B lymphocytes or B cells shortly belong to the leukocytes (white blood cells). You are the only cells able to produce antibodies and together with the T- lymphocytes the crucial part of the adaptive immune system from. Whereas T - cells are involved in cell-mediated immune response, the B cells are the carriers of the humoral immune response ( production of antibodies ). If they are activated by exogenous antigens, they can differentiate into antibody-producing plasma cells or memory cells. The term " B- cell " originated from their education center in the bursa of Fabricius in birds. In humans and some other mammals, the B cells originate in the bone marrow, therefore, received the letter B here subsequently the importance of bone marrow (English for bone marrow), for many mammals, the origin is not clear yet, here one uses the term " bursa equivalent organ ".
- 4.1 T- cell-dependent activation of
- 4.2 T cell - independent activation
The development of B- cells occurs in humans and also in some other mammals in the bone marrow or fetal liver. The signals that are necessary for the development program, received the evolving lymphocytes of so-called stromal cells. Of B -cell development, the formation of a functional B cell receptor ( membrane bound form of the antibody ) is essential. Only with this antigen receptor mature B cells are later to recognize able foreign antigens and fight through the formation of corresponding antibodies enemy structures. Antigen specificity of the receptor is determined by the combination of certain gene segments. The segments are called V, D and J segments, which is why the process as V ( D) J recombination is called. While these segments, which form the antigen-binding part of the B- cell receptor, rearranged. The entire receptor is composed of two identical light chains and two identical heavy protein protein chains, which are linked via disulfide bridges. In VDJ recombination out the V, D and J segments of the heavy chain of the B- cell receptor to be linked, followed by the V- and J- segments of the light receptor chain. Only if the genes are thereby successfully rearranged, which is referred as a productive Genumordnung that cell can proceed in the next developing step.
B cells that react to self-antigens during their maturation in the bone marrow, die in most cases from by apoptosis. In the blood of healthy people can be small amounts of autoreactive cells, including against thyroglobulin or collagen, demonstrate.
Stages of B cell development
The first stage of B -cell development represent the pro-B cells derived from the pluripotent stem cells ( hematopoietic stem cells). In pro-B cells, the rearrangement of the heavy chain is performed. In the case of a productive gene rearrangements thereby a so-called μ heavy chain is formed, which leads to the inlet in the stage of pre-B - cell. In the first pre-B -cell stage, the so-called large pre-B cells, the heavy μ - chain is expressed along with a replacement for the light chain in the form of a pre-B -cell receptor on the cell surface. The large pre-B cells divide several times and eventually develop into small pre-B cells that do not form a pre-B cell receptor has indeed become more and intracellular μ heavy chains. In small pre-B cells is initiated with the VJ rearrangement of the light chain. After the genes have been successfully migrated for the light chain, the cell passes to an immature B- cell stage. In this case, a complete B cell IgM receptor molecule expressed on the surface. Mature B - cells ultimately are characterized that are formed among them by alternative splicing of IgD receptors.
- 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 rearrangement of the light chain
- Immature B- cell: IgM receptor on the surface of
- Mature B - cell: IgM and IgD on the surface receptors.
B cells are capable of some with their B -cell receptors, exogenous structures usually - called antigens - to detect and then directed to produce antibodies against these antigens. However, these B cells begin only with the production of antibodies, if they have previously been fully activated. Naive B lymphocytes (mature B cells, the antigen had no contact with her yet) circulate in the blood and lymphoid organs ( thymus, spleen, lymph nodes, bone marrow ) of the body of vertebrates. Once a B cell, with its B-cell receptor binds to a foreign antigen, while a costimulatory signal of T-helper cells (which must also be recognized that the same antigen ) receives, it migrates to the germinal centers so-called lymph nodes or spleen. Here they strongly divided (proliferation ) and differentiated the so-called plasma cell and then secreted antibodies. These antibodies have the same specificity as the B-cell receptor of the cell, that is, they bind to the same antigen. In addition to their antibody genes, mutations are introduced, which can lead to the improvement of antibody affinity for the antigen recognized (somatic hypermutation ). Also in this case, a grade change of the constant ( conserved ) part of the antibody that determines the function ( eg, as a membrane-bound receptor ), to take place. Which in turn is important for the way in which the antibody further act on the pathogen or where the antibody access in the body.
