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B cells, also known as B lymphocytes, are a type of white blood cell of the
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
subtype. They function in the humoral immunity component of the
adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
. B cells produce
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of
B-cell receptor The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protei ...
s. When a naïve or
memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
s. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the
bursa of Fabricius In birds, the bursa of Fabricius ( Latin: ''bursa cloacalis'' or ''bursa fabricii'') is the site of hematopoiesis. It is a specialized organ that, as first demonstrated by Bruce Glick and later by Max Dale Cooper and Robert Good, is necessary ...
, a lymphoid organ where they were first discovered by Chang and Glick, 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. BCRs allow the B cell to
bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name daemon''), performs both of the main DNS server roles, acting as an authoritative n ...
to a foreign
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
, against which it will initiate an antibody response. B cell receptors are extremely specific, with all BCRs on a B cell recognizing the same
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
.


Development

B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow. HSCs first differentiate into multipotent progenitor (MPP) cells, then
common lymphoid progenitor Lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, which are one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis. Disruption in lymphopoiesis can lead t ...
(CLP) cells. 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. 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. If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. 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 In immunology, clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, m ...
,
receptor editing Receptor editing is a process that occurs during the maturation of B cells, which are part of the adaptive immune system. This process forms part of central tolerance to attempt to change the specificity of the antigen receptor of self reactive imma ...
,
anergy In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune syste ...
, or ignorance (B cell ignores signal and continues development). This negative selection process leads to a state of
central tolerance In immunology, central tolerance (also known as negative selection) is the process of eliminating any ''developing'' T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, to ...
, in which the mature B cells do not bind self antigens present in the bone marrow. 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. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. Within the spleen, T1 B cells transition to T2 B cells. 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. Once differentiated, they are now considered mature B cells, or naive B cells.


Activation

B cell activation occurs in the
secondary lymphoid organs The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoi ...
(SLOs), such as the spleen and
lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
. 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. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR. 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 , initially determined in T lymphocytes. This model denotes that before antigen stimulation, receptors diffuse through the membrane coming into contact with
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of th ...
and
CD45 Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the ''PTPRC'' gene. PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocy ...
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 pathway. 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. B cell activation is enhanced through the activity of
CD21 Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21 (cluster of differentiation 21), is a protein that in humans is encoded by the CR2 gene. CR2 is involved in the complement system. I ...
, a surface receptor in complex with surface proteins
CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
and CD81 (all three are collectively known as the B cell coreceptor complex). 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.


T cell-dependent activation

Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins. They are named as such because they are unable to induce a humoral response in organisms that lack T cells. 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. 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. T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR). Following TCR-MHC-II-peptide binding, T cells express the surface protein
CD40L CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects dependin ...
as well as cytokines such as IL-4 and IL-21. CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor
CD40 Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 ( CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of d ...
, which promotes B cell proliferation,
immunoglobulin class switching Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the ...
, and
somatic hypermutation Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM ...
as well as sustains T cell growth and differentiation. T cell-derived cytokines bound by B cell
cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...
s also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation. After B cells receive these signals, they are considered activated. 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. The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO. 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. 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 In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...
directed by somatic hypermutation. These processes are facilitated by TFH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells. Resultant plasma cells secrete large amounts of antibody and either stay within the SLO or, more preferentially, migrate to bone marrow.


T cell-independent activation

Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens and include foreign polysaccharides and unmethylated CpG DNA. They are named as such because they are able to induce a humoral response in organisms that lack T cells. 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. 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. 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.


Memory B cell activation

Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell. 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. 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. 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. 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. It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs. '' In vitro'' activation of memory B cells can be achieved through stimulation with various activators, such as pokeweed mitogen or anti-
CD40 Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 ( CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of d ...
monoclonal antibodies, however, a study found a combination of R-848 and recombinant human IL-2 to be the most efficient activator.


B cell types

; Plasmablast: A short-lived, proliferating antibody-secreting cell arising from B cell differentiation. Plasmablasts are generated early in an infection and their antibodies tend to have a weaker affinity towards their target antigen compared to plasma cell. Plasmablasts can result from T cell-independent activation of B cells or the extrafollicular response from T cell-dependent activation of B cells. ;
Plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substa ...
: A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation. There is evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma cell. 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. 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. ; 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 dyscrasia Plasma cell dyscrasias (also termed plasma cell disorders and plasma cell proliferative diseases) are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells ...
s that are associated with the secretion of
IgM Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
monoclonal proteins; these dyscrasias include IgM monoclonal gammopathy of undetermined significance and Waldenström's macroglobulinemia. ;
Memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
: Dormant B cell arising from B cell differentiation. 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). 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. ; B-2 cell: FO B cells and MZ B cells. :; 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). They are responsible for generating the majority of high-affinity antibodies during an infection. :; 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. They can undergo both T cell-independent and T cell-dependent activation, but preferentially undergo T cell-independent activation. ;
B-1 cell B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: makin ...
: Arises from a developmental pathway different from FO B cells and MZ B cells. In mice, they predominantly populate the
peritoneal cavity The peritoneal cavity is a potential space between the parietal peritoneum (the peritoneum that surrounds the abdominal wall) and visceral peritoneum (the peritoneum that surrounds the internal organs). The parietal and visceral peritonea are lay ...
and pleural cavity, generate natural antibodies (antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T cell-independent activation. 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. ; Regulatory B (Breg) cell: An
immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
B cell type that stops the expansion of pathogenic, pro-inflammatory lymphocytes through the secretion of IL-10, IL-35, and TGF-β. Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs. No common Breg cell identity has been described and many Breg cell subsets sharing regulatory functions have been found in both mice and humans. It is currently unknown if Breg cell subsets are developmentally linked and how exactly differentiation into a Breg cell occurs. There is evidence showing that nearly all B cell types can differentiate into a Breg cell through mechanisms involving inflammatory signals and BCR recognition.


B cell-related pathology

Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies. Autoimmune diseases where disease activity is correlated with B cell activity include
scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas of t ...
, multiple sclerosis,
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
, type 1 diabetes, post-infectious IBS, and rheumatoid arthritis.
Malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing benign tumor. Causes There are ...
of B cells and their precursors can cause a host of cancers, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),
hairy cell leukemia Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all leu ...
,
follicular lymphoma Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells norma ...
,
non-Hodgkin's lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness ...
,
Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition ...
, and plasma cell malignancies such as
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anem ...
, Waldenström's macroglobulinemia, and certain forms of
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
. Abnormal B cells may be relatively large and some diseases include this in their names, such as
diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,00 ...
s (DLBCLs) and
intravascular large B-cell lymphoma Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other tyes of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, ot ...
. Patients with B cell alymphocytosis are predisposed to infections.


Epigenetics

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 DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
signatures.


See also

* A20 cells


References

{{DEFAULTSORT:B Cell B cells Lymphocytes Human cells Immunology Immune system