B cell

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This article is about the immune system cell. For the electrical cell, see Battery (vacuum tube)#Wings.
B cell
Original antigenic sin.svg
The cells of the immune system that make antibodies to invading pathogens such as viruses. They form memory cells that remember the same pathogen for faster antibody production in future infections.
Latin lymphocytus B
Code TH H2.00.04.1.02005
TH H2.00.04.3.07002
Anatomical terminology
3D Rendering of a B cell.

B cells or B lymphocytes are a type of lymphocyte in the humoral immunity of the adaptive immune system. B cells can be distinguished from other lymphocytes, such as T cells and natural killer cells (NK cells), by the presence of a protein on the B cell's outer surface known as a B cell receptor (BCR). This specialized receptor protein allows a B cell to bind to a specific antigen. In birds, B cells mature in the bursa of Fabricius.[1] In mammals, immature B cells are formed in the bone marrow.[2]

The principal functions of B cells are to make antibodies against antigens, to perform the role of antigen-presenting cells (APCs), and to develop into memory B cells after activation by antigen interaction. B cells also release cytokines (proteins), which are used for signaling immune regulatory functions.[3]

Development[edit]

B cell development occurs through several stages, each stage representing a change in the genome content at the antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H) chains, and the genes specifying them are found in the 'V' (Variable) region and the 'C' (Constant) region. In the heavy-chain 'V' region there are three segments; V, D, and J, which recombine randomly, in a process called VDJ recombination, to produce a unique variable domain in the immunoglobulin of each individual B cell. Similar rearrangements occur for light-chain 'V' region except there are only two segments involved: V and J.

A Pre-B cell is a precursor to the development of B cells.[4] Certain leukemias/lymphomas are associated with immature B cells, and observing pre-B cell populations can be useful in the identification of these conditions. It expresses CD19 and CD127, and the immunoglobulin heavy chain is rearranged, but the immunoglobulin light chain is not yet rearranged at this stage.

The list below describes the process of immunoglobulin formation at the different stages of B cell development.

Stage Heavy chain Light chain Ig IL-7 receptor? CD19?
Progenitor (or pre-pro) B cells germline germline - Yes No
Early Pro (or pre-pre)-B cells undergoes D-J rearrangement germline - Yes No
Late Pro (or pre-pre)-B cells undergoes V-DJ rearrangement germline - Yes Yes[5]
Large Pre-B cells is VDJ rearranged germline IgM in cytoplasm and surface (IgH + pseudo light chain) Yes[6] Yes
Small Pre-B cells is VDJ rearranged undergoes V-J rearrangement IgM in cytoplasm and surface Yes Yes
Immature B cells is VDJ rearranged VJ rearranged IgM on surface No Yes
Mature B cells is VDJ rearranged VJ rearranged IgM and IgD on surface No Yes

When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis, here called clonal deletion.[7] B cells are continuously produced in the bone marrow. When the B cell receptor, on the surface of the cell, matches the detected antigens present in the body, the B cell proliferates and secretes a free form of those receptors (antibodies) with identical binding sites as the ones on the original cell surface. After activation, the cell proliferates and B memory cells would form to recognise the same antigen. This information would then be used as a part of the adaptive immune system for a more efficient and more powerful immune response for future encounters with that antigen.

B cell membrane receptors evolve and change throughout the B cell lifespan.[8] The proteins TACI, BCMA, and BAFF-R (B cell-activating factor receptor) are present on both immature B cells and mature B cells. Belimumab is a monoclonal inhibitor of the soluble form of B cell-activating factor (BAFF), whereas blisibimod is an inhibitor of both membrane and soluble forms of BAFF. CD20 is expressed on all stages of B cell development except the first and last; it is present from pre-B cells through memory cells, but not on either pre-pro-B cells or plasma cells.[9]

Immune tolerance[edit]

Like their fellow lymphocytes the T cells, immature B cells are tested for auto-reactivity by the immune system before leaving the bone marrow. In the bone marrow (the central lymphoid organ), central tolerance is produced. The immature B cells whose B cell receptors (BCRs) bind too strongly to self antigens will not be allowed to mature. If B cells are found to be highly reactive to self, three mechanisms can occur.

