*5.2.2 SHM: features and molecular mechanisms*

Following antigenic stimulation, B-cell IG genes undergo SHM and CSR within GCs.

### *5.2.2.1 Genes concerned by SHM*

The process of somatic hypermutation-a process targeting the V genes of the H and L chains-is the basis for the antibody affinity maturation. It is induced during humoral responses of conventional B-follicular cells in response to TD antigen. In contrast to the somatic-V(D)J-recombination that takes place in the bone marrow, the SHM process takes place in the SLOs, in the DZ of the GCs, at a stage where the B-cell is called centroblast.

#### *5.2.2.2 Roles and objectives of SHM*

Since the specificity and affinity of the BCR/mIg of the B-cell that left the bone marrow, and subsequently the circulating antibody produced, are determined before the encounter with the antigen (antigenic epitope), the phenomenon of SHM occurs in the activated B-cell clone through mutations in the sequence of genes derived from V(D)J somatic recombination, in order to adjust the hypervariable regions to the epitope and thus to modulate/increase the antibody affinity and the effective and adapted recognition of the antigen triggering the humoral immune response. As mentioned above, such a phenomenon participates in the generation of Igs diversity.

#### *5.2.2.3 Mechanisms of SHM process*

#### *5.2.2.3.1 SHM features*

SHM introduces mutations that replace one or more amino acids in the Ig, producing closely related B-cell clones that differ subtly in terms of antigenic specificity and affinity [48]. Despite recent advances, the molecular mechanisms responsible for them remain little known. Nevertheless, the results of *in vitro* or *in* 

**37**

*Immunogenetic Aspect of B-Cell Antigen Receptor Diversity Generation*

AID, which is expressed solely by the B-cells of the CG [48].

c.It occurs in the peripheral lymphoid organs in the DZ GC B-cells.

g.Random mutations can enhance the affinity of the antibodies.

*vivo* studies on mouse models expressing an IG transgene have made it possible to

b.It occurs during an extremely brief stage of differentiation of B-cells at the

d.Numerous point mutations are introduced in the hypervariable regions of the BCR or Ig H and L chain V gene following the activation of antigen-specific

f. Purine-purine or pyrimidine-pyrimidine mutations are mainly observed; A

i. The mutations essentially concern the variable gene and the adjacent 3′ region

k.It also affects the DNA flanking the rearranged V gene, but does not generally

l. Mutations are mostly nucleotide substitutions, but insertions and deletions are

m. SHMs only occur during the secondary response, but not during the primary

n. The cis sequences of IG locus are indispensable for triggering or regulating the

o. There is an important involvement of the IG promoter and enhancer sequences of the IG locus, suggesting a link between transcription and SHM [49].

• *Cytosine deamination*. AID initiates the SHM process within target sequences by cytosine deamination in the rearranged variable regions and focuses on 3–4 bp SHM motifs that are greatly enriched in S regions and in portions of variable region exons that encode antigen-binding sites (CDR region). SHM of V(D)J exons in GC B-cells require transcription for AID targeting, as during CSR, and begins ∼150 bp downstream of the transcription start site (TSS) and extend

*5.2.2.3.2 AID, adaptive mutagenesis, and erroneous repair of uracil bases*

j. The mutation domain extends in 3′ from the promoter to the intronic J-C

a.It corresponds to an adaptive mutagenesis initiated by the action of the enzyme

*DOI: http://dx.doi.org/10.5772/intechopen.90637*

GCs.

B-cell clones.

region.

possible.

responses.

define certain characteristics of this process:

e.The mutations extend over about 1 kb.

and G are more often mutated than T and C.

h.It relates to TD antigen immune responses.

of the rearranged V(D)J segment.

extend to C region exons.

hypermutation process.

*Normal and Malignant B-cell*

further stimulation.

licular corona.

within GCs.

• *Lymphoid follicles fate*. The persistence of lymphoid follicles depends on

antigenic stimulation. So they begin to reduce their size from the beginning of the 2nd week and disappear completely at the 3rd week in the absence of any

• *Nonspecific B-cells*. Small B cells that are not specific for the antigen are repelled from the primary follicles, as the blast cells divide, and thus form the perifol-

• *Memory B-cells*. Memory B-cells have the ability to respond rapidly to antigens that give rise to a primary response and to present it quickly and efficiently to T-cells during a secondary response, and also differentiate into plasma cells. Although they are a minority group of long-lived cells, they are able to persist in the quiescent state from several months to several decades in humans. They are usually IgD(−) and may have preferential localizations such as mucous

Following antigenic stimulation, B-cell IG genes undergo SHM and CSR

The process of somatic hypermutation-a process targeting the V genes of the H and L chains-is the basis for the antibody affinity maturation. It is induced during humoral responses of conventional B-follicular cells in response to TD antigen. In contrast to the somatic-V(D)J-recombination that takes place in the bone marrow, the SHM process takes place in the SLOs, in the DZ of the GCs, at a stage where the

Since the specificity and affinity of the BCR/mIg of the B-cell that left the bone

marrow, and subsequently the circulating antibody produced, are determined before the encounter with the antigen (antigenic epitope), the phenomenon of SHM occurs in the activated B-cell clone through mutations in the sequence of genes derived from V(D)J somatic recombination, in order to adjust the hypervariable regions to the epitope and thus to modulate/increase the antibody affinity and the effective and adapted recognition of the antigen triggering the humoral immune response. As mentioned above, such a phenomenon participates in the

SHM introduces mutations that replace one or more amino acids in the Ig, producing closely related B-cell clones that differ subtly in terms of antigenic specificity and affinity [48]. Despite recent advances, the molecular mechanisms responsible for them remain little known. Nevertheless, the results of *in vitro* or *in* 

membranes for cells that have switched to produce IgA.

*5.2.2 SHM: features and molecular mechanisms*

*5.2.2.1 Genes concerned by SHM*

B-cell is called centroblast.

generation of Igs diversity.

*5.2.2.3.1 SHM features*

*5.2.2.3 Mechanisms of SHM process*

*5.2.2.2 Roles and objectives of SHM*

**36**

*vivo* studies on mouse models expressing an IG transgene have made it possible to define certain characteristics of this process:

