L10- B Cell Development

Question 1

The common lymphoid progenitor gives rises to which cells?

Answer 1

Mainly to B and T cells but may also contribute to NK cells and some dendritic cells

Question 2

Pro-B cells can eventually differentiate into which type of cells?

Answer 2

Follicular (FO) B cells, marginal zone (MZ) B cells, and B-1 cells.

Question 3

Commitment to different lineages in B cell development is driven by various transcription factors. Name a few

Answer 3

EBF, E2A and Pax-5

Question 4

What are the functions of RAG-1 and RAG-2 (recombination-activating gene) proteins?

Answer 4

The protein encoded by this gene is involved in antibody and T-cell receptor V(D)J recombination. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG-2. The RAG-1/2 complex recognizes recombination signal sequences (RSSs) that flank the V, D and J regions in the genes that encode the heavy and light chains of antibodies and components of T-cell receptors. The complex binds to the RSSs and nicks the DNA. This leads to the removal of the intervening DNA and the eventual ligation of the V, D and J sequences. Defects in this gene can cause several different diseases.

Question 5

How is the body able to produce so many unique B and T cells?

Answer 5

The rearrangement of antigen receptor genes is the key event in lymphocyte development that is responsible for generation of a diverse repertoire. Each lymphocyte clone produces an antigen receptor with a unique antigen binding structure producing roughing 10^7 unique B and T cells.

Functional antigen receptor genes are produced in immature B cells in the bone marrow by a process of gene rearrangement, which is able to generate a large number of variable region encoding exons using a relatively small fraction of the genome

In any given developing B cell, one of many variable region gene segments is randomly selected and joined to a downstream DNA segment. The DNA rearrangement events that lead to production of antigen receptors are not dependent on or influenced by the presence of antigens

Question 6

D (diversity) segments are found in both heavy and Ig light chain loci. T or F?

Answer 6

False. Heavy only

Question 7

Explain briefly the germline organization of Ig genetic loci

Answer 7

The germline organization of Ig genetic loci is characterized by spatial segregation of many different sequences that encode variable domains, and relatively few sequences that encode constant domains of receptor proteins; distinct variable region sequences are joined to constant region sequences in different lymphocytes

Question 8

Heavy chain locus is found on which chromosome?

Answer 8

Chromosome 14

Question 9

The variable region of immunoglobulin heavy chain is encoded by three separate genes on the germline, what are they?

Answer 9

Variable (VH), diversity (DH) and joining (JH) genes

Question 10

There are two Ig light chains, what are they and what chromosomes are they found?

Answer 10

• A.kappa (κ) chain, encoded by the immunoglobulin kappa locus on chromosome 2
• lambda (λ) chain, encoded by the immunoglobulin lambda locus on chromosome 22

Question 11

Which Ig light chains are expressed for each B cell?

Answer 11

Only one class of light chain is expressed at one time, either kappa (κ) chain or lambda (λ) chain. Thus the two light chains of an individual antibody are identical. Once set, light chain class remains fixed for the life of the B lymphocyte. In a healthy individual, the total kappa-to-lambda ratio is roughly 2:1 in serum (measuring intact whole antibodies) or 1:1.5 if measuring free light chains, with a highly divergent ratio indicative of neoplasm.

Question 12

Each light chain is composed of two tandem immunoglobulin domains, what are they?

Answer 12

One constant (CL) domain and one variable (VL), that is important for binding antigen. Remember No diversity domain for light chains.

Question 13

What is the approximate length of a light chain protein and which region determines what class the light chain is?

Answer 13

Length of the protein is between 211 and 217 amino acids. The constant region determines what class (kappa or lamda) the light chain is. The lambda class has 4 subtypes (λ1, λ 2, λ3, and λ7).

Question 14

Where is the constant region located of the Ig molecule?

Answer 14

The constant region is located 3’ of the J segments.

Question 15

How many constant regions are found in both the heavy and light chains of an Ig molecule?

Answer 15

For light chain locus;
• kappa (κ) chain has a single C gene;
• lambda (λ) chain has 4 functional C genes. (λ1, λ 2, λ3, and λ7)

For heavy chain locus;
• nine functional C genes (CH), arranged in tandem array, that encode the C regions of the nine different Ig isotypes and subtypes.