  • Clonal deletion: the removal, usually by apoptosis, of B cells of a particular self antigen specificity.
  • Receptor editing: The BCRs of self reactive B cells are given an opportunity to rearrange their conformation. This process occurs via the continued expression of the Recombination activating gene (RAG). Through the help of RAG, receptor editing involves light chain gene rearrangement of the B cell receptor. If receptor editing fails to produce a BCR that is less autoreactive, apoptosis will occur. Note that defects in the RAG-1 and RAG-2 genes are implicated in Severe Combined Immunodeficiency (SCID). The inability to recombine and generate new receptors lead to failure of maturity for both B cells and T cells.
  • Anergy: B cells enter a state of permanent unresponsiveness when they bind with weakly cross-linking self antigens that are small and soluble.

Functions[edit]

The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic system performing the role of immune surveillance. They do not produce antibodies until they become fully activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can further differentiate into one of the two types of B cells: plasma B cells and memory B cells. The B cell may either become one of these cell types directly or undergo an intermediate differentiation step, the germinal center reaction, where the B cell will hypermutate the variable region of its immunoglobulin gene ("somatic hypermutation") and possibly undergo class switching. Other functions for B cells include antigen presentation, cytokine production, and lymphoid tissue organization.

Clonality[edit]

B cells exist as clones. All B cells derive from a particular cell, and, thus, the antibodies that their differentiated progenies (see below) produce can recognize and/or bind the same specific surface components composed of biological macromolecules (epitope) of given antigen. Such clonality has important consequences, as immunogenic memory relies on it. The great diversity in immune response comes about because there are up to 109 clones with specificities for recognizing different antigens. A single B cell or a clone of cells with shared specificity, upon encountering its specific antigen, divides to produce many B cells. Most of such B cells differentiate into plasma cells that secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place. A small minority survives as memory cells that can recognize only the same epitope. However, with each cycle, the number of surviving memory cells increases. The increase is accompanied by affinity maturation, which induces the survival of B cells that bind to the particular antigen with high affinity. This subsequent amplification with improved specificity of immune response is known as secondary immune response. B cells that have not been activated by antigen are known as naive lymphocytes; those that have met their antigen become activated, and have differentiated further into fully functional lymphocytes are known as effector B lymphocytes.

B cell types[edit]

A suspected plasma cell. Plasma cells are normally detected in tissue rather than circulation.
  • Plasma B cells (also known as plasma cells, plasmocytes, and effector B cells) are large B cells that have been exposed to antigen and produce and secrete large amounts of antibodies, which assist in the destruction of microbes by binding to them and making them easier targets for phagocytes and activation of the complement system. They are sometimes referred to as antibody factories. An electron micrograph of these cells reveals large amounts of rough endoplasmic reticulum, responsible for synthesizing the antibody, in the cell's cytoplasm. These are short-lived cells and undergo apoptosis when the inciting agent that induced immune response is eliminated. This occurs because of cessation of continuous exposure to various colony-stimulating factors, which is required for survival.
  • Memory B cells differentiate from activated B cells predominantly from a germinal center and are specific to the antigen encountered during the primary immune response. These cells are able to live for a long time, and can respond quickly following a second exposure to the same antigen.
  • B-1 cells express IgM in greater quantities than IgG and their receptors show polyspecificity, meaning that they have low affinities for many different antigens. Polyspecific immunoglobulins often have a preference for other immunoglobulins, self antigens, and common bacterial polysaccharides. B-1 cells are present in low numbers in the lymph nodes and spleen and are instead found predominantly in the peritoneal and pleural cavities.[10][11]
  • B-2 cells are the cells intended when using the unqualified "B cell."
  • Marginal-zone B cells
  • Follicular B Cells
  • Regulatory B cells (Bregs) are B-cells involved in immune regulation via various mechanism including secretion of IL-10 and TGFbeta.[12] Subset of Bregs are found both within the B-1 and B-2 cell population. the two best-described phenotypes are the B10 (CD5+CD1d+) subset and the T2-MZP B cells (CD21+CD23+CD24+CD93+) subset in mice and the CD24+CD38+ subset in humans. But a lot of controversity still exists regarding surface markers.[13]

