B lymphocytes, or B cells for short, belong to the group of leukocytes (white blood cells). They are the only cells able to form plasma cells, which in turn release antibodies , and together with the T lymphocytes make up the crucial part of the adaptive immune system . While T cells are involved in the cell-mediated immune response , the B cells are the carriers of the humoral immune response (formation of antibodies). When activated by foreign antigens , they can differentiate into antibody-producing plasma cells and memory cells. The designation "B cells" originally comes from their place of formation in the bursa Fabricii in birds. In humans and some other mammals, the B cells are created in the bone marrow , which is why the letter B was subsequently given the meaning of bone marrow . The origin of many mammals has not yet been clearly established. The term " bursa-equivalent organ " is used here.
The development of the B cells takes place in humans and also in some other mammals in the bone marrow or the fetal liver. The signals that are necessary for the development program are received by the developing lymphocytes from so-called stromal cells . In B-cell development, the formation of a functioning B-cell receptor (the membrane-bound form of the antibody) is of crucial importance. Only with this antigen receptor are mature B cells later able to recognize foreign antigens and to fight hostile structures through the formation of appropriate antibodies. The antigen specificity of the receptor is determined by linking certain gene segments. The segments are called V, D, and J segments, which is why the process is known as V (D) J recombination . In the process, these segments, which form the antigen-binding part of the B cell receptor, are rearranged. The entire receptor consists of two identical light protein chains and two identical heavy protein chains that are linked by disulfide bridges . In VDJ recombination, first the V, D and J segments of the heavy chain of the B cell receptor are linked, then the V and J segments of the light receptor chain. Only when the genes are successfully rearranged, which is known as productive gene rearrangement, the cell can move on to the next development step.
B cells that react to endogenous antigens during their maturation in the bone marrow die in the vast majority of cases as a result of apoptosis . Small amounts of autoreactive cells, including those against thyroglobulin or collagen , can be detected in the blood of healthy people .
Stages of B cell development
The first stage of B-cell development are the pro-B cells, which are derived from pluripotent stem cells ( hematopoietic stem cells ). The rearrangement of the heavy chain occurs in Pro-B cells. In the case of a productive gene rearrangement, a heavy μ chain is formed, which leads to entry into the pre-B cell stage. In the first pre-B-cell stage, the large pre-B cells, 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 cells divide several times and finally develop into the small pre-B cells, which no longer form a pre-B cell receptor and only have intracellular heavy μ-chains. In the small pre-B cells, VJ rearrangement of the light chain begins. After the genes for the light chain have been successfully rearranged, the cell changes to the stage of an immature B cell. A complete B-cell receptor molecule IgM is expressed on the surface. Mature B cells are ultimately characterized by the fact that they also form IgD receptors through alternative splicing .
- early pro-B cell: DJ rearrangement of the heavy chain
- late pro-B cell: V-DJ rearrangement of the heavy chain
- large pre-B-cell: μ-chain as part of the pre-B-cell receptor on the surface
- small pre-B cell: VJ light chain rearrangement
- immature B-cell: IgM receptor on the surface
- mature B cell: IgM and IgD receptors on the surface.
With their B-cell receptors , B cells are able to recognize certain, usually foreign structures - antigens - and then to produce antibodies directed against these antigens. However, these B cells do not begin to produce antibodies until they have been fully activated. Naive B-lymphocytes (mature B-cells that have not yet had contact with their antigen) circulate in the blood and lymphatic organs ( thymus , spleen , lymph nodes , bone marrow ) of the body of vertebrates. As soon as a B cell with its B cell receptor binds to a foreign antigen and at the same time receives a costimulatory signal from T helper cells (which must also have recognized the same antigen), it migrates to the so-called germinal centers in the lymph nodes or spleen. Here it divides strongly ( proliferation ), differentiates into plasma cells and then secretes antibodies. These antibodies have the same specificity as the cell's B-cell receptor, that is, they bind to the same antigen. In addition, mutations are introduced into their antibody genes , which can lead to an improvement in the antibody affinity for the recognized antigen ( somatic hypermutation ). In addition, a change in class of the constant (conserved) part of the antibodies, which determines the function (e.g. as membrane receptor), can take place. This in turn is important for the way in which the antibodies subsequently act on the pathogen or where the antibodies go in the body.
B-lymphocytes carry a number of proteins (so-called surface markers ) on their surface , which are functionally important and, for their identification, e.g. B. can be used in human blood or in tissue samples. In addition to the membrane-bound immunoglobulins (antibodies), these include z. B. CD19 , CD20 and CD21 .
