Template:Short description Template:About Template:Infobox cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype.<ref name=":0">Template:Cite book</ref> They function in the humoral immunity component of the adaptive immune system.<ref name=":0" /> B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors.<ref name="Alberts 2002">Template:Cite book</ref> When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell.<ref name="Alberts 2002"/> In addition, B cells present antigens (they are also classified as professional antigen-presenting cells, APCs) and secrete cytokines.<ref name=":0" /> In mammals B cells mature in the bone marrow, which is at the core of most bones.<ref name=":1">Template:Cite journal</ref> In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick,<ref>Template:Cite journal</ref> which is why the B stands for bursa and not bone marrow, as commonly believed.
B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane.<ref name=":0" /> BCRs allow the B cell to bind to a foreign antigen, against which it will initiate an antibody response.<ref name=":0" /> B cell receptors are extremely specific, with all BCRs on a B cell recognizing the same epitope.<ref>Template:Cite journal</ref>
DevelopmentEdit
B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow.<ref name="BCDTfBcells">Template:Cite journal</ref><ref name=":2">Template:Cite journal</ref> HSCs first differentiate into multipotent progenitor (MPP) cells, then common lymphoid progenitor (CLP) cells.<ref name=":2" /> From here, their development into B cells occurs in several stages (shown in image to the right), each marked by various gene expression patterns and immunoglobulin H chain and L chain gene loci arrangements, the latter due to B cells undergoing V(D)J recombination as they develop.<ref name=":3">Template:Cite journal</ref>
B cells undergo two types of selection while developing in the bone marrow to ensure proper development, both involving B cell receptors (BCR) on the surface of the cell. Positive selection occurs through antigen-independent signalling involving both the pre-BCR and the BCR.<ref name=":4">Template:Cite journal</ref><ref name=":5">Template:Cite journal</ref> If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop.<ref name=":4" /><ref name=":5" /> Negative selection occurs through the binding of self-antigen with the BCR; if the BCR can bind strongly to self-antigen, then the B cell undergoes one of four fates: clonal deletion, receptor editing, anergy, or ignorance (B cell ignores signal and continues development).<ref name=":5" /> This negative selection process leads to a state of central tolerance, in which the mature B cells do not bind self antigens present in the bone marrow.<ref name=":3" />
To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2.<ref>Template:Cite journal</ref> Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells.<ref name=":6">Template:Cite journal</ref> Within the spleen, T1 B cells transition to T2 B cells.<ref name=":6" /> T2 B cells differentiate into either follicular (FO) B cells or marginal zone (MZ) B cells depending on signals received through the BCR and other receptors.<ref>Template:Cite journal</ref> Once differentiated, they are now considered mature B cells, or naïve B cells.<ref name=":6" />
ActivationEdit
B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes.<ref name=":0" /> After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph.<ref>Template:Cite journal</ref> At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.<ref name=":7">Template:Cite journal</ref> Although the events taking place immediately after activation have yet to be completely determined, it is believed that B cells are activated in accordance with the kinetic segregation model Template:Citation needed, initially determined in T lymphocytes. This model denotes that before antigen stimulation, receptors diffuse through the membrane coming into contact with Lck and CD45 in equal frequency, rendering a net equilibrium of phosphorylation and non-phosphorylation. It is only when the cell comes in contact with an antigen presenting cell that the larger CD45 is displaced due to the close distance between the two membranes. This allows for net phosphorylation of the BCR and the initiation of the signal transduction pathwayTemplate:Citation needed. Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells and B1 B cells preferentially undergo T cell-independent activation.<ref name=":8">Template:Cite journal</ref>
B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81 (all three are collectively known as the B cell coreceptor complex).<ref>Template:Cite journal</ref> When a BCR binds an antigen tagged with a fragment of the C3 complement protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and signals are transduced through CD19 and CD81 to lower the activation threshold of the cell.<ref>Template:Cite journal</ref>
T cell-dependent activationEdit
Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins.<ref name=":0" /> They are named as such because they are unable to induce a humoral response in organisms that lack T cells.<ref name=":0" /> B cell responses to these antigens takes multiple days, though antibodies generated have a higher affinity and are more functionally versatile than those generated from T cell-independent activation.<ref name=":0" />
Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis, degraded, and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane.<ref>Template:Cite journal</ref> T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR).<ref name=":9">Template:Cite journal</ref> Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21.<ref name=":9" /> CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as sustains T cell growth and differentiation.<ref name=":0" /> T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation.<ref name=":9" /> After B cells receive these signals, they are considered activated.<ref name=":9" />
Once activated, B cells participate in a two-step differentiation process that yields both short-lived plasmablasts for immediate protection and long-lived plasma cells and memory B cells for persistent protection.<ref name=":8" /> The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO.<ref name=":8" /> During this step activated B cells proliferate, may undergo immunoglobulin class switching, and differentiate into plasmablasts that produce early, weak antibodies mostly of class IgM.<ref>Template:Cite journal</ref>
The second step consists of activated B cells entering a lymphoid follicle and forming a germinal center (GC), which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and affinity maturation directed by somatic hypermutation.<ref name=":10">Template:Cite journal</ref> These processes are facilitated by TFH and follicular dendritic cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.<ref name=":8" /><ref>Template:Cite journal</ref> Resultant plasma cells secrete large numbers of antibodies and either stay within the SLO or, more preferentially, migrate to bone marrow.<ref name=":10" />
T cell-independent activationEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens<ref name=":0" /> and include foreign polysaccharides and unmethylated CpG DNA.<ref name=":8" /> They are named as such because they are able to induce a humoral response in organisms that lack T cells.<ref name=":0" /> B cell response to these antigens is rapid, though antibodies generated tend to have lower affinity and are less functionally versatile than those generated from T cell-dependent activation.<ref name=":0" />
As with TD antigens, B cells activated by TI antigens need additional signals to complete activation, but instead of receiving them from T cells, they are provided either by recognition and binding of a common microbial constituent to toll-like receptors (TLRs) or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell.<ref name=":0" /> B cells activated by TI antigens go on to proliferate outside lymphoid follicles but still in SLOs (GCs do not form), possibly undergo immunoglobulin class switching, and differentiate into short-lived plasmablasts that produce early, weak antibodies mostly of class IgM, but also some populations of long-lived plasma cells.<ref name=":11">Template:Cite journal</ref>
Memory B cell activationEdit
Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell.<ref name=":13">Template:Cite journal</ref> Some memory B cells can be activated without T cell help, such as certain virus-specific memory B cells, but others need T cell help.<ref name=":12" /> Upon antigen binding, the memory B cell takes up the antigen through receptor-mediated endocytosis, degrades it, and presents it to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane.<ref name=":13" /> Memory T helper (TH) cells, typically memory follicular T helper (TFH) cells, that were derived from T cells activated with the same antigen recognize and bind these MHC-II-peptide complexes through their TCR.<ref name=":13" /> Following TCR-MHC-II-peptide binding and the relay of other signals from the memory TFH cell, the memory B cell is activated and differentiates either into plasmablasts and plasma cells via an extrafollicular response or enter a germinal center reaction where they generate plasma cells and more memory B cells.<ref name=":13" /><ref name=":12" /> It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs.<ref name=":13" /> In vitro activation of memory B cells can be achieved through stimulation with various activators, such as pokeweed mitogen or anti-CD40 monoclonal antibodies, however, a study found a combination of R-848 and recombinant human IL-2 to be the most efficient activator.<ref>Template:Cite journal</ref>
B cell typesEdit
- Plasmablast
- A short-lived, proliferating antibody-secreting cell arising from B cell differentiation.<ref name=":0" /> Plasmablasts are generated early in an infection and their antibodies tend to have a weaker affinity towards their target antigen compared to plasma cell.<ref name=":8" /> Plasmablasts can result from T cell-independent activation of B cells or the extrafollicular response from T cell-dependent activation of B cells.<ref name=":0" />
- Plasma cell
- A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation.<ref name=":0" /> There is evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma cell.<ref name=":8" /> Plasma cells are generated later in an infection and, compared to plasmablasts, have antibodies with a higher affinity towards their target antigen due to affinity maturation in the germinal center (GC) and produce more antibodies.<ref name=":8" /> Plasma cells typically result from the germinal center reaction from T cell-dependent activation of B cells, though they can also result from T cell-independent activation of B cells.<ref name=":11" />
