6. Antigen receptors and their formation

Question 1

Non-specific immunreceptors

Answer 1

1) PRRs
2) Opsonic receptors
- Fc R
- Complement R

Question 2

Specific immunreceptors

Answer 2

Antigenreceptors

• BCR (B cell)
• Antibody (Plasma cell)
• TCR (T cell)

Question 3

What kind of epitope can be recognized by TCR/BCR

Answer 3

BCR:
- Whole molecule
- Conformational epitope
TCR
- Processed peptide (presented by MHC)
- Linear epitope

Question 4

T cell receptor structure

Answer 4

• Not secreted
• Heterodimer (α and β chain)
• One peptide binding region

Question 5

T cell receptor complex

Answer 5

• TCR (α+β)
• 2x CD3 (γ+ε and δ+ε) w/ITAM
• 2x ζ-chains w/ITAM-motif

Question 6

B cell receptor complex

Answer 6

• BCR (heavy+light chain)

- 2x Igβ+Igα w/ITAM motif

Question 7

B cell receptor structure

Answer 7

• Can be secreted
• Heavy + light chain
• 2 peptide binding regions

Question 8

Bound and secreted B cell receptors

Answer 8

Naive B cell - bound (TM region+cytoplasmic tail):
- IgM and IgD
Plasma cell - secreted (Tail piece):
- IgG, IgM, IgE, IgA and IgD

Question 9

Pentameric Ig

Answer 9

IgM

Question 10

Dimeric Ig

Answer 10

IgA

Question 11

Isotypic differences

Answer 11

Antibody classes
Heavy chains: α, γ, δ, ε and μ (IgA, IgG osv.)
(Light chains: κ and λ)

Question 12

Allotypic differences

Answer 12

Different alleles of a gene
Allotypes represent the genetically determined differences in antibodies between people
Used for paternity testing

Question 13

Idiotypic differences

Answer 13

Idiotypes are antibodies that recognize different specific epitopes (antigens)
The variable region can have different idiotopes

Question 14

Affector and effector region of antibody

Answer 14

Fab: affector region
Fc: effector region

Question 15

Hypervariable CDR on antibody

Answer 15

“Complementary determining region”

• Variable region of antibody (heavy+light end chains)
• Consists of CDR1, CDR2 and CDR3

Question 16

T cell receptor CDR

Answer 16

• 2 polymorphic residues on MHC (CDR1+CDR2)
• CDR3 is on peptide (T cell contact residue)
  (Peptide also contains anchor residues that attaches to MHC)

Question 17

Genetic dogma

Answer 17

One gene-> one RNA-> one protein

Question 18

Provides huge diversity of BCRs

Answer 18

Somatic gene rearrangement (VDJ recombination)
V: variable
D: diversity
J: joining
Light chain: V, J and C (constant region)
Heavy chain: V, D, J and C
*D and J are “parts of” variable chain

Question 19

Heavy chain rearrangement (VDJ)

Answer 19

1) D-J joining

2) V-DJ joining

Question 20

TCR VDJ recombination

Answer 20

Happens in the thymus
α-chain
- Variable region: L (leader), V and J
*CDR1 and -2 on V, CDR3 on J
β-chain
- Variable region: L, V, D and J
*CDR1 and -2 on V, CDR3 on D

Question 21

Theoretical diversity of Ab and TCR

Answer 21

1) Combination diversity
- Antibody: 210^6
- TCR:
-> α+β: 5,810^6
-> γ+δ: 2160
2) Juntional diversity
- Antibody: 10^13
- TCR (α,β,γ,δ): 10^18
Generelt: TCR more diverse than Ab

Question 22

Enzyme complex that mediate recombination

Answer 22

RAG1/RAG2 enzyme complex (recombinases)

• Only expressed in developing lymphocytes
• Recognized RSS (recomb. signal sequence) and cuts DNA

Question 23

Total diversity TCR and Ab

Answer 23

TCR: 10^18
AB: 5*10^13

Question 24

Allelic exclusion

Answer 24

Only one allele expressed

- Each B cell makes BCR of a single specificity

Question 25

Human heavy chain genes

Answer 25

``` Variable region: - V: 50 - D: 25 - J: 6 Constant region: - α, γ, δ, ε, μ ```

Question 26

Steps in H-chain synthesis of Ab

Answer 26

1) D-J joining 2) V-DJ joining => Rearranged H-chain DNA 3) RNA transcription 4) Post-transcriptional modifications (polyadenylation, RNA splicing) => mature mRNA 5) Translation => Polypeptide 6) Post-translational modifications => Finished H-chain

Question 27

Immature B cell

Answer 27

Only IgM

Question 28

Mature B cell

Answer 28

IgM and IgD

Question 29

Generation of antibody diversity

Answer 29

1) VDJ 2) Somatic hypermutation 3) Junctional flexibility 4) P-nucleotide addition 5) N-nucleotide addition 6) Combinatorial association of H- and L-chains

Question 30

Dangers in diversity

Answer 30

- Mechanism is random draw - Some Ig and TCRs will be autoreacive (must be eliminated!) - Chromosomal translocations can lead to lymphoid malignancies

Question 31

V(D)J recombination defects

Answer 31

Leads to SCID (severe combined immune deficiency) with a lack of T and B cells - Ommen syndrome (partial activity RAG1, RAG2 or Artemis endonuclease) - Bubble boy disease (IL-2 R-gamma mutation)