Antigen recognition by B cells
A fundamental difference between B and T cells is how they recognize their corresponding antigen. B cells bind antigens in unbound (soluble) form directly with the help of their membrane-bound B cell receptor. T cells, on the other hand, only bind peptide fragments of the antigen with the help of their T cell receptor, after these (after appropriate processing of the antigen) are presented on the surface of antigen-presenting cells together with their MHC molecule as an antigen-MHC complex become.
Activation of B cells
Recognition of the antigen by the B cell is not necessarily the only necessary element required for its activation. Naive B cells, i.e. those that have not yet had contact with their antigen, often need additional stimulation by T cells in order to be activated. Depending on the type of antigen, B cells can be activated in a T cell dependent or T cell independent manner.
T cell-dependent activation
Most antigens are T-cell-dependent, which means that T-cells must be involved for maximum antibody production. Two different signals are necessary to activate the B cell: The first is created by the cross-linking of the antigen receptor on the surface of the cell after it has bound a corresponding antigen. The second receives the B cell from a "T helper cell". The antigen - after binding by the B-cell receptor - is absorbed into the interior of the B-cell and presented on the surface together with an MHC molecule. Here an appropriate T cell ( T helper cell ) can bind to the antigen-MHC complex with the help of its T cell receptor. The T cell now activates the B cell by releasing certain cytokines . The B cell then multiplies ( clonal expansion ) and differentiates into an antibody-producing B cell (plasma cell). The class change of the B-cell, after which antibodies of the classes IgG, IgA and IgE can now also be formed, as well as the formation of memory B-cells are T-cell-dependent responses of a B-cell.
The activation of the B cells by T helper cells takes place in the secondary lymphatic organs. B-lymphocytes that have previously recognized a foreign antigen take it up and break down the antigen proteins into individual peptides , which are then presented on the surface together with the MHC- II. Such B cells migrate through the T cell zone of lymphatic organs, where they are held in place if they encounter a T helper cell that can recognize the presented antigenic peptide and thus can bind to the antigen-MHC-II complex.
T-cell independent activation
Some antigens are T-cell independent, so they only need a single signal that is generated by cross-linking the B-cell receptors. In particular, repeating polysaccharides , such as those found on the surface of bacteria, can be recognized in this way. The B-cell is activated, multiplies and forms antibodies of the IgM class. A change of class does not occur with this form of activation, as does the formation of memory cells . For this reason, the vaccination leads with polysaccharide - vaccines usually only a temporary protection of 3 to 6 years.
B cell types
In addition to the various maturity and terminal stages of B cells, there are two fundamentally different types of B cells.
- B2 cells: They make up the majority of the B cells, one could call them the “normal” 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, they are absent in peripheral lymph nodes . They react relatively weakly to protein antigens, but better to carbohydrate antigens and, compared to B2 cells, show less somatic hypermutation (see under function) and fewer class changes. B1 cells differ from B2 cells by certain surface markers; in contrast to B2 cells, they carry less IgD, more IgM, no CD23 but CD43. Originally, B1 cells were differentiated from B2 cells by the presence of the T cell surface marker CD5. In the meantime, however, a subpopulation has been discovered among the B cells of the abdominal cavity that does not carry CD5, but is identical to B1 cells in other surface features. Therefore, the CD5 positive B1 cells were named B1a cells and the CD5 negative cells were named B1b cells. Whether B1a cells arise from a separate lineage and originate in the fetus or whether they can develop from ordinary B2 cells is still a matter of dispute. The characteristics mentioned relate primarily to mice that have been best studied in this regard. Humans have two classes of CD5 positive B cells. One of them resembles the B1a cells of mice in other respects. In contrast, no CD5 positive B cells are known in rats. In rabbits, cattle, and chickens, most peripheral B cells carry CD5. In the context of haemato-oncological and autoimmune diseases , increased expression of CD5 on B cells can occur.
- Marginal zone B cells: Marginal zone B cells (MZ B cells) are found in the marginal zone of the spleen , they only make up about 5% of the B cells of a spleen, but they are an important part of the early immune response against pathogens in the blood.
