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HIS > HIS10 Antibody Structure And Function > Flashcards

HIS10 Antibody Structure And Function Flashcards

1
Q

How can B cells recognise so many different antigens

A

Gene rearrangement

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2
Q

Antigen recognition process

A
  1. Immunoglobulins (Ig)

2. T cell antigen receptor (TCR)

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3
Q

Immunoglobulin

A
  • Glycoprotein
  • present in serum and tissue fluid
  • some carried on B cell surface as receptors for specific antigens
  • some free in blood / lymph —> Antibodies
  • 10^7-10^8 different specificities
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4
Q

Structure of Immunoglobulins

A
  • Y-shaped
  • 4 polypeptide chains: 2 Heavy + 2 Light (κ + λ chains)
  • Joined by Disulphide bond —> make Fab area
  • Both heavy and light composed of Constant + Variable regions
  1. V regions (VH + VL) (Amino-terminal sequences):
    - Hypervariable region + Framework region
    - amino acid sequences of both Heavy and Light chains **vary greatly between different Ab
    - Each Ab have 2 **    identical Antigen binding sites (each via pairing of VH + VL)
    —> ***Antigen recognition
  2. C regions (Carboxy-terminal sequences):
    - **Constant between chains
    —> **    Effector functions

(Fab + Fc region: Top + bottom part)

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5
Q

V regions

A
  • Sequence variability not distributed evenly throughout
  • Background: 5-15% variation (0% for C region)
  1. Hypervariable regions (HV1-HV3) / Complementarity determining regions (CDR)
    - Maximum variation in **3 areas of VL / VH domains (same positions in IgG of different specificities)
    —> form loops at the edge
    —> when VH pair with VL
    —> **    Hypervariable loops from each domain brought together by folding
    —> single ***Hypervariable surface
    —> Antigen binding site at tip of each arm
    —> Antigen recognition
  • Hypervariable regions project around a cleft which is capable of containing an ***Epitope of 6-9 amino acids / carbohydrates

(Hypervariable regions:
H chain residues: 31-37, 51-68, 92-103
L chain residues: 24-34, 50-56, 89-97)

  1. Framework regions (FR1-FR4)
    - Intervening regions of **lesser variability (i.e. regions between Hypervariable regions)
    —> **    β sheets (provide ***structural framework of domain)
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6
Q

***Antigen specificity of combined VH, VL regions

A
  1. ***Amino acid sequences of V regions in the antigen binding site (Hypervariable regions)
  2. ***3-dimensional shape of antigen binding site
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7
Q

Germline theory, Somatic mutation theory

A

Germline theory:
- separate gene for each antibody
- antibody repertoire is inherited
—> BUT not enough genes in human body for such diversity

Somatic mutation theory:
- limited number of inherited antibody genes undergo mutation
—> generate repertoire during lifetime of individual

Recent discovery:
- antibody repertoire is generated from large but limited number of Ig genes by DNA **rearrangement
—> diversity enhanced by process of **somatic mutation

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8
Q

***Immunoglobulin gene structure

A

2 functionally distinct groups of exons encoding:
- V region
- C region
—> “2 genes, 1 polypeptide chain”

Ig genes encoding H and L chain are on different chromosomes:

  • H chain: 14
  • κ chain: 2
  • λ chain: 22

C region:
- both H and L chain is encoded by a separate exon

V region in H chain is encoded by 3 gene segments:

  1. V (variable)
  2. D (diversity)
  3. J (joining)

V region in L chain (κ + λ chains) is encoded by 2 gene segments:

  1. V (variable)
  2. J (joining)

簡單而言:
Different chromosome (for H + κ + λ chains)
—> separate genes for V / C region respectively
—> V region of L chain: 2 exons (V + J) (每一個exon都有幾種gene segments e.g. V1, V2, J1, J2 —> different combinations during gene rearrangement)
—> V region of H chain: 3 exons (V + D + J)
—> C region of L/H chain: 1 exon (C)

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9
Q

***Ig gene rearrangement process

A

H chain genes rearranged first (Pro-B cells stage)
—> then L chain genes (Pre-B cells stage)

H chain: D-J —(DNA recombination)—> V-DJ (i.e. VH) —(DNA recombination)—> VDJ-C —(RNA splicing)—> VDJC
L chain: V-J (i.e. VL) —(DNA recombination)—> VJ-C —(RNA splicing)—> VJC

Steps:
1. **Locating V, D, J gene segments
—> by **RAG-1 and ***RAG-2 genes (Recombination-activating genes)
—> Initiate Ig gene recombination