In humans, there are about 109-1010 different, specific B lymphocytes that differ in their antigen receptors and caused J recombination by V ( D).
B lymphocytes bear on their surface a series of proteins ( the so-called surface markers ) that are functionally important, and can be used to identify, for example, in human blood or tissue samples. In addition to the membrane-bound immunoglobulins ( antibodies), these include, for example, CD19, CD20 and CD21.
Antigen recognition by B- cells
A fundamental difference between B - and T- cells lies in how they recognize their corresponding antigen. B cells bind in unbound (soluble ) form present antigens directly through its membrane-bound B-cell receptor. T cells, however, bind with the aid of their T- cell receptor peptide fragments of the antigen only after it (after proper processing of the antigen ) presented on the surface of antigen presenting cells together with the MHC molecule as an antigen - MHC complex be.
Activation of B cells
The recognition of the antigen by B cell is not necessarily the only essential element which is required for their activation. Naive B cells, ie, those who had no contact with their antigen, often an additional stimulation by T cells need to become activated. Depending on the nature of the antigen, B cells can be activated in a T cell dependent or T cell - independent manner.
T cell - dependent activation of
Most antigens are T cell - dependent, ie for maximum antibody production is a participation of T cells required. Here, two different signals are required to activate the B cell: the first is formed by the cross-linking of antigen receptors on the surface of the cell, after the latter has a corresponding antigen bound. The second obtains the B- cell of a so-called T-helper cell. In this case, the antigen - by the binding of the B-cell receptor - was added into the cell of the B cell and presented in conjunction with an MHC molecule on the surface. Here, an appropriate T- cell ( helper T cell) binding to the antigen - MHC complex by means of their T cell receptor. The T cell then activates the B cell secretes by certain cytokines. In response, the B- cell ( clonal expansion ) and differentiated into an antibody- producing B cell ( plasma cell) increased. The class change of the B cell, after whom antibodies of classes IgG, IgA and IgE can be made now, and the formation of memory B cells are T cell-dependent responses of a B cell.
The activation of B- cells by T-helper cells will take place in the secondary lymphoid organs. B- lymphocytes which have previously detected a foreign antigen, refer to this and decompose the antigen proteins into individual peptides, which are then presented, together with the MHC-II on the surface. Such B cells migrate through the T cell zone of lymphoid organs, where they are held if they encounter armed helper T cells that recognize these peptide - MHC complexes. Armed in this case means that the T cell has itself been previously primarily activated by other antigen-presenting cells such as dendritic cells.
T-cell independent activation
Some antigens are T cell - independent, meaning that they require only a single signal, which is generated by cross-linking the B -cell receptors. Especially repeating polysaccharides, such as those found on the surface of bacteria can be detected in this way. The B- cell is activated by proliferates and makes antibodies of the IgM class. A class change is omitted in this form of activation as well as the formation of memory cells. For this reason, the vaccination leads with polysaccharide vaccines usually only a temporary protection of 3 to 6 years.
Besides the various maturity and terminal stages of B- cells, there are two fundamentally different types of B cells.
- B2- cells: they constitute the majority of the B cells, they could be called the " ordinary " B - cells, respectively.
- B1 cells: B1- B2 cells are larger than cells, and are mainly found in the abdominal cavity. In the spleen, they make a total of only about 5% of B cells in peripheral lymph nodes they are missing. They respond relatively weakly to protein antigens, for better carbohydrate antigens and, in comparison to B2 cells less somatic hypermutation (see function) and less class switching. B1 cells differ in certain surface markers of B2 cells, so they wear unlike B2 cells less IgD, IgM more, no CD23 but for CD43. Originally B1- B2 cells were distinguished from cells by the presence of the T-cell surface marker CD5. Meanwhile, a sub-population was detected at the B-cells of the abdominal cavity, however, that bears no CD5, but in other surface features is identical to B1 cells. Therefore, the CD5 positive cells B1- called B1a cells, CD5 negative is called B1b cells. Whether B1a cells arise from a separate line and have their origin in the fetus, or whether it can evolve from ordinary B2 cells, is still controversial. The features mentioned are based primarily on mice in this regard are the best studied. People have two classes of CD5 positive B cells. One of them compensates the B1a cells from mice in other aspects. In contrast, no rat CD5 positive B cells are well known. In rabbits, cattle and chicken, most peripheral B cells carry CD5. In the context of hemato - oncology and autoimmune diseases may occur on B cells for enhanced expression of CD5.