Question 16

How many exons can be found on both the heavy and light chains?

Answer 16

The Cκ and Cλ genes are each composed of a single exon that encodes the entire C domain of the light chains. In contrast, each CH gene is composed of five or six exons. Three or four exons (each similar in size to a V gene segment) each encode a CH domain of the Ig heavy chain, and two smaller exons code for the carboxy-terminal ends if the membrane form of each Ig heavy chain, including the transmembrane and cytoplasmic domains of the heavy chains.

Question 17

From the same germline DNA, is it possible to generate recombined DNA sequences and mRNAs that differ in their V-D-J junctions?

Answer 17

Yes, for example, three distinct antigen receptor mRNAs are produced from the same germline DNA by the use of different gene segments and the addition of nucleotides to the junctions. The somatic recombination (V-D-J joining) also produces additional N and P nucleotides, transcription and RNA processing in the 3 different B cell clones used in the example.

Question 18

Lymphocyte-specific proteins that mediate V(D)J recombination recognize certain DNA sequences called what?

Answer 18

Recombination signal sequences (RSSs)

Question 19

What are recombination signal sequences (RSSs) and where are they located?

Answer 19

Lymphocyte-specific proteins that mediate V(D)J recombination recognize certain DNA sequences. There located 3’ of each V gene segment, 5’ of each J segment, and flanking each side of every D segment

Question 20

The RSSs consist of a highly conserved stretch of 7 nucleotides, called what?

Answer 20

Heptamer

Question 21

Where is the heptamer located?

Answer 21

Located adjacent to the coding sequence, followed by a spacer, followed by the nonamer.

Question 22

During V(D)J recombination, what happens with the heptamer of the RSS and adjacent V, D or J coding sequences?

Answer 22

Double-stranded breaks are generated between the heptamer of the RSS and the adjacent V, D, or J coding sequence

Question 23

How is the circle formed in V (D) J recombination?

Answer 23

During V (D) J recombination, double stranded breaks are generated between the heptamer of the RSS and the adjacent V, D or J coding sequence. In Ig light chain V to J recombination, for example, breaks will be made 3’ of a V segment and 5’ of a J segment. The intervening double-stranded DNA containing signal ends (the ends that contain the heptamer and the rest of the RSS), is removed in the form of a circle, and the V and J coding ends are joined.

Question 24

In some V genes, especially in the Ig κ locus; the RSSs are 3’ of a Vκ and 3’ of Jκ, and therefore do not face each other, so what happens in this case?

Answer 24

In these cases, the intervening DNA is inverted and the V and J segments are properly aligned; the fused RSSs are not deleted but retained in the chromosome. Inversion occurs up to 50% of rearrangements in the Ig κ locus.

Question 25

Double-stranded breaks are enzymatically generated at RSS-coding sequences by which proteins?

Answer 25

Recombination-activating gene 1 and recombination-activating gene 2 (RAG1 and RAG2) proteins

Question 26

What is the RAG1/RAG2 complex also known as?

Answer 26

V(D)J recombinase

Question 27

Double-stranded breaks are enzymatically generated at which sites?

Answer 27

At RSS coding sequences. The RAG1 protein, in a manner similar to a restriction endonuclease, recognises the DNA sequence at the junction between the heptamer and a coding segment and cleaves it.

Question 28

Explain in great detail how the V(D)J recombinase generates double stranded breaks at RSS coding sequence and how the hairpin is formed?

