Adaptive Immunity 2

Question 1

How do we ensure that there is a BCR and/or TCR that can recognise every antigen?

Answer 1

The diversity of both the B and T cell repertoires is primarily produced by a process called somatic recombination or V (D) J recombination.

Question 2

The primary mechanism for generating immune cell diversity is through the process of …

Answer 2

The primary mechanism for generating immune cell diversity is through the process of VDJ recombination - this is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Question 3

VDJ recombination is the genetic recombination of a variable region with a … region and a … region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Answer 3

VDJ recombination is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Question 4

VDJ recombination is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (… gene) and T cells (… … … gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Answer 4

VDJ recombination is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Question 5

VDJ recombination is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, …-1 and …-2

Answer 5

VDJ recombination is the genetic recombination of a variable region with a diversity region and a joining region. This process occurs in both B cells (immunoglobulin gene) and T cells (T cell receptor gene) and generates a vast array of different B cell receptors and T cell receptors. The key enzymes responsible for this process are the recombination-activating genes, RAG-1 and RAG-2

Question 6

BCR germline sequences

• In B cells, V(D)J recombination takes place in the immunoglobin heavy chain gene (found on chromosome …) and kappa or lambda light chain genes found on chromosome … and … respectively
• The D in V(D)J is always in brackets because only the heavy chain gene contains diversity segments and so the light chain only undergoes VJ recombination.
• These recombination events can result in a vast array of new immunoglobulin genes. In B cells there are approximately 100 trillion possible combinations

Answer 6

• In B cells, V(D)J recombination takes place in the immunoglobin heavy chain gene (found on chromosome 14) and kappa or lambda light chain genes found on chromosome 2 and 22 respectively
• The D in V(D)J is always in brackets because only the heavy chain gene contains diversity segments and so the light chain only undergoes VJ recombination.
• These recombination events can result in a vast array of new immunoglobulin genes. In B cells there are approximately 100 trillion possible combinations

Question 7

In B cells, V(D)J recombination takes place in the … heavy chain gene (found on chromosome 14) and kappa or lambda … chain genes found on chromosome 2 and 22 respectively

Answer 7

In B cells, V(D)J recombination takes place in the immunoglobin heavy chain gene (found on chromosome 14) and kappa or lambda light chain genes found on chromosome 2 and 22 respectively

Question 8

The D in V(D)J is always in brackets because only the … chain gene contains diversity segments and so the … chain only undergoes VJ recombination.

Answer 8

The D in V(D)J is always in brackets because only the heavy chain gene contains diversity segments and so the light chain only undergoes VJ recombination.

Question 9

Recombination events can result in a vast array of new immunoglobulin genes. In B cells there are approximately … trillion possible combinations

Answer 9

Recombination events can result in a vast array of new immunoglobulin genes. In B cells there are approximately 100 trillion possible combinations

Question 10

TCR germline sequences

• V(D)J recombination takes place in the alpha chain gene (found on chromosome ….) and the beta chain gene found on chromosome … Like B cell immunoglobulin light chains, the alpha chain does not contain diversity segments and so only undergoes VJ recombination.
• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations!
• The probable reasons for this are two-fold:
  
  • New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution.
  • B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Answer 10

• V(D)J recombination takes place in the alpha chain gene (found on chromosome 14) and the beta chain gene found on chromosome 7. Like B cell immunoglobulin light chains, the alpha chain does not contain diversity segments and so only undergoes VJ recombination.
• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations!
• The probable reasons for this are two-fold:
  
  • New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution.
  • B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Question 11

TCR germline sequences

• V(D)J recombination takes place in the … chain gene (found on chromosome 14) and the … chain gene found on chromosome 7. Like B cell immunoglobulin light chains, the … chain does not contain diversity segments and so only undergoes VJ recombination.
• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations!
• The probable reasons for this are two-fold:
  
  • New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution.
  • B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Answer 11

• V(D)J recombination takes place in the alpha chain gene (found on chromosome 14) and the beta chain gene found on chromosome 7. Like B cell immunoglobulin light chains, the alpha chain does not contain diversity segments and so only undergoes VJ recombination.
• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations!
• The probable reasons for this are two-fold:
  
  • New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution.
  • B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Question 12

V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations! Why is this?