Signal conduction in B cells
The reaction of mature B cells to external influences is primarily mediated by the B cell receptor, which determines the antigen specificity of the B cell and is a membrane-bound form of the antibody. B cells whose B cell receptors recognize antigens can be activated. Since the B-cell receptor itself only has a short intracellular area, the signal it receives is conducted into the interior of the cell via associated chains (Igα and Igβ). This takes place via so-called ITAMs , which can be found in the intracellular domains of Igα and Igß. Antigen binding by the B-cell receptor triggers the activation of various proteins. These include the kinases of the Src family, which are represented in B cells by Lyn , Fyn , Blk and Hck. To be activated, they need, among other things, the phosphatase CD45. Activated Src kinases phosphorylate the ITAMs in the receptor-associated chains, to which the Syk kinase can then bind. Syk is also phosphorylated and activated by the Src kinases, whereupon it in turn phosphorylates the adapter protein BLNK (also SLP-65). BLNK now activates the phospholipase PLCγ2 together with another kinase ( Btk ) . This is then able to hydrolyze phosphatidylinositol-4,5-bisphosphate (PIP 2 ) into diacylglycerol (DAG) and inositol trisphosphate (IP 3 ). These two secondary messenger substances (DAG and IP 3 ) transmit the signals until, among other things, transcription factors are differentially regulated, which directly influence the cell's response to antigen contact.
IP 3 binds to corresponding receptors in the endoplasmic reticulum (ER), which leads to the expulsion of Ca 2+ from the ER. This in turn triggers the influx of Ca 2+ from extracellular areas through the plasma membrane into the cell. The calcium ions activate calmodulin , which activates the serine / threonine phosphatase calcineurin . Calcineurin then dephosphorylates the important transcription factor NFAT, which can penetrate the cell nucleus and influence the transcription of DNA.
DAG, the second product of the PLCγ2-induced PIP 2 cleavage, together with the increased Ca 2+ concentration, leads to the activation of PKCβ, which is important for the activation of the transcription factor NF-κB. This takes place in several intermediate stages. PKCβ initially phosphorylates CARMA1, which leads to the recruitment of BCL-10 and MALT. This complex activates the IκB kinase (IKK), which leads to phosphorylation and then to the breakdown of IκB . Without IκB, NF-κB can penetrate the nucleus and act as a transcription factor.
The activation of the B-cell receptor also leads to the activation of the small G protein Ras . Ras is activated by changing from the GDP- bound to GTP- bound form. This is done primarily through so-called GTP exchange factors (GEFs). The most important Ras activation mediated for the B-cell receptor seems to be GEFs from the group of Ras-GRPs, which are guided to the membrane by DAG and are phosphorylated by PKCβ. The GEF Sos probably also plays a role. The activation of Ras leads to the activation of the transcription factors Erk1 / 2 via the two kinases Raf-1 and Mek.
The B-cell receptor is supported in these signal lines by the co-receptor CD19, the effect of which lowers the threshold value of the activation strength. Phosphorylated CD19 acts as a docking point for numerous important signal proteins such as Vav, BCAP and PI3K . The membrane recruitment of PI3K leads to the conversion of PIP 2 to PIP 3 . This membrane-bound molecule in turn represents binding sites for proteins with PH domains such as PDK1 / 2, Akt , Btk and PLCγ2. An important substrate of Akt, which is activated after B-cell receptor stimulation by PDK1 / 2, is the kinase GSK-3. Activation of Akt makes GSK-3 inactive and can no longer phosphorylate the transcription factor NFAT, which inactivates it less. As a result, Akt ultimately has an activating effect on NFAT. Akt also inhibits the Foxo transcription factor. There are also inhibitory receptors that counteract the B-cell receptor. These include CD22 and the Fc receptor FcγRIIB. In addition to the B cell receptor, a second important receptor in the signal transmission of mature B cells is the Baff receptor .
- Charles A. Janeway Jr. including: immunology. 5th edition. Spectrum Academic Publishing House, Heidelberg / Berlin 2002, ISBN 3-8274-1078-9 .
- Janis Kuby et al: Immunology. 5th edition. WH Freeman and Company, New York 2003, ISBN 0-7167-4947-5 .
- Abul K. Abbas: Diseases of Immunity in Vinay Kumar, Abul K. Abbas, Nelson Fausto: Robbins and Cotran - Pathologic Basis of Disease. 7th edition. Philadelphia 2005, pp. 224f.
- Robert Berland, Henry H. Wortis: Origins and Functions of B-1 Cells With Notes on the Role of CD5. In: Annual Review of Immunology . Vol. 20, April 2002, pp. 253-300.
- I. Böhm: Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them. In: Biomed Pharmacother . 58, 2004, pp. 338-343.
- Thiago Lopes-Carvalho, John F. Kearney: Development and selection of marginal zone B cells. In: Immunological Reviews . Volume 197 Issue 1, February 2004, pp. 192-205.
- Mackay et al: B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. In: Immunological Reviews. Vol. 237, 2010, pp. 205-225.