Answer 28

Double-stranded breaks are enzymatically generated at RSS-coding sequence junctions by RAG1 and RAG2 which form a complex, containing two molecules of each protein, that plays an essential role in V(D)J recombination. The RAG1 protein, in a manner similar to a restriction endonuclease, recognises the DNA sequence at the junction between the heptamer and a coding segment and cleaves it, but it is enzymatically active only when complexed with the RAG2 protein. Rag2 protein may help link the RAG1-RAG2 tetramer to other proteins, including accessibility factors that bring these proteins to specific open receptor gene loci at specific times and at defined stages of lymphocyte development. Rag1 and Rag2 contribute to holding together gene segments during the process of chromosomal folding or synapsis (why these proteins are so important for B cell existence). Rag1 then makes a nick (on one DNA strand) between the coding end and the heptamer. The released 3’ OH of the coding end then attacks a phosphodiester bond on the other DNA strand, forming a covalent hairpin. The signal end (including the heptamer and the rest of the RSS) does not form a hairpin and is generated as a blunt double-stranded DNA terminus that undergoes no further processing. This double-stranded break results in a closed hairpin of one coding segment being held in apposition to the closed hairpin of the other coding end and two blunt recombination signal ends are placed next to each other. RAG1 and RAG2, apart from generating the double-stranded breaks, also hold the hairpin ends and the blunt ends together before the modification of the coding ends and the process of ligation. In layman’s terms: The V(D)J recombinase recognizes the DNA sequence at the junction between a heptamer and a coding segment and cleaves it; makes a nick on one DNA strand; forms a covalent hairpin; generates a blunt end; holds the hairpin ends and blunt ends together before ligation.

Question 29

What is the function of terminal deoxynucleotidyl transferase (TdT)?

Answer 29

Terminal deoxynucleotidyl transferase (TdT) is a lymphoid-specific enzyme which adds bases to broken DNA ends to generate junctional diversity (up to 20 non-template-encoded nucleotides called N nucelotides)

Question 30

What other ways that create junctional diversity?

Answer 30

1. ​Addition of nucleotides at the junctions of the V and D, D and J, or V and J segments at the time these segments are joined, greatly increases diversity. 2. ​New nucleotide sequences, not present in the germline, may be added at junctions 3. ​Addition of P and N nucleotides

Question 31

Which enzyme is responsible for addition of P nucleotides?

Answer 31

Artemis

Question 32

How does Artemis form P nucleotides?

Answer 32

Coding segments (e.g., V and J gene segments) that are cleaved by Rag-1 form hairpin loops whose ends are often cleaved asymmetrically by the enzyme Artemis so that one DNA strand is longer than the other. The shorter strand has to be extended with nucleotides complementary to the longer strand before the ligation of the two segments. The longer strand serves as a template for the addition of short lengths of nucleotides called P nucleotides, and this process introduces new sequences at the VD-J junctions.

Question 33

When does a cell go from being called a pro-B cell and into a pre-B stage?

Answer 33

Once production of Ig μ arrangement is made and has differentiated.

Question 34

What is a pre-B cells?

Answer 34

Pre-B cells are developing B lineage cells that express the Ig μ protein but have yet to rearrange their light chain loci.

Question 35

What forms the pre-B cell receptor? (pre-BCR)?

Answer 35

Complexes of μ heavy chain, surrogate light chains, and signal transducing proteins called Igα and Igβ form the pre-antigen receptor of the B lineage, known as the pre-B cell receptor (pre-BCR).

Question 36

What does the pre-BCR do?

Answer 36

The B-cell receptor (BCR) is composed of immunoglobulin molecules that form a type 1 transmembrane receptor protein usually located on the outer surface of a lymphocyte type known as B cells Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation.

Question 37

What are the surrogate light chains that assist to make the pre-BCR?

Answer 37

λ5 and V pre-B proteins

Question 38

Why are λ5 and V pre-B proteins referred to as surrogate light chains?

Answer 38

Because they are structurally homologous to κ and λ light chains but are invariant (i.e., they are identical in all pre-B cells) and are synthesized only in pro-B and pre-B cells.

Question 39

It is not known what the pre-BCR recognizes; what is the consensus view?

Answer 39

That this receptor functions in a ligand-independent manner and that it is activated by the process of assembly. The expression of the pre-BCR is the first checkpoint in B cell maturation.

Question 40

What is the function for Bruton’s tyrosine kinase (Btk)?

Answer 40

Bruton’s tyrosine kinase (Btk) is activated downstream of the pre-BCR and is required for delivery of signals from this receptor that mediate survival, proliferation, and maturation at and beyond the pre-B cell stage.

Question 41

Mutations in the BTK gene result in what disease?

Answer 41

X-linked agammaglobulinemia (XLA), which is characterized by a failure of B cell maturation.

Question 42

The pre-BCR regulates further rearrangement of Ig genes in which two ways?