Answer 12

• The probable reasons for this are two-fold:
  
  • New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution.
  • B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Question 13

• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations! Why is this?
• The probable reasons for this are two-fold: 1) New B cells are being born every day whereas the T cell pool is pretty much fixed from late … due to … involution. 2) B cells can induce further diversity due to … … – T cells do not undergo this process.

Answer 13

• V(D)J recombination in T cells can theoretically produce even more diversity than B cells – approximately a million trillion combinations! Why is this?
• The probable reasons for this are two-fold: 1) New B cells are being born every day whereas the T cell pool is pretty much fixed from late adolescence due to thymic involution. 2) B cells can induce further diversity due to somatic hypermutation – T cells do not undergo this process.

Question 14

Like B cell immunoglobulin light chains, the … chain does not contain diversity segments and so only undergoes VJ recombination (In T cells)

Answer 14

Like B cell immunoglobulin light chains, the alpha chain does not contain diversity segments and so only undergoes VJ recombination. (In T cells)

Question 15

New gene sequences are produced through V(D)J recombination

• During the pro B (and pro T) cell phase of development, the cells undergo … recombination. In the case of B cells this occurs in the Immunoglobin Heavy chain gene and in T cells this occurs in the beta chain gene. Subsequently, these respective genes recombine their new … segments with a new … segment. Finally, the light chain genes undergo … recombination.
• These new pieces of genetic code are then transcribed into mRNA and then translated into proteins. Assembly of the IgH chain and one of the light chains (either kappa or lambda) results in the formation of membrane bound immunoglobulin IgM (and IgD) that are expressed on the surface of immature B cells.

Answer 15

• During the pro B (and pro T) cell phase of development, the cells undergo DJ recombination. In the case of B cells this occurs in the Immunoglobin Heavy chain gene and in T cells this occurs in the beta chain gene. Subsequently, these respective genes recombine their new DJ segments with a new V segment. Finally, the light chain genes undergo VJ recombination.
• These new pieces of genetic code are then transcribed into mRNA and then translated into proteins. Assembly of the IgH chain and one of the light chains (either kappa or lambda) results in the formation of membrane bound immunoglobulin IgM (and IgD) that are expressed on the surface of immature B cells.

Question 16

New gene sequences are produced through V(D)J recombination

• During the … B (and … T) cell phase of development, the cells undergo DJ recombination. In the case of B cells this occurs in the … gene and in T cells this occurs in the … chain gene. Subsequently, these respective genes recombine their new DJ segments with a new V segment. Finally, the light chain genes undergo VJ recombination.
• These new pieces of genetic code are then transcribed into mRNA and then translated into proteins. Assembly of the IgH chain and one of the light chains (either kappa or lambda) results in the formation of membrane bound immunoglobulin IgM (and IgD) that are expressed on the surface of immature B cells.

Answer 16

• During the pro B (and pro T) cell phase of development, the cells undergo DJ recombination. In the case of B cells this occurs in the IgH gene and in T cells this occurs in the beta chain gene. Subsequently, these respective genes recombine their new DJ segments with a new V segment. Finally, the light chain genes undergo VJ recombination.
• These new pieces of genetic code are then transcribed into mRNA and then translated into proteins. Assembly of the IgH chain and one of the light chains (either kappa or lambda) results in the formation of membrane bound immunoglobulin IgM (and IgD) that are expressed on the surface of immature B cells.

Question 17

… chain rearrangement is a single step VJ recombination

Answer 17

Light chain rearrangement is a single step VJ recombination

Question 18

… chain rearrangement involves a DJ recombination event followed by a VDJ rearrangement

Answer 18

Heavy chain rearrangement involves a DJ recombination event followed by a VDJ rearrangement

Question 19

How Does Rearrangement Occur?

• Rearrangement occurs between specific sites on the DNA called … … … (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Answer 19

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Question 20

How Does Rearrangement Occur?