  1. Action by **DNA-PK (cutting), **DNA ligase (joining) etc.
    —> DNA cutting and rejoining (Deletional joining)
    —> able to rearrange different gene segments together
    —> forming functional regions
    (—> still contains additional J + D segments between rearranged segment and C genes)
  2. Whilst joining DNA ends of gene segments together
    —> not complementary
    —> require base substitution / **adding of nucleotides to single-strand (broken/naked) DNA ends
    —> by **    TdT (Terminal deoxynucleotidyl transferase)
    —> different nucleotides added into junctional region
    —> encoding different amino acids
    —> contribute to ***Junctional diversity
  3. Primary RNA transcript produced
    —> mRNA produced
    —> C region genes recombined with VJ / VDJ complex by **RNA splicing
    —> Light chain mRNA: VJC; Heavy chain mRNA: VDJC
    —> Heavy chain: **    first transcript always μ (i.e. **IgM)
    —> later in immune response **    H chain transcript will change and switch to other isotypes
  4. Polypeptides produced
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10
Q

***How is Antibody diversity generated?

A
  1. ***Numerous Ig gene segments (V region)
    - H chain: 65x variable, 27x diversity, 6x joining
    - L chain: 70x variable, 5x joining (κ) / 4x joining (λ)
  2. Random ***recombination of gene segments
    - H chain: 11,000 gene combinations
    - L chain: 350 gene combinations
  3. ***Junctional diversity (x 100 Heavy x 100 Light = 10^4 combinations)
  4. ***Pairing of H and L chain (same H chain can combine with different L chain)
    - 11,000 x 350 —> 3.5x10^6 different specificities

Overall:
Total potential antibody diversity at V regions&raquo_space; 10^11 combinations

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11
Q

Clinical significance of RAG genes

A

If lack RAG genes
—> Cannot initiate Ig gene recombination
—> NO functional (mature) B / T cell generated

Severe combined immunodeficiency disease (SCID)

  • genetic disorders result in impaired B and T cell immunity
  • 1-5 per 500,000
  • early death due to severe infection
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12
Q

Allelic exclusion

A

Productive Ig gene rearrangement only occurs on one chromosome
—> ensure each B cell only one specificity (e.g. either κ or λ but not both)

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13
Q

How antibodies produced by B cells?

A
  1. Recognition
  2. Activation (Proliferation + Differentiation)
  3. Reaction
    - Effector B cells
    - Memory B cells
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14
Q

Antibody isotopes

A

IgG, IgM, IgD, IgA, IgE

Variation in Constant region of Heavy chain

B cell can switch from producing one isotype (IgM mainly) to other isotypes during Ab-mediated immune response

Clinical significance:
- Defect in CD40/CD40L signaling
—> Ig cannot undergo class-switching
—> Hyper IgM syndrome (rare, inherited immune deficiency disorder)

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15
Q

IgG

A
  • Major Ig in normal human serum (80% of total Ig pool)
  • single 4-chain molecule (2 ***γ heavy + 2 κ/λ light)
  • 4 subclasses (difference in ***γ chain)
  • IgG1, IgG2, IgG3, IgG4 (decreasing average serum concentration)
  • distributed evenly between intravascular and extravascular
  • Major Ab for ***secondary immune response
  • all classes ***cross placenta —> confer high degree of passive immunity to newborn
  • Maternal IgG confers immunity to neonates during first few months of life
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16
Q

IgM

A
  • 10% of Ig pool
  • ***monomeric IgM: membrane-bound Ab on B cells
  • first Ig class produced in ***primary response to antigenically complex infectious organisms —> “early” Ab
  • first Ig synthesised by neonates
  • secreted by plasma cells as a ***pentamer (5 monomer units held by S-S bond linking carboxyl-terminal heavy chain domains)
  • each pentamer contains additional Fc-linked polypeptide —> **J chain —> allow IgM to bind to receptors on **secretory cells —> transport ***across epithelial lining to external secretions —> accessory role as secretory Ig
  • large size —> does not diffuse well —> largely confined ***intravascularly
17
Q

IgA

A
  • 15-20%
  • ***monomer
  • polymeric forms (dimers / trimers) (with J chain) sometimes seen
  • predominantly in external **seromucous secretions (breast milk, saliva, tears, mucus) as **Dimer / Tetramer + **J chain + **Secretory component polypeptide chain (produced by epithelial cells of mucous membrane)
  • transported across cells from tissue fluid to outside environment
18
Q

IgD

A
  • <1% of plasma Ig
  • present in large amount on B cell membrane
  • functions relatively ***unknown, may play a role in antigen-triggered lymphocyte differentiation

Recent research:
Bind to surface receptor on Basophils
—> activate Basophil
—> enhance immune surveillance (Antibacterial information)

19
Q

IgE

A
  • scarce in serum
  • found on surface of **Basophils and **Mast cells
  • ***Type 1 hypersensitivity reaction (Allergy: hay fever, asthma, hives, anaphylactic shock)
  • role in immunity of ***helminthic parasites
Type 1 hypersensitivity reaction:
IgE bind to Fc receptor on Mast cells
—> allergens bind to IgE
—> trigger ***degranulation of Mast cells
—> Histamine and other substances
20
Q

B cells are bad for heart

A
  1. B lymphocytes trigger monocyte mobilisation
    —> macrophages
    —> induce inflammation
    —> impair healing of heart after acute MI
  2. Also involved in Atherosclerosis process

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