Answer 42

1. If a μ protein is produced from the recombined heavy chain locus on one chromosome and forms a pre-BCR, this receptor signals to irreversibly inhibit rearrangement of the Ig heavy chain locus on the other chromosome. (An individual B cell can express an Ig heavy chain protein encoded by only one of the two inherited alleles. This phenomenon is called allelic exclusion, and it ensures that every B cell will express a single receptor, thus maintaining clonal specificity). If the first rearrangement is non-productive, the heavy chain allele on the other chromosome can complete VDJ rearrangement at the Ig H locus. Thus, in any B cell clone, one heavy chain allele is productively rearranged and expressed, and the other is either retained in the germline configuration or non-productively rearranged. 2. The second way in which the pre-BCR regulates the production of the antigen receptor is by stimulating κ light chain gene rearrangement

Question 43

What is allelic exclusion?

Answer 43

If a μ protein is produced from the recombined heavy chain locus on one chromosome and forms a pre-BCR, this receptor signals to irreversibly inhibit rearrangement of the Ig heavy chain locus on the other chromosome. (An individual B cell can express an Ig heavy chain protein encoded by only one of the two inherited alleles. This phenomenon is called allelic exclusion, and it ensures that every B cell will express a single receptor, thus maintaining clonal specificity). If the first rearrangement is non-productive, the heavy chain allele on the other chromosome can complete VDJ rearrangement at the Ig H locus. Thus, in any B cell clone, one heavy chain allele is productively rearranged and expressed, and the other is either retained in the germline configuration or non-productively rearranged.

Question 44

Following the pre-B cell stage, what happens next?

Answer 44

Each developing B cell initially rearranges a κ light chain gene.

Question 45

How is the light chain assembled?

Answer 45

Similar to the heavy chain except there are no D segments in the light chain loci. Therefore recombination involves only the joining of one V segment to one J segment, forming a VJ exon. Splicing of the primary transcript results in the removal of the intron between the VJ and C exons and generates an mRNA that is translated to produce the κ or λ protein.

Question 46

The assembled IgM molecules are expressed on the cell surface in association with _____ and ______where they function as specific receptors for ______. The IgM-expressing B cells are called ______.

Answer 46

The assembled IgM molecules are expressed on the cell surface in association with Igα and Igβ, where they function as specific receptors for antigens. The IgM-expressing B cells are called immature B cells.

Question 47

What happens to immature B cells in the presence of antigen such as self-antigen?

Answer 47

Immature B cells do not proliferate and differentiate in response to antigens. If they recognize antigens in the bone marrow with high avidity, which may occur if the B cells express receptors for multivalent self-antigens that are present in the bone marrow, the B cells may undergo receptor editing or cell death.

Question 48

What is central B cell tolerance?

Answer 48

Central tolerance, also known as negative selection, is the process of changing specificity or deleting any immature B lymphocytes that recognize self-antigens in the bone marrow with high affinity.Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides.

Question 49

How does receptor editing alter an immature B cell that recognizes self with high avidity?

Answer 49

* If immature B cells recognize self-antigens that are present at high concentration in the bone marrow and especially if the antigen is displayed in multivalent form (e.g., on cell surfaces), many antigen receptors on each B cell are cross-linked, thus delivering strong signals to the cells. * The B cells reactivate their RAG1 and RAG2 genes and initiate a new round of VJ recombination in the immunoglobulin (Ig) κ light chain gene locus. * A new Ig light chain is expressed, thus creating a B cell receptor with a new specificity * If the edited light chain rearrangement is non-productive, rearrangement may proceed at the κ locus on the other chromosome, and if that is nonproductive, rearrangements at the λ light chain loci may follow * A B cell expressing a λ light chain is frequently a cell that has undergone receptor editing * If editing fails, the immature B cells may die by apoptosis.

Question 50

What is meant by a B cell that is anergic?

Answer 50

Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. So if developing B cells recognize self-antigens weakly (e.g., if the antigen is soluble and does not cross-link many antigen receptors or if the B cell receptors recognize the antigen with low affinity), the cells become functionally unresponsive (anergic) and exit the bone marrow in this unresponsive state. Anergy is due to downregulation of antigen receptor expression as well as a block in antigen receptor signalling.

Question 51

What is peripheral tolerance?