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a …, a spacer and a …
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Answer 20

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Question 21

How Does Rearrangement Occur?

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of … segments, the 5’ side of … segments and both the 3’ and 5’ side of … segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Answer 21

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Question 22

How Does Rearrangement Occur?

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: … and …

Answer 22

• Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs)
  
  • These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer
  • They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments
• Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2

Question 23

The … encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination

Answer 23

The RAGs encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination

Question 24

Steps in V(D)J Joining

• Rearrangement begins with the binding of the …-1:…-2 complexes to the recombination signal sequences or RSSs which flank the coding sequences to be joined.
• The … complex is then activated to cut one strand of the double-stranded DNA precisely at the end of the heptamer sequences. The 5′ cut end of this DNA strand then reacts with the complementary uncut strand, breaking it to leave a double-stranded break at the end of the heptamer sequence, and forming a hairpin by joining to the cut end of its complementary strand on the other side of the break.
• Subsequently, through the action of additional proteins such as Ku70:Ku80 that join the complex, the DNA hairpin is cleaved at a random site to yield a single-stranded DNA end.
• This end is then modified by the action of TdT (indicated in pink), which creates diverse, imprecise ends.
• Finally, the two heptamer sequences, which are not modified, are ligated to form the precise signal joint, while the coding joint is also ligated, both by the action of DNA ligase IV.

Answer 24

• Rearrangement begins with the binding of the RAG-1:RAG-2 complexes to the recombination signal sequences or RSSs which flank the coding sequences to be joined.
• The RAG complex is then activated to cut one strand of the double-stranded DNA precisely at the end of the heptamer sequences. The 5′ cut end of this DNA strand then reacts with the complementary uncut strand, breaking it to leave a double-stranded break at the end of the heptamer sequence, and forming a hairpin by joining to the cut end of its complementary strand on the other side of the break.
• Subsequently, through the action of additional proteins such as Ku70:Ku80 that join the complex, the DNA hairpin is cleaved at a random site to yield a single-stranded DNA end.
• This end is then modified by the action of TdT (indicated in pink), which creates diverse, imprecise ends.
• Finally, the two heptamer sequences, which are not modified, are ligated to form the precise signal joint, while the coding joint is also ligated, both by the action of DNA ligase IV.

Question 25

_V(D)J recombination - summary_ * V(D)J recombination is the primary mechanism for generating diversity in B and T lymphocytes. * The first recombination event takes place in pro B and pro T cells and involves ... recombination in the IgH gene and the TCR beta chain gene respectively * The next step involves the recombination of there new ... sequences with a new ... sequence * Subsequently the light chain genes (... or ...) in B cells and the ... chain gene in T cells undergo VJ recombination * These new genes are then transcribed into mRNA and translated into proteins, which are assembled and then expressed on the surface of B and T lymphocytes as unique B cell receptors and T cell receptors, respectively.

Answer 25

* V(D)J recombination is the primary mechanism for generating diversity in B and T lymphocytes. * The first recombination event takes place in pro B and pro T cells and involved **DJ** recombination in the IgH gene and the TCR beta chain gene respectively * The next step involves the recombination of there new **DJ** sequences with a new **V** sequence * Subsequently the light chain genes (**kappa** or **lambda**) in B cells and the **alpha** chain gene in T cells undergo VJ recombination * These new genes are then transcribed into mRNA and translated into proteins, which are assembled and then expressed on the surface of B and T lymphocytes as unique B cell receptors and T cell receptors, respectively.

Question 26

_V(D)J recombination - summary_ * V(D)J recombination is the primary mechanism for generating diversity in B and T lymphocytes. * The first recombination event takes place in pro B and pro T cells and involved DJ recombination in the ... gene and the TCR ... chain gene respectively * The next step involves the recombination of there new DJ sequences with a new V sequence * Subsequently the ... chain genes (kappa or lambda) in B cells and the ... chain gene in T cells undergo VJ recombination * These new genes are then transcribed into ... and translated into proteins, which are assembled and then expressed on the surface of B and T lymphocytes as unique B cell receptors and T cell receptors, respectively.

