end of VDJ after P and N nucleotide addition
28
Q

Describe allelic exclusion?

A

Two copies of Ig (mum + dad) -> In cells, both genes expressed - AB gene is different: Only 1 HC + LC allele expressed
- Antibody exclusion is where B cell make one type of Antibody
- Order of rearrangement -> Heavy > kappa> lambda -> Each one - 1st allele then 2nd -> if recombination is not successful -> cell becomes apoptosed

29
Q

Summary

A
  • Life cycle of B cell - antigen-independent phase (bone marrow)
  • B cell receptor diversity at this stage generated by:
  • Multiple germline genes
  • Heavy and light chain combinations
  • V (D)J recombination (one-turn/two-turn rule)
  • Additional diversity: P and N nucleotide addition; Junctional flexibility
  • Mature, naive B cells expresses IgM and IgD
  • Somatic recombination vs differential splicing
  • Allelic exclusion
30
Q
A

Mature B cell -> spleen/lymph node -> activated B cell (via binding pathogen + Th cell) -> Affinity maturation (GC) : 1. clonal expansion 2. Somatic hypermutation 3. Selection -> cycle occurs several times -> class switching (app. effector functions) -> plasma cells (some move into blood)

31
Q

State the processes involved within B cell activation?

A

1) T-cell independent -> Pathogen encountered -> diff. + clonal expansion of activated B cells - Same time T cell activated
2) T-cell dependent -> 3 signals required -> Antigen binding to BCRs, Co-stimulation by activated Th cell specific to same antigen, Th cell-derived cytokines production
- signal transduction pathway -> BC binding -> Tyrosine kinase activation
- cell pro., diff. + survival

32
Q

Describe the purpose of clonal expansion

A

Pathogen attacks B cell -> combines + activates -> B cell cloned -> affinity maturation

33
Q

What is affinity maturation and state key features?

A
  • Improves affinity of AB to antigen -> somatic mutations in lg V genes -> selection of high-affinity B cells (AB) for specific antigen
  • Site of AM -> Germinal centre in Lymph node -> Aided via T follicular helper cells (only T cells that can enter GC) + Follicular dendritic cells
34
Q

Describe how affinity maturation occurs?

A
  • GC -> Dark zone + light zone
  • Dark zone -> clonal expansion -> AID (Activation-induced cvtidine deaminase) causes somatic hypermutation: point mutations in DNA of B cells -> Light zone -> Selection -> Increased affinity or decreased affinity pathway
  • Increased Affinity -> FDC presents antigen -> AB compete for limited antigens -> Successful AB present antigen to TfH cell -> survival sign to AB
  • Decreased affinity -> cells apoptose
  • B cells survive whole cycle -> enter dark zone -> Repeat cycle until AB affinity is increased
35
Q

State the relationship between AB affinity and cycles of affinity maturation?

A

Increased cycles -> Increased AB (present) affinity to antigen

Microbiology And Immunology (32 decks)

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