Answer 51

Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs) where mature B lymphocytes that recognize self-antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive or die by apoptosis. Peripheral tolerance main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery. B cells that have encountered self-antigens have a shortened life span and are eliminated more rapidly in lymphoid follicles than cells that have not recognized self-antigens. The high rate of somatic mutation of Ig genes that occurs in germinal centres has the risk of generating self-reactive B cells. These B cells may be actively eliminated by the interaction of FasL on helper T cells with Fas on the activated B cells.

Question 52

What is the function of CD22 inhibitory receptor?

Answer 52

It is an Inhibitory receptor which sets a threshold for B cell activation, allowing responses to foreign antigens with T cell help but does not allow responses to self-antigens.

Question 53

Immature B cells that are not strongly self-reactive leave the bone marrow and complete their maturation where?

Answer 53

In the spleen before migrating to other peripheral lymphoid organs.

Question 54

Mature B cells start off as which type of antibody isotope?

Answer 54

IgM +IgD+

Question 55

What is the function of IgD ?

Answer 55

Not too much Is known about the function of IgD. It is thought that in B cells, the function of IgD is to signal the B cells to be activated. By being activated, B cells are ready to take part in the defense of the body as part of the immune system. During B cell differentiation, IgM is the exclusive isotype expressed by immature B cells. IgD starts to be expressed when the B cell exits the bone marrow to populate peripheral lymphoid tissues. When a B cell reaches its mature state, it co-expresses both IgM and IgD. IgD may have some role in allergic reactions. Recently, IgD was found to bind to basophils and mast cells and activate these cells to produce antimicrobial factors to participate in respiratory immune defense in humans. It also stimulates basophils to release B cell homeostatic factors.

Question 56

Most immature B cells leaving the bone marrow will not survive to become fully mature B cells - >______ die every ______days. • Selection occurs at the ________; limited number of cells can enter

Answer 56

Most immature B cells leaving the bone marrow will not survive to become fully mature B cells - >50% die every 3 days • Selection occurs at the lymphoid follicle – limited number of cells can enter

Question 57

Most B cells that develop from ________ ________ , differentiate into the ______ lineage. They are found in ______and ________.

Answer 57

Most B cells that develop from fetal liver-derived stem cells differentiate into the B-1 lineage. They are found in peritoneal and pleural cavity fluid

Question 58

B lymphocytes that arise from bone marrow precursors after birth give rise to the ________. Two major subsets are derived from these cell precursors: (1) _________? (2) _________?

Answer 58

B lymphocytes that arise from bone marrow precursors after birth give rise to the B-2 lineage. Two major subsets are derived from B-2 B cell precursors: (1) follicular B cells are recirculating lymphocytes (2) marginal zone B cells are found in in spleen and lymph nodes

Question 59

Where do follicular recirculating B cells populate?

Answer 59

They populate follicles in the spleen and lymph nodes

Question 60

Where are static marginal-zone B cells enriched?

Answer 60

In the marginal zone of the spleen

Question 61

Where do B1 cells recirculate?

Answer 61

Between the blood and the body cavities

Question 62

Antigen may be delivered to naive B cells in lymphoid organs in different forms and by multiple routes. Provide examples.

Answer 62

Most antigens from tissue sites are transported to lymph nodes by afferent lymphatic vessels that drain into the subcapsular sinus of the nodes Subcapsular sinus macrophages capture large microbes and antigen-antibody complexes and deliver these to follicles, which lie under the sinus Large antigens may be captured in the medullary region by resident dendritic cells and transported into follicles, where they can activate B cells Antigens in immune complexes may bind to complement receptor CR2 on marginal zone B cells, and these cells can transfer the immune complex–containing antigens to follicular B cells. Blood-borne pathogens may be captured by plasmacytoid dendritic cells in the blood and transported to the spleen, where they may be delivered to marginal zone B cells.

Question 63

How long do extrafolliular plasma cells live for?

Answer 63

~3 days

Question 64

How long do follicular/germinal centre plasma cells live for?

Answer 64

Follicular/Germinal Centre plasma cells are long-lived, migrate to bone marrow, MALT; memory cells

Question 65

Protein antigens are recognized by specific B and T lymphocytes in peripheral lymphoid organs, and the activated cell populations come together in these organs to initiate humoral immune responses. Briefly explain.