Answer 26

* V(D)J recombination is the primary mechanism for generating diversity in B and T lymphocytes. * The first recombination event takes place in pro B and pro T cells and involved DJ recombination in the **IgH** gene and the TCR **beta** chain gene respectively * The next step involves the recombination of there new DJ sequences with a new V sequence * Subsequently the **light** chain genes (kappa or lambda) in B cells and the **alpha** chain gene in T cells undergo VJ recombination * These new genes are then transcribed into **mRNA** and translated into proteins, which are assembled and then expressed on the surface of B and T lymphocytes as unique B cell receptors and T cell receptors, respectively.

Question 27

_Somatic hypermutation and affinity maturation_ * Somatic hypermutation takes place following ... cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of ... cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for ... cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Answer 27

* Somatic hypermutation takes place following **B** cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of **B** cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for **B** cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Question 28

_Somatic hypermutation and affinity maturation_ * Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the ... stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce ...-... antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Answer 28

* Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the **centroblast** stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce **high**-**affinity** antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Question 29

_Somatic hypermutation and affinity maturation_ * Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-... antibodies, such as antibodies that cannot ... correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Answer 29

* Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-**functional** antibodies, such as antibodies that cannot **fold** correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed affinity maturation.

Question 30

_Somatic hypermutation and affinity maturation_ * Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed ... ....

Answer 30

* Somatic hypermutation takes place following B cell recognition of antigen * This accumulation of mutations occurs at the centroblast stage of B cell differentiation in the germinal centers of secondary lymphoid organs. * The overall goal of this process is to produce high-affinity antibodies, in the absence of selection, SHM does not distinguish between favourable and unfavourable mutations and can produce antibodies with (1) higher affinity for antigen, (2) lower affinity for antigen, and (3) no change in affinity for antigen. Somatic hypermutation can also lead to non-functional antibodies, such as antibodies that cannot fold correctly * Whereas SHM does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed **affinity maturation.**

Question 31

Whereas Somatic Hypermutation does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed ... ...

Answer 31

Whereas Somatic Hypermutation does not always produce a higher-affinity antibody, the selection process for antigen binding that occurs in the light zone of the germinal center selects for B cells that produce the highest-affinity antibodies. This process is termed **affinity maturation.**

Question 33

What is Somatic hypermutation?

Answer 33

* Somatic hypermutation or SHM is a diversity-generating process * It adds further diversity to already rearranged (V(D)J recombined) segments through the introduction of point mutations * The mutation rate is ~1 base per 1000 – this is ~ 1 million times higher mutation rate than is observed during normal cell division

Question 34

Somatic hypermutation or SHM is a ...-generating process

Answer 34

Somatic hypermutation or SHM is a **diversity**-generating process

Question 35

_Somatic Hypermutation_ * The massive increase in the incidence of mutation events justifies the name “hypermutation”. * Fortunately, these mutations occur at very restricted loci known as ... regions * These regions correspond to the complementarity determining regions of CDRs - the sites involved in antigen recognition on the antibody. * The most common type of mutation involves nucleotide ... rather than addition or deletion. * Two critical enzymes guide the process of SHM – activation-induced cytidine deaminase (AID) and Uracil N-glycosylase, which removes uracil bases generated by AID-mediated deamination

Answer 35

* The massive increase in the incidence of mutation events justifies the name “hypermutation”. * Fortunately, these mutations occur at very restricted loci known as **hypervariable** regions * These regions correspond to the complementarity determining regions of CDRs - the sites involved in antigen recognition on the antibody. * The most common type of mutation involves nucleotide **substitution** rather than addition or deletion. * Two critical enzymes guide the process of SHM – activation-induced cytidine deaminase (AID) and Uracil N-glycosylase, which removes uracil bases generated by AID-mediated deamination

Question 36

Two critical enzymes guide the process of Somatic Hypermutation – ... and Uracil N-glycosylase, which removes uracil bases generated by ...-mediated deamination

Answer 36

Two critical enzymes guide the process of Somatic Hypermutation – **activation-induced cytidine deaminase (AID)** and Uracil N-glycosylase, which removes uracil bases generated by **AID**-mediated deamination

Question 37

In the case of B cells, further refinement of B cell receptor recognition of antigen occurs via a process called somatic hypermutation. The critical enzyme involved in this process is ...