- Marginal zone B cells: marginal zone B cells ( MZ B cells) are found in the marginal zone of the spleen, they make up only about 5% of the B cells of the spleen, but are an important part of the early immune response against pathogens in the blood.
Signal line B- cells
The reaction of mature B - cells to external influences is mediated mainly through the B-cell receptor, which determines the antigen specificity of the B- cell, and is a membrane-bound form of the antibody. B- cells, the B-cell receptors recognize antigens that can be activated. Since the B-cell receptor itself only has a short intracellular region, the signal that it receives, via associated chains ( Igα and Igβ ) is directed into the cell. This is done via so-called ITAMs, which are found in each of the intracellular domains of Igα and Igβ. 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, which then can bind to the kinase Syk. Syk is also phosphorylated by Src kinases and activated by what is, in turn, the adapter protein BLNK (also SLP -65) phosphorylated. BLNK activated now along with another kinase ( Btk ), phospholipase PLCγ2. This is then to hydrolyze in diacylglycerol (DAG) and inositol triphosphate (IP3 ) capable of phosphatidylinositol 4 ,5 -bisphosphate ( PIP2 ). These two second messengers (DAG and IP3) transmit the signals on, until finally, among other transcription factors, are regulated differentially affecting the response of the cell directly to contact with the antigen.
IP3 binds about to corresponding receptors in the endoplasmic reticulum ( ER) resulting in the ejection of Ca2 from the ER. This in turn triggers the influx of Ca2 from the extracellular areas across the plasma membrane into the cell from inside. The calcium ions activate calmodulin, whereby the serine / threonine phosphatase calcineurin is activated. Calcineurin dephosphorylates the transcription factor NFAT then important that by penetrating into the cell nucleus and influence the transcription of DNA.
DAG, the second product of PIP2 PLCγ2 -induced cleavage results together with the increased Ca2 concentration for activation of the PKCβ, which is important for the activation of the transcription factor NF-KB. This takes place via several intermediate steps. PKCβ phosphorylates CARMA1 first, which entails the recruitment of Bcl- 10 and MALT by itself. This complex activates the IkB kinase ( IKK ), which results in phosphorylation and then degradation of IkB. Without IkB NF-KB can enter 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 the switch from the GDP-bound to GTP-bound form. This is done primarily by so-called GTP exchange factors ( GEFs ). Most important for the B -cell receptor -mediated Ras activation seems to be involved and GEFs from the group of Ras - GRPs, which are led by DAG to the membrane and be phosphorylated by PKCβ. Also, probably the GEF Sos plays a role. Activation of Ras leads on the two kinases Raf -1 and Mek to the activation of transcription factors, ERK1 / 2
The B- cell receptor is supported in these signal lines through the CD19 co-receptor, the effect lowers the threshold Aktvierungsstärke. Phosphorylated CD19 acts as a docking site for a number of important signaling proteins, such as Vav, and PI3K BCAP. The membrane recruitment of PI3K leads to the conversion of PIP2 to PIP3. This membrane-bound molecule in turn provides binding sites for proteins with PH domains, such as PDK1 / 2, Akt, Btk and PLCγ2 constitutes a major substrate of Akt, which is activated by B- cell receptor stimulation by PDK1 / 2, the kinase GSK- third Through the activation of Akt, GSK -3 is inactive and can no longer phosphorylate the transcription factor NFAT, causing it to be less disabled. This act affects ultimately activating effect on NFAT. Akt also inhibits the transcription factor Foxo. In addition, there are inhibitory receptors which counteract the B-cell receptor. These include CD22 and the Fc receptor FcγRIIB. A second important receptor of signal line of mature B - cells in addition to the B-cell receptor in addition to the BAFF receptor.