Molecular mechanisms behind B receptor diversity

Question 1

Heavy chains are 5 main types. What are they?

Answer 1

alpha, gamma, mu, epsilon and delta

Question 2

2 types of light chains

Answer 2

lamba and kappa

Question 3

What are 3 sets of immuglobin chain?

Answer 3

Kappa light chain
Lambda light chain
Heavy light chain

Question 4

The genes encoding the variable region (light and heavy chain) of each immunoglobin chain are present as multiple gene segments. What are those segments?

Answer 4

Variable (V) segments
Diversity (D) segment - only in heavy chains
Joining (J) segment

Question 5

Where is kappa chain locus present at

Answer 5

Chromosome 2

Question 6

Where is lamda chain locus present at

Answer 6

Chromosome 22

Question 7

Where is a heavy chain locus present at?

Answer 7

Chromosome 14

Question 8

Which gene segment is present at 5’ end of each locus and what does it do

Answer 8

V segment
It codes for a portion of variable region of immunoglobin chain
The no of v gene segment is different in each locus

Question 9

How many V gene segments are present in each of the locus

Answer 9

Kappa- 31 to 36
Light - 29 to 33
Heavy- 38 to 46

Question 10

Each variable gene segment has which sequence? What’s the function of this sequence?

Answer 10

Leader sequence
Encodes a leader peptide which facilitates the transport of Immunoglobulin through endoplasmic recticulum.

Not present in mature immunoglobulin as they are cleaved

Question 11

Which segment is present after V gene segment in each locus?

Answer 11

Joining Segment
J segment also encodes the portion of the variable region of the immunoglobulin chain.
Distance between V and J clusters varies in each locus

Question 12

How many J segments are present in each locus

Answer 12

K - 5
L- 4-5
H- 6

Question 13

Which gene segments are present only on heavy chain?

Answer 13

Diversity (D) gene segments
Present between V and J

Question 14

How many D gene segments are found at heavy chain locus?

Answer 14

23

Question 15

In light and heavy chain, variable region of an immunoglobulin is encoded by?

Answer 15

Light - V and J
Heavy- V D J

Question 16

The genes which code for constant region of an immunoglobulin are located where?

Answer 16

3’ of each locus
No and arrangment of C constant gene varies in each locus

Question 17

How many C genes are present in kappa chain locus

Answer 17

1 C gene which encodes the entire constant region
(no subtypes as there is only 1 C region)

Question 18

How many C genes are present in lamba chain locus and how are the arranged?

Answer 18

4-5 (give rise to multiple subtypes)
Each J segment is associated with 1 C gene

Question 19

How many C genes are present ?

Answer 19

9
C genes are arranged in order they appear in immune response

Question 20

What is V(D) J recombination?

Answer 20

A process by which B cells randomly assemble immunoglobulin gene segments (V, D, J) to form functional variable region exon
This process occurs in early development of lymphocytes

Question 21

What is the order of gene segments arrangement in light and heavy chain?

Answer 21

Light- V → J → C
Heavy- V → D → J → C

Question 22

How many recombination does L chains need?

Answer 22

1 recombination which joins 1 random V and 1 random J segment

Question 23

What are the steps in VDJ recombination of light chain

Answer 23

1 - Gene rearrangement - Randomly selected V gene segment is joined to random J gene segment. This joining creates an exon which encodes the whole light chain variable region.
Occurs during early development of each lymphocyte
2- Transcription occurs in which v-j joined rearranged dna is copied to pre-mRNA.
3- RNA splicing occurs in which introns are removed and variable region exon is joined to constant region exon.
4- Translation occurs in which mRNA is decoded into light chain polypeptide by ribosomes

Question 24

How many recombination does H chain need?

Answer 24

2 recombinations - 1 which joins random D segment to random J segment
1 which joins random V segment to DJ segment

Question 25

Which gene segments encode the variable region of the heavy chain?

Answer 25

V (Variable), D (Diversity), and J (Joining) segments recombine to form the variable region exon.

Question 26

Steps of VDJ recombination of heavy chain?

Answer 26

1- Random D and J joining 2- Random V and D-J joining 3- Transcription occurs in which v-d- joined rearranged dna is copied to pre-mRNA. 4- RNA splicing occurs in which introns are removed and VDJ exon is joined to constant region exon. 5- Translation occurs in which mRNA is decoded into heavy chain polypeptide by ribosomes

Question 27

Why is IgM the first antibody produced?

Answer 27

The Cμ (IgM) constant region is the first in the heavy chain locus, so it is transcribed first after VDJ recombination.

Question 28

What is the order of constant region genes in the heavy chain locus?

Answer 28

Cμ (IgM) → Cδ (IgD) → Cγ (IgG) → Cε (IgE) → Cα (IgA)

Question 29

The heavy chain locus consists of 9 constant regions but there are only 5 antibodies. Why>

Answer 29

The 9 constant regions encode the heavy chains for 5 antibody classes, but some classes have subtypes e.g. IgG has 4 subtypes whereas IgA has 2 subtypes So, even though there are 9 constant region genes, they group into 5 major antibody classes based on their function.

Question 30

Why do different antibodies have subtypes?

Answer 30

Different IgG subtypes have different abilities to bind Fc receptors and activate complement. IgA subtypes differ in function—IgA1 is found more in the blood, while IgA2 is more resistant to bacterial enzymes in mucosal surfaces.

Question 31

Define junctional diversity

Answer 31

Introduction of random mutations and deletions during V-(D)- J recombination which leads to amplification of the antibody diversity

Question 32

In junctional diversity, which region do the mutations occur

Answer 32

In variable region

Question 33

Which gene segments rearrange first in B-cell development?

