B cells, also known as B lymphocytes, are a type of
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
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 ad ...
subtype.
They function in the
humoral immunity
Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it ...
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 Viral disease, viruses. The antibody recognizes a unique m ...
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 prote ...
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 quiesc ...
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 a ...
s.
In
mammals, B cells
mature in the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
, which is at the core of most
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
s.
In
bird
Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...
s, B cells mature in the
bursa of Fabricius, 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 cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
s and
natural killer cell
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
s, express
B cell receptors (BCRs) on their
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
.
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 ...
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 ...
.
Development
B cells develop from
hematopoietic stem cells (HSCs) that originate from
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
.
HSCs first differentiate into
multipotent 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 lea ...
(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 lea ...
(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
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...
patterns and
immunoglobulin
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 ...
H chain and
L chain gene loci arrangements, the latter due to B cells undergoing
V(D)J recombination
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell re ...
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
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
, 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,
receptor editing,
anergy, or ignorance (B cell ignores signal and continues development).
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.
To complete development, immature B cells migrate from the bone marrow into the spleen as
transitional B cells Transitional B cells are B cells at an intermediate stage in their development between bone marrow immature cells and mature B cells in the spleen. Primary B cell development takes place in the bone marrow, where immature B cells must generate a fun ...
, 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 (SLOs), such as the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . 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 incl ...
.
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
Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues ...
. 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 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 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, 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 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, which promotes B cell
proliferation
Proliferation may refer to:
Weapons
*Nuclear proliferation, the spread of nuclear weapons, material, and technology
*Chemical weapon proliferation, the spread of chemical weapons, material, and technology
* Small arms proliferation, the spread of ...
,
immunoglobulin class switching, and
somatic hypermutation 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 b ...
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 directed by somatic hypermutation.
These processes are facilitated by T
FH 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 (T
H) cells, typically memory follicular T helper (T
FH) 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 T
FH 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
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...
'' activation of memory B cells can be achieved through stimulation with various activators, such as pokeweed mitogen or anti-
CD40 monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
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 sub ...
: 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 dyscrasias that are associated with the secretion of
IgM 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 quiesc ...
: 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: 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
The pleural cavity, pleural space, or interpleural space is the potential space between the pleurae of the pleural sac that surrounds each lung. A small amount of serous pleural fluid is maintained in the pleural cavity to enable lubrication b ...
, 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 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 o ...
,
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. Comm ...
,
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
,
post-infectious IBS, and
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...
.
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
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
s, including
chronic lymphocytic leukemia (CLL),
acute lymphoblastic leukemia (ALL),
hairy cell leukemia,
follicular lymphoma,
non-Hodgkin's lymphoma,
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 w ...
, 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, ane ...
,
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, weig ...
.
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.
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 ...
signatures.
See also
*
A20 cells
References
{{DEFAULTSORT:B Cell
B cells
Lymphocytes
Human cells
Immunology
Immune system