2.4 Transmembrane vs. secreted B-cell receptor

The only structural difference between transmembrane and secreted B-cell receptors (soluble immunoglobulins, sIgs) is that the C-terminal region of the heavy

#### Figure 3.

2.2 Transmembrane B-cell receptor

Key Point 1jMain features of human Ig classes and subclasses mIg sIg Properties

Normal and Malignant B-cell

active [24, 25].

8

B-cells are defined by the presence of membrane-bound Igs (mIg) that act as specific receptors for the appropriate antigen in mature B-cell but, also as an excellent marker of the B-cell line. The mIg constitutes, with other glycoprotein chains, the B-cell antigen receptor complex (BCR). These correspond to non-covalently associated transmembrane disulfide-linked heterodimer phosphoprotein Igα/Igβ (CD79a and CD79b), which are encoded by mb-1 and B29 genes, and are structurally similar to CD3γ, δ, and ε chains on T-cells and therefore involved in signal transduction of B-cell [23] (Figure 3). The intracytosolic portion size of the heterodimer allows it to initiate signal transduction, following the binding of the specific antigen to the mIg.

inducing the activation and infiltration of immune cells

None

0.002%

12%

Function Protects against parasites

None

Distribution Basophils and mast cells in saliva and nasal secretions

Classical complement pathway activation

Valency 2 Structure Monomers H chain typejMW εj70–73 kDa Serum concentration: 10–400 ng/mL In vivo serum half life 2.5 days

Relative serum abundance to total immunoglobulin

Carbohydrate content by weight (glycosylation)

Crosses placenta None

Classical complement pathway activation

Molecular formula ε2κ<sup>2</sup> or ε2λ<sup>2</sup> Subclasses None MW 190–200 kDa

Igs are very mobile on the surface of B-cells. In addition, various specific ligands cause what is called capping, i.e., a rapid redistribution of complexes on the surface of the cell, followed by internalization of the complexes or their release into the surrounding environment. This transient disappearance of the mIg receptor via its binding to specific ligands, like anti-immunoglobulin antibodies or antigens, is called antigenic modulation, which constitutes the initial signal for B-cell activation. The modulated membrane receptor may also be synthesized by the cell and returned to the surface when the B-cell is metabolically

2.3 Mobility of mIgs, capping, and antigenic modulation

mIg: membrane-bound immunoglobulin, sIg: secreted immunoglobulin (serum or secretory Ig).

BCR complex structure. The BCR complex is composed of a mIg non-covalently bonded to a transmembrane disulfide-linked heterodimer phosphoprotein composed of CD79a (Igα)/CD79b (Igβ). CD, cluster of differentiation; mIg, membrane-bound immunoglobulin.

#### Figure 4.

Structural difference between the C-terminus of the H chain constant region of mIgM and sIgM. mIgM and sIgM differ simply by the COOH ends of the μ chain and therefore by mRNAs that differ at their 3<sup>0</sup> ends. Membrane-bound IgM (membrane μ) is slightly larger than that of secreted IgM (secreted μ) [27]. The numbers indicate the position of amino acids. N-CHO represents the position of glycosylation of asparagine (N, Asn) (N-glycosylation site). mIgM, membrane immunoglobulin M; sIgM, secreted immunoglobulin M.

chains contains a short hydrophobic stretch which spans the lipid bilayer of the membrane [26] (Figure 4).

3. B-cell ontogeny

Introductory Chapter: B-Cells

The differentiation of B-cells from hematopoietic stem cells into pro-B, then pre-B, then immature B-cells, and finally into mature B-cells is characterized by several events, including (i) modification of membrane differentiation markers; (ii) Ig gene rearrangement, which takes place at the pro-B and pre-B stages, allowing

B-cell ontogenesis occurs in the fetal liver, then in the bone marrow, and continues throughout life. It starts from a hematopoietic stem cell and leads to the development of a so-called "immature" B-cell with the same and unique antigenic specificity. The immature B-cell migrates to the peripheral lymphoid organs, where the different stages of maturation will take place, leading to the Ig-producing plasma cells and memory B-cells [24]. Ultra-complex regulatory mechanisms are involved during all stages of B-cell development and lead to the generation of B-cell

Knowing that B-cells, T-cells, and natural killer (NK) cells all develop from the early lymphoid progenitors that originate from totipotent hematopoietic stem cells, cell fate results from several lineage choices. The B-cell progenitors continue to

During their development, B-cell and T-cell undergo a dual process of positive

In the case of B-cells, outside the negative selection mechanisms, cell survival depends essentially on their ability to compete for survival factors such as the B-cell activating factor (BAFF, also known as B lymphocyte stimulator (BLyS), a subset of the tumor necrosis factor (TNF) tumor necrosis factor ligand superfamily member 13B), which is present in the circulation and produced by resident cells within secondary lymphoid organs [24]. Positive selection mainly corresponds to BCR functionality test and depends on a moderate response to the self-antigen, which stimulates cell maturation and survival. When self-reactivity exceeds a certain level, a process so-called receptor reformatting is triggered by inducing a new cycle of gene rearrangements, principally in the IG L chain loci (see Chapter 2). If the receptor reformatting fails, or if the developing B-cell leaves the bone marrow and encounters the self-antigen soon after it arrives in the spleen, this cell will be

The differentiation of hematopoietic stem cell (HSC) into immature B-cell passes through four successive steps, which could be identified by the presence of certain markers, corresponding to the different stages of rearrangement of Ig genes:

and negative selection in which cells that react with high affinity against selfantigens are eliminated because they constitute a significant danger of triggering

the expression of BCR; and (iii) negative clonal selection.

repertoire with a vast diversity of antigen recognition capacity.

3.1.2 Positive and negative selection and B-cell receptor reformatting

3.1.1 Lymphoid progenitor cells and cell fate decisions

develop in the bone marrow [21].

autoimmune responses.

eliminated [21].

11

3.1.3 Immature B-cell generation

3.1 B-cell ontogenesis and maturation

DOI: http://dx.doi.org/10.5772/intechopen.90636

sIgs play a complementary role to that of T-cells. It needs to use other mechanisms for antigen removal. This implies that they bind other molecules, like complement molecules, or specialized receptors, called Fc receptors (FcRs, receptors of fragment crystallizable region), on the surface of effector cells that they activate, including phagocyte cells (Figure 5).

Antibodies allow B-cells to provide systemic protection of the host and immune surveillance through pathogen recognition and organization of immune reactions. Their expression varies according to the state of differentiation of B-cells. After activation, B-cells transform into plasma cells that secrete antibodies of the same specificity as their membrane BCR. Secreted antibodies are transported rapidly throughout the body by blood or lymph or secreted through the epithelia to protect the interface between the body and its environment. IgG antibodies also provide a mechanism by which acquired immunity can be transmitted from the mother to the fetus or infant, thus providing acquired immune protection during the critical period of early life. Nevertheless, some antibodies can bind to self-structures, referred to as autoreactive antibodies, and induce, under certain conditions, aberrant immune responses and tissue damage [28].

#### Figure 5.

Human FcRs and their cell localization and immune functions. DCs, dendritic cells; FcRn, neonatal fc receptor; FcRs, receptors of fragment crystallizable region; FDCs, follicular dendritic cells; Fl58, phenylalanine at position 158; GC, germinal center; H131, histidine at position 131; ICs, antigen-antibody immune complexes; PIgR, polymeric immunoglobulin receptor; R131, arginine at position 131; V158, valine at position 158.