Answer 37

In the case of B cells, further refinement of B cell receptor recognition of antigen occurs via a process called somatic hypermutation. The critical enzyme involved in this process is **activation-induced cytidine deaminase (AID)**.

Question 38

Somatic Hypermutation is triggered by the enzyme activation-induced ... ...

Answer 38

SHM is triggered by the enzyme **activation-induced cytidine deaminase**

Question 39

_Activation-induced cytidine deaminase_ * ... ... is triggered by the enzyme activation-induced cytidine deaminase * This enzyme deaminates cytidine to uracil and this base mismatch is incorrectly repaired by several different mechanisms to generate mutations – mismatch repair and base excision repair.

Answer 39

* **Somatic Hypermutation** is triggered by the enzyme activation-induced cytidine deaminase * This enzyme deaminates cytidine to uracil and this base mismatch is incorrectly repaired by several different mechanisms to generate mutations – mismatch repair and base excision repair.

Question 40

_Affinity maturation_ * This is the process by which B cells produce antibodies with increased ... for ... during an immune response * Follicular ... cells found in the germinal centres present antigen to the B cells that have undergone SHM. Only those with high ... for antigen will be selected to survive * B cells that have undergone SHM but bind antigen with lower ... are out competed and die by apoptosis

Answer 40

* This is the process by which B cells produce antibodies with increased **affinity** for **antigen** during an immune response * Follicular **dendritic** cells found in the germinal centres present antigen to the B cells that have undergone SHM. Only those with high **affinity** for antigen will be selected to survive * B cells that have undergone SHM but bind antigen with lower **affinity** are out competed and die by apoptosis

Question 41

_Affinity maturation_ * This is the process by which B cells produce antibodies with increased affinity for antigen during an immune response * Follicular dendritic cells found in the germinal centres present antigen to the B cells that have undergone SHM. Only those with high affinity for antigen will be selected to survive * B cells that have undergone SHM but bind antigen with lower affinity are out competed and die by ...

Answer 41

* This is the process by which B cells produce antibodies with increased affinity for antigen during an immune response * Follicular dendritic cells found in the germinal centres present antigen to the B cells that have undergone SHM. Only those with high affinity for antigen will be selected to survive * B cells that have undergone SHM but bind antigen with lower affinity are out competed and die by **apoptosis**

Question 42

_Class Switch Recombination_ * Whereas the processes of Somatic Hypermutation and affinity maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the ... isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one isotype for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the ...-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell memory to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or memory B cells.

Answer 42

* Whereas the processes of Somatic Hypermutation and affinity maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the **IgM** isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one isotype for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the **heavy**-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell memory to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or memory B cells.

Question 43

_Class Switch Recombination_ * Whereas the processes of Somatic ... and ... maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the IgM isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one ... for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the heavy-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell memory to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or memory B cells.

Answer 43

* Whereas the processes of Somatic **Hypermutation** and **affinity** maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the IgM isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one **isotype** for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the heavy-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell memory to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or memory B cells.

Question 44

_Class Switch Recombination_ * Whereas the processes of Somatic Hypermutation and affinity maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the IgM isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one isotype for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the heavy-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell ... to occur as class switched B cells can become ... ... ... cells (antibody secreting cells) or ... B cells.

