B lymphocyte

B-lymphocytes, also called B-cells (Note: B-lymphocytes were originally named after their place of formation in the Bursa Fabricii in birds; later the "B" got its meaning from "bone marrow", the bone marrow, because the hematopoietic progenitor cells are generated there) B cells belong to the leukocytes and develop in the bone marrow from hematopoietic progenitor cells, the lymphoid stem cells. In their development, B cells need close interaction with bone marrow stromal cells, which provide VCAM-1 for interaction, SCF (stem cell factor) for differentiation and other growth factors such as interleukin-7. In bone marrow, both the isotype and the specificity of the B cells are determined. B lymphocytes or the B plasma cells and the antibodies they produce are the central elements of the humoral immune system.

Antigen recognition by B cells: A fundamental difference between B and T cells lies in the different ways in which they recognise an antigen. T-cells bind only peptide fragments of the antigen with the help of their T-cell receptor, after these (after appropriate processing) are presented on the surface of antigen presenting cells (together with their MHC molecule) as antigen-MHC complex (see below antigen presentation).

B lymphocytes, on the other hand, attach themselves to an intruded antigen (e.g. a bacterium) by means of a precisely fitting antibody in order to eliminate it. Antigen recognition and binding leads to monospecific antibody production. In the bone marrow the maturing B cells also undergo negative selection by contacting them with autoantigens. B cells, which react to the body's own antigens during their maturation in the bone marrow, die in most cases by apoptosis. However, small amounts of autoreactive cells can be detected in the blood of healthy people, for example against thyroglobulin or collagen. Cells that leave the germinal centre differentiate into memory B cells or antibody-secreting plasma cells.

Stages of B-cell development: The first stage of B-cell development is represented by the Pro-B cells (early and late Pro-B cells), which develop from the lymphoid stem cell. In Pro-B cells, the heavy chain is rearranged. In the case of a productive gene rearrangement, a so-called heavy μ chain is formed, which leads to the entry into the pre-B cell stage.

In the first pre-B cell stage, the so-called large pre-B cell(CD43+^, CD40+, CD19+, CD20+), the heavy μ chain is expressed on the cell surface together with a replacement for the light chain in the form of a pre-B cell receptor.

The large pre-B-cell divides several times. It finally matures into the small pre-B cell, which no longer forms a pre-B cell receptor and only has intracellular heavy μ chains. In the small pre-B cell, the V-J rearrangement of the light chain begins.

Once the light chain genes have been successfully rearranged, the cell enters the stage of immature (naive) B-cells. The immature or naive B cell is able to express IgM as the first B cell receptor molecule on the surface. Furthermore, the naive B cell expresses CD45+, CD19+, CD20+, CD40+.

Different types of B-cells: Besides the different maturation and final stages of B-cells, there are two fundamentally different types of B-cells.

• B2 cells: They represent the majority of B cells.
• B1 cells: B1 cells are larger than B2 cells and are mainly found in the abdominal cavity. In the spleen, they make up only about 5% of the B cells, in peripheral lymph nodes they are completely absent. They react relatively weakly to protein antigens, but more strongly to carbohydrate antigens. B1 cells differ from B2 cells by certain surface markers. They express less strongly IgD, no CD23; but significantly stronger IgM and CD43.
• In addition, there are also marginal zone B cells (MZ B cells). These are found in the marginal zone of the spleen and make up about 5 % of the B cells. They are an important component of the early immune response against pathogens.

Activation of B-cells:

T-cell dependent activation: After a first antigen contact the isotope switch (class change) is initiated. B cells are capable of producing up to¹⁰¹³ different antibodies. Each B-cell has about 10,000 antibody molecules on its cell surface. Approximately 300 genes are involved in antibody production. These genes are rearranged to form a specific antibody (so-called complex genes). To form a specific antibody 2 signals are necessary. The first signal is generated by cross-linking the antigen receptor on the surface of the cell after it has bound a suitable antigen. The second signal originates from a T-helper cell. The antigen - after binding to the B-cell receptor - is taken up into the cell interior of the B-cell, processed there and finally presented to a T-cell together with an MHC molecule on the surface of the B-cell. The T-cell is able to bind to this antigen-MHC complex through its T-cell receptor (TCR). The T cell then activates the B cell by secreting various cytokines(interleukin-2, interleukin-4, interleukin-5, interferon alpha, TGF-beta). This cytokine pattern induces clonal expansion of the B cell and its differentiation into an antibody-producing B cell(plasma cell).

T-cell independent activation of B cells: Some antigens induce T-cell independent B-cell responses. Therefore, they require only a single signal, which is generated by cross-linking of B-cell receptors. In particular, repetitive polysaccharide motifs, such as those found on the surface of bacteria, are recognized and bound in this way. This signal enables a T-cell and CD40-independent class change. This T-cell independent class change leads to IgG antibodies that are specifically directed against numerous microbial antigens (e.g. bacterial lipopolysaccharides). Toll-like receptors (TLR) or the "transmembrane activator and cyclophilin ligand interactor" also called TACI, together with IL-4, TGF-beta or interferon gamma, play a decisive role in this process.

AID-a key enzyme: Class change in B cell maturation requires AID (activation induced cytidine deaminase), a key enzyme that is upregulated during B cell activation. NF-κB plays a crucial role in this process, AID causes by generating numerous point mutations in the variable region together with uracil DNA glycosilase (UNG). B cells with higher affinity can bind the antigen better and present it more effectively, which represents a selection advantage and, as a result, enables the production of more specific antibodies. This process is called affinity maturation. The antigen affinity of the new BCR of the centrocytes is checked by means of T cells and follicular dendritic cells in the germinal center. Receptors with lower affinity or autoreactivity guide the cell to apoptosis.

Class change (to IgG, IgA or IgE) is also mediated by the AID by recombination in the constant region of the Ig gene. An intact BCR (B-cell receptor) and the binding of the survival factor BAFF (B-cell activating factor from the TNF family) to its receptor BAFF-R is necessary for the survival of peripheral B-cells.

Migration behaviour of B-cells: The migration behaviour of B-cells is decisively controlled by chemokine receptors. The cellular expression of the receptors in interaction with ligand expression in lymphatic and inflammatory tissues directs the corresponding leukocytes to the site of the immunological event. Chemokine receptors such as CXCR4, CXCR5 and CCR7 (see below the respective ligand) mediate the migration and recirculation of leukocytes into primary and secondary lymphatic organs. Inflammatory chemokine receptors such as CXCR3 (see below CXCL3) antigen contact upregulates and iduce the migration of B cells into inflammatory tissue.

Standard value: 1.500-4.000 cells/µl

In humans, there are about 10 ⁹ to¹⁰¹³ different, specific B lymphocytes that differ in their antigen receptors and are formed by V(D)J recombination. B-lymphocytes carry a number of surface markers on their surface that are functionally eminently important and can be used for their identification. In addition to the membrane-bound immunoglobulins, these include CD19, CD20 and CD21.