Answer 65

Naive CD4 + T cells are activated in the T cell zones by antigen processed and presented by dendritic cells, and differentiate into helper T cells. Naive B cells are activated in the follicles by the same antigen (in its native conformation) transported there. The helper T cells and activated B cells migrate toward one another and interact at the edges of the follicles, where the initial antibody response develops. Some of the cells migrate back into follicles to form germinal centres, where the more specialized antibody responses are induced.

Question 66

On activation, helper T cells express _____ ligand, which engages its receptor, _______, on antigen stimulated _________ and induces ________ proliferation and differentiation, initially in extrafollicular foci and later in _______ centers.

Answer 66

On activation, helper T cells express CD40 ligand (CD40L), which engages its receptor, CD40, on antigenstimulated B cells and induces B cell proliferation and differentiation, initially in extrafollicular foci and later in germinal centers.

Question 67

Mutations in the CD40L gene result in which disease?

Answer 67

X-linked hyper-IgM syndrome

Question 68

What is X-linked hyper-IgM syndrome?

Answer 68

Mutations in CD40L gene cause defects in antibody production, isotype switching, affinity maturation, and memory B cell generation in response to protein antigens, as well as deficient cell-mediated immunity

Question 69

What are germinal centres?

Answer 69

Germinal centers or germinal centres (GCs) are sites within secondary lymphoid organs – lymph nodes and the spleen where the characteristic events of helper T cell–dependent antibody responses, including affinity maturation, isotype switching, and generation of long-lived plasma cells and memory B cells, occur primarily in organized structures called germinal centres that are created within lymphoid follicles during T-dependent immune responses.

Question 70

Where are human follicular dendritic cells (FDC) found and what receptors do they possess that allow them to to display antigens to the selection of germinal centre B cells?

Answer 70

FDCs are found only in lymphoid follicles and express complement receptors (CR1, CR2, and CR3) and Fc receptors. These molecules are involved in displaying antigens for the selection of germinal centre B cells.

Question 71

Do follicular dendritic cells express MHC class II molecules or MHC class I?

Answer 71

Neither! They express complement receptors (CR1, CR2, and CR3) and Fc receptors. These molecules are involved in displaying antigens for the selection of germinal centre B cells.

Question 72

In T-dependent responses, some of the progeny of activated IgM- and IgD-expressing B cells undergo heavy chain isotype (class) switching and produce antibodies with heavy chains of different classes, such as transcription through which locus?

Answer 72

γ, α, and ε

Question 73

Explain how Ig heavy chain isotope switching happens?

Answer 73

The Ig heavy chain DNA in B cells is cut and recombined such that a previously formed VDJ exon that encodes the V domain is placed adjacent to a downstream C region, and the intervening DNA is deleted. Activation-induced cytidine deaminase (AID) is the initiator of mutations in somatic hypermutation and class switching.

Question 74

What function does Activation-induced cytidine deaminase (AID) have?

Answer 74

Activation-induced cytidine deaminase (AID) is the initiator of mutations in somatic hypermutation and class switching.

Question 75

Affinity maturation leads to increased affinity of antibodies for a particular antigen as a T-dependent humoral response progresses, and it is the result of somatic hypermutation of Ig genes followed by selective survival of the B cells producing the antibodies with the highest affinities. T or F?

Answer 75

True.

Question 76

Explain somatic hypermutation of Ig genes.

Answer 76

Somatic hypermutation is the phenomenon in which a high frequency of point mutations are generated within a 1–2-kb segment in the variable region of expressed immunoglobulin genes in response to the presence of an antigen. These processes occur in the germinal centres of secondary lymphoid organs.

Question 77

Where does V(D)J rearrangement occur?

Answer 77

Antigen independent phase (bone marrow, foetal liver)

Question 78

Where does Class switch, somatic hypermutation occur?

Answer 78

Antigendependent phase (spleen, lymph node)

Question 79

Where do the following cellular events occur? proB > preB > mature B cell

Answer 79

Antigen independent phase (bone marrow, foetal liver)

Question 80

Where do the following cellular events occur? B cell activation, memory and plasma B cell differentiation

Answer 80

Antigendependent phase (spleen, lymph node)