Answer 44

* Whereas the processes of Somatic Hypermutation and affinity maturation allow for the selection of higher-affinity antibody-producing B cells, the resulting antibodies will still be of the IgM isotype and have a very short half-life and limited functional capacity. * The process of CSR allows for the substitution of one isotype for another, thus providing the antibody with new functions and a different distribution throughout the body. Induction of CSR is orchestrated by different cytokines that result from cellular interactions of the B cell with different types of T cells and these interactions direct CSR toward a specific isotype. * Class switch recombination occurs exclusively at the heavy-chain antibody locus, because this is the location of the different constant region genes that encode each isotype. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell **memory** to occur as class switched B cells can become **long lived plasma cells (antibody secreting cells) or memory B cells.**

Question 45

_Class Switch Recombination_ * It is a biological mechanism that changes a B cell's production of immunoglobin from one type to another, such as from the ... IgM to the ... IgG. * During this process, the ...-region portion of the antibody heavy chain is changed, but the ... region of the heavy chain stays the same. Since the ... region does not change, class switching does not affect antigen specificity. * Instead, the antibody retains ... for the same antigens, but can interact with different effector molecules.

Answer 45

* It is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the **isotype** IgM to the **isotype** IgG. * During this process, the **constant**-region portion of the antibody heavy chain is changed, but the **variable** region of the heavy chain stays the same. Since the **variable** region does not change, class switching does not affect antigen specificity. * Instead, the antibody retains **affinity** for the same antigens, but can interact with different effector molecules.

Question 46

Antibody class switching, or class switch recombination is the last step in a B cell’s response to antigen. The class switching **does not affect the ...** of the B cell receptor for antigen but instead **replaces the ... region** of the antibody so that it can interact with **different ... molecules**. The process of class switching is mediated by a process of DNA breakage and recombination.

Answer 46

Antibody class switching, or class switch recombination is the last step in a B cell’s response to antigen. The class switching **does not affect the affinity** of the B cell receptor for antigen but instead **replaces the constant region** of the antibody so that it can interact with **different effector molecules**. The process of class switching is mediated by a process of DNA breakage and recombination

Question 47

Antibody class switching, or class switch recombination is the last step in a B cell’s response to antigen. The class switching does not affect the affinity of the B cell receptor for antigen but instead replaces the constant region of the antibody so that it can interact with different effector molecules. The process of class switching is mediated by a process of DNA ... and ...

Answer 47

Antibody class switching, or class switch recombination is the last step in a B cell’s response to antigen. The class switching does not affect the affinity of the B cell receptor for antigen but instead replaces the constant region of the antibody so that it can interact with different effector molecules. The process of class switching is mediated by a process of DNA **breakage** and **recombination**

Question 48

_Alternative splicing results in IgM and IgD in naive B-cells_ * Class switch recombination requires specific sequences of DNA that lie upstream of each set of constant region genes, known as switch regions (S-regions). Each Switch-region is also associated with an upstream promoter and an exon, which allows for the production of sterile (noncoding) germline transcripts through the S-region. Although S-regions are present upstream of each set of the constant region genes, the ... constant region lacks a defined Switch region. Rather than using CSR, ... is generated through an alternative splicing mechanism with the μ constant region.

Answer 48

* Class switch recombination requires specific sequences of DNA that lie upstream of each set of constant region genes, known as switch regions (S-regions). Each Switch-region is also associated with an upstream promoter and an exon, which allows for the production of sterile (noncoding) germline transcripts through the S-region. Although S-regions are present upstream of each set of the constant region genes, the **IgD** constant region lacks a defined Switch region. Rather than using CSR, **IgD** is generated through an alternative splicing mechanism with the μ constant region.

Question 49

_Alternative splicing results in IgM and IgD in naive B-cells_ * Class switch recombination requires specific sequences of DNA that lie upstream of each set of constant region genes, known as switch regions (S-regions). Each Switch-region is also associated with an upstream promoter and an exon, which allows for the production of sterile (noncoding) germline transcripts through the S-region. Although S-regions are present upstream of each set of the constant region genes, the IgD constant region lacks a defined Switch region. Rather than using CSR, IgD is generated through an alternative splicing mechanism with the ... constant region.

Answer 49

* Class switch recombination requires specific sequences of DNA that lie upstream of each set of constant region genes, known as switch regions (S-regions). Each Switch-region is also associated with an upstream promoter and an exon, which allows for the production of sterile (noncoding) germline transcripts through the S-region. Although S-regions are present upstream of each set of the constant region genes, the IgD constant region lacks a defined Switch region. Rather than using CSR, IgD is generated through an alternative splicing mechanism with the **μ** constant region.