- Lymphoplasmacytoid cell
- A cell with a mixture of B lymphocyte and plasma cell morphological features that is thought to be closely related to or a subtype of plasma cells. This cell type is found in pre-malignant and malignant plasma cell dyscrasias that are associated with the secretion of IgM monoclonal proteins; these dyscrasias include IgM monoclonal gammopathy of undetermined significance and Waldenström's macroglobulinemia.<ref name="pmid25899140">Template:Cite journal</ref>
- Memory B cell
- Dormant B cell arising from B cell differentiation.<ref name=":0" /> Their function is to circulate through the body and initiate a stronger, more rapid antibody response (known as the anamnestic secondary antibody response) if they detect the antigen that had activated their parent B cell (memory B cells and their parent B cells share the same BCR, thus they detect the same antigen).<ref name=":12">Template:Cite journal</ref> Memory B cells can be generated from T cell-dependent activation through both the extrafollicular response and the germinal center reaction as well as from T cell-independent activation of B1 cells.<ref name=":12" />
- B-2 cell
- FO B cells and MZ B cells.<ref name=":14" />
- Follicular (FO) B cell (also known as a B-2 cell)
- Most common type of B cell and, when not circulating through the blood, is found mainly in the lymphoid follicles of secondary lymphoid organs (SLOs).<ref name=":8" /> They are responsible for generating the majority of high-affinity antibodies during an infection.<ref name=":0" />
- Marginal-zone (MZ) B cell
- Found mainly in the marginal zone of the spleen and serves as a first line of defense against blood-borne pathogens, as the marginal zone receives large amounts of blood from the general circulation.<ref>Template:Cite journal</ref> They can undergo both T cell-independent and T cell-dependent activation, but preferentially undergo T cell-independent activation.<ref name=":8" />
- B-1 cell
- Arises from a developmental pathway different from FO B cells and MZ B cells.<ref name=":14">Template:Cite journal</ref> In mice, they predominantly populate the peritoneal cavity and pleural cavity, generate natural antibodies (antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T cell-independent activation.<ref name=":14" /> A true homologue of mouse B-1 cells has not been discovered in humans, though various cell populations similar to B-1 cells have been described.<ref name=":14" />
- Regulatory B (Breg) cell
- An immunosuppressive B cell type that stops the expansion of pathogenic, pro-inflammatory lymphocytes through the secretion of IL-10, IL-35, and TGF-β.<ref name=":15">Template:Cite journal</ref> Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs.<ref name=":15" /> No common Breg cell identity has been described and many Breg cell subsets sharing regulatory functions have been found in both mice and humans.<ref name=":15" /> It is currently unknown if Breg cell subsets are developmentally linked and how exactly differentiation into a Breg cell occurs.<ref name=":15" /> There is evidence showing that nearly all B cell types can differentiate into a Breg cell through mechanisms involving inflammatory signals and BCR recognition.<ref name=":15" />
Edit
Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies.<ref name=":16">Template:Cite journal</ref> Autoimmune diseases where disease activity is correlated with B cell activity include scleroderma, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, post-infectious IBS, and rheumatoid arthritis.<ref name=":16" />
Malignant transformation of B cells and their precursors can cause a host of cancers, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and plasma cell malignancies such as multiple myeloma, Waldenström's macroglobulinemia, and certain forms of amyloidosis.<ref>Template:Cite journal</ref><ref name="pmid27866585">Template:Cite journal</ref>
Abnormal B cells may be relatively large and some diseases include this in their names, such as diffuse large B-cell lymphomas (DLBCLs) and intravascular large B-cell lymphoma.
Patients with B cell alymphocytosis are predisposed to infections.<ref>Grammatikos Alexandros, Donati Matthew, Johnston Sarah L., Gompels Mark M. Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies. Frontiers in Immunology (12)2021 https://www.frontiersin.org/articles/10.3389/fimmu.2021.731643 DOI=10.3389/fimmu.2021.731643</ref>
EpigeneticsEdit
A study that investigated the methylome of B cells along their differentiation cycle, using whole-genome bisulfite sequencing (WGBS), showed that there is a hypomethylation from the earliest stages to the most differentiated stages. The largest methylation difference is between the stages of germinal center B cells and memory B cells. Furthermore, this study showed that there is a similarity between B cell tumors and long-lived B cells in their DNA methylation signatures.<ref>Template:Cite journal</ref>
See alsoEdit
ReferencesEdit
Template:Lymphocytes Template:Immune system Template:Authority control