Answer 33

Heavy chain (H chain) V-D-J segments rearrange first, followed by light chain (L chain) V-J segments.

Question 34

Which immunoglobulin do the immature B cells present

Answer 34

After successful VDJ and VJ rearrangement, the B cell produces a complete B-cell receptor (BCR). At the immature stage, only IgM is expressed on the surface. If the B cell passes negative selection (doesn’t react strongly to self-antigens), it matures.

Question 35

Which immuglobulins do the mature naive B cells express

Answer 35

Both IgM and IgD

Question 36

How do mature naïve B cells express both IgM and IgD?

Answer 36

Through alternative RNA splicing, allowing the same VDJ exon to be linked to either Cμ (IgM) or Cδ (IgD)

Question 37

What are blood-borne antigens and where are they filtered?

Answer 37

Antigens that enter blood stream e.g bacteria, virus. Filtered in spleen

Question 38

What are tissue derived antigens and where are they filtered?

Answer 38

Antigens which enter the body through tissues, like from cuts. Filtered in lymph nodes

Question 39

How can naive B cell recognise antigens

Answer 39

Recognizes free antigens directly. Recognizes antigens presented by APCs. Interacts with T helper (CD4) cells for full activation.

Question 40

What happens after a B cell is activated?

Answer 40

Somatic hypermutation (SHM) – Improves antigen binding. Class-switch recombination (CSR) – Changes antibody type. Clonal expansion – Multiplies to fight infection.

Question 41

Which T helper cells signal for which antibody types?

Answer 41

TH1 cells → IgG, IgA TH2 cells → IgE

Question 42

Define somatic hypermutation and why is it important?

Answer 42

Somatic hypermutation (SHM) is a process where mutations (small changes) occur in rapidly proliferating B lymphocytes within a week of exposure. It increases antibody affinity for antigens, making the immune response more effective.

Question 43

Which enzyme is responsible for inducing random mutations in the somatic hypermutation process and where does it induce mutation?

Answer 43

Activation-induces cytidine deaminase (AID) Induces high rate random point mutation in VJ and VDJ hypervariable complementary regions but not in the constant regions

Question 44

Do immune responses start with lower or higher affinity immunoglobulins?

Answer 44

Lower affinity Igs After SHM, B cells with stronger antigen binding (through BCR) are selected. These selected B cells proliferate (clonal expansion) and turn into plasma cells. Plasma cells mass-produce antibodies (immunoglobulins) that match their high-affinity BCR. Over time, higher-affinity immunoglobulins (antibodies) dominate the immune response.

Question 45

Where does somatic hypermutation occur?

Answer 45

In the germinal centre of lymphoid organs (spleen, lymph nodes)

Question 46

What happens to B cells with weak antigen binding after SHM?

Answer 46

They undergo apoptosis and are eliminated

Question 47

What is affinity maturation?

Answer 47

The process where B cells with high-affinity BCRs are selected and expanded, leading to stronger antibodies

Question 48

Define class switching

Answer 48

A process where a B cell changes its antibody type (IgM → IgG, IgA, or IgE) without altering variable region

Question 49

Why do B cells undergo class switching?

Answer 49

To produce antibodies with different effector functions (e.g., IgG for long-term immunity, IgA for mucosal immunity, IgE for allergy responses).

Question 50

Does class switching happen before or after somatic hypermutation?

Answer 50

After somatic hypermutation, so that only high-affinity B cells undergo class switching.

Question 51

What are the mechanisms of class switching

Answer 51

The VDJ recombined unit is moved next to a different C region. Intervening C regions are deleted via DNA recombination. Specificity not affected, only class.

Question 52

Can a B cell switch back to IgM after class switching?

Answer 52

No, class switching is irreversible because the deleted DNA cannot be restored.

Question 53

What role do T helper cells play in class switching?

Answer 53

They provide cytokine signals that determine which antibody class the B cell switches to: TH1 cells → IgG, IgA TH2 cells → IgE

Question 54

Which cytokine promotes switching to IgG2a or Ig3?

Answer 54

Interferon gamma

Question 55

Which cytokine promotes switching to IgA or IgG2b?

Answer 55

TGF-B

Question 56

How do TH cells influence B cells

Answer 56

T_H cells recognize antigen-presenting cells (APCs) → They get activated. Activated T_H cells produce cytokines, signaling B cells to switch antibody types. B cells receive these cytokine signals, leading to class switch recombination (CSR) based on the cytokine environment. Different antibodies are produced, depending on the infection type.

Question 57

What problems may arise from such diversity?

Answer 57

1- BCRs and antibodies are so diverse they could potentially recognize our own self molecules e.g. insulin (type 1 diabetes) 2- During B cell and T cell development, they are "educated" to distinguish between self and non-self in the bone marrow (B cells) and thymus (T cells). Cells that react strongly to self-antigens are usually eliminated or inactivated. If this tolerance fails, the immune system starts attacking the body’s own cells, leading to autoimmune diseases like lupus, rheumatoid arthritis, or Type 1 diabetes.

Question 58

What are the positive consequences of this diversity?

Answer 58

1- Through somatic hypermutation and affinity maturation, B cells evolve to produce higher-affinity antibodies that bind more strongly to pathogens. 2- Once exposed to an antigen, memory B and T cells remain in the body. Upon re-exposure, these memory cells respond faster and more effectively, providing long-term immunity 3- Clonal selection ensures that only non-self-reactive B and T cells are activated. This process prevents autoimmunity while ensuring an efficient immune response to pathogens.