Question 50

Naïve B cells express two alternative isotypes of immunoglobulin, ... and ...

Answer 50

Naïve B cells express two alternative isotypes of immunoglobulin, **IgM and IgD.**

Question 51

Naïve B cells express two alternative isotypes of immunoglobulin, IgM and IgD. These two alternative classes of immunoglobulin are not produced by ... ... ... as the naïve B cell has not yet experienced antigen. Instead, both IgM and IgD are produced by alternative mRNA ... due to the close proximity of the m and d constant regions in the immunoglobulin gene structure.

Answer 51

Naïve B cells express two alternative isotypes of immunoglobulin, IgM and IgD. These two alternative classes of immunoglobulin are not produced by **class switch recombination** as the naïve B cell has not yet experienced antigen. Instead, both IgM and IgD are produced by **alternative mRNA splicing** due to the close proximity of the m and d constant regions in the immunoglobulin gene structure.

Question 52

_How is Class Switch Recombination achieved?_ * The first targeted switch region is always the S... switch region. The other, partner, switch region is determined by the cytokines present * Activation induced cytidine deaminase (AID) is the critical enzyme in this process

Answer 52

* The first targeted switch region is always the **Sµ** switch region. The other, partner, switch region is determined by the cytokines present * Activation induced cytidine deaminase (AID) is the critical enzyme in this process

Question 53

_Class Switch Recombination_​ * The first targeted switch region is always the Sµ switch region. The other, partner, switch region is determined by the cytokines present * Activation induced cytidine deaminase (AID) is the critical enzyme in this process * ... regions are spliced out using switch regions located upstream of each ... region * First cut is always just before the ... region * The second cut is determined by the ... secreted by follicular T helper cells

Answer 53

* The first targeted switch region is always the Sµ switch region. The other, partner, switch region is determined by the cytokines present * Activation induced cytidine deaminase (AID) is the critical enzyme in this process * **Constant** regions are spliced out using switch regions located upstream of each **constant** region * First cut is always just before the **Cµ** region * The second cut is determined by the **cytokines** secreted by follicular T helper cells

Question 54

_Why does Class Switch Recombination matter?_ * CSR matters because it determines the type of response that the Immunoglobulin can promote. For example, non class switched IgM immunoglobulins are great at activating complement but are not able to sensitize cells for NK killing. IgG1 class switched immunoglobulins are really effective at antigen neutralisation and opsonisation i.e. making the invading pathogen “visible” to phagocytes. * It is important to remember that CSR does not change the ... of the BCR for antigen, but it does allow for the ... of the B cell response. It also allows long term B cell ... to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or ... B cells

Answer 54

* CSR matters because it determines the type of response that the Immunoglobulin can promote. For example, non class switched IgM immunoglobulins are great at activating complement but are not able to sensitize cells for NK killing. IgG1 class switched immunoglobulins are really effective at antigen neutralisation and opsonisation i.e. making the invading pathogen “visible” to phagocytes. * It is important to remember that CSR does not change the **affinity** of the BCR for antigen, but it does allow for the **tuning** of the B cell response. It also allows long term B cell **memory** to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or **memory** B cells

Question 55

Why does Class Switch Recombination matter?

Answer 55

* CSR matters because it determines the type of response that the Immunoglobulin can promote. For example, non class switched IgM immunoglobulins are great at activating complement but are not able to sensitize cells for NK killing. IgG1 class switched immunoglobulins are really effective at antigen neutralisation and opsonisation i.e. making the invading pathogen “visible” to phagocytes. * It is important to remember that CSR does not change the affinity of the BCR for antigen, but it does allow for the tuning of the B cell response. It also allows long term B cell memory to occur as class switched B cells can become long lived plasma cells (antibody secreting cells) or memory B cells

Question 56

What are the TWO isotypes of immunoglobulin expressed by naïve B cells?

Answer 56

IgD and IgM