Recognition of antigen by B cells[edit]

A critical difference between B cells and T cells is how each lymphocyte recognizes its antigen. B cells recognize their cognate antigen in its native form. They recognize free (soluble) antigen in the blood or lymph using their BCR or membrane bound-immunoglobulin. In contrast, T cells recognize their cognate antigen in a processed form, as a peptide fragment presented by an antigen-presenting cell's MHC molecule to the T cell receptor.

Activation of B cells[edit]

T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction molecules
Mechanism of action.

B cell recognition of antigen is not the only element necessary for B cell activation (a combination of clonal proliferation and terminal differentiation into plasma cells). B cells can be activated in a T cell-dependent or -independent manner.

T cell-dependent activation[edit]

Once a pathogen is ingested by an antigen-presenting cell such as a macrophage or dendritic cell, the pathogen's proteins are then digested to peptides and attached to a class II MHC protein. This complex is then moved to the outside of the cell membrane. The macrophage is now activated to deliver multiple signals to a specific T cell that recognizes the peptide presented. The T cell is then stimulated to produce autocrines, resulting in the proliferation or differentiation to effector or memory T cells. A certain portion of the resulting effector T cells then activate specific B cells through a phenomenon known as an Immunological synapse. Activated B cells subsequently produce antibodies that assist in inhibiting pathogens until phagocytes (i.e., macrophages, neutrophils) or the complement system, for example, clears the host of the pathogen(s).

Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With a T-dependent antigen, the first signal comes from antigen's cross-linking the B cell receptor (BCR), and the second signal comes from co-stimulation provided by a T cell. T-dependent antigens consist of peptides mounted on B cell Class II MHC to be presented to one of two distinct subtypes of T cells: (i) follicular helper T cells (TFH cells) or (ii) Th2 cell. When a B cell processes and presents the same antigen to the primed Th cell, the T cell secretes cytokines that activate the B cell. These cytokines trigger B cell proliferation and differentiation into plasma cells. Isotype switching to IgG, IgA, and IgE and memory cell generation occur in response to T-dependent antigens. This isotype switching is known as Class Switch Recombination (CSR). Once this switch has occurred, that particular B cell will usually no longer make the earlier isotypes, IgM or IgD.

T cell-independent activation[edit]

There are two types of T cell-independent activation: Type 1 T cell-independent (polyclonal) activation, and type 2 T cell-independent activation. An advantage of forgoing T cell involvement is that an expedited immune response can be mobilized, however germinal center formation, isotype switching and affinity maturation do not occur during this form of activation. Also, because almost all memory B cells are derived from germinal centers, effective antibody-mediated memory is compromised by T-independent B cell activation. Most important antibodies produced (by T cell-independent activation) against polysaccharide capsules of encapsulated bacteria (most commonly Haemophilus influenzae and Streptococcus pneumoniae) are IgG2 (most common) and IgG3.[14]

Type 1 T cell-independent activation occurs when a B cell binds to an antigen and receives secondary activation by toll-like receptors, such as TLR4 for LPS and TLR9 for DNA. The resulting activated B cell is restricted to IgM antibodies that are specific to the TLR-binding antigen.

Type 2 T cell-independent activation occurs when antigens that are expressed on the surface of pathogens with an organized and repetitive form can activate specific B cells by the cross-linking of antigen receptors in a multivalent fashion. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, cross-linking their IgM antigen receptors, leading to IgM synthesis in the absence of T cell stimulation.

Many antigens are T cell-independent in that they can deliver both of the signals to the B cell. Mice without a thymus (nude or athymic mice that do not produce any T cells) can respond to T-independent antigens. Conjugate vaccines are made to provide a stronger immune response against these foreign molecules.

In 2011, it was discovered that immortalized rhesus monkey B cells may be activated by the binding of monoamine ligands to TAAR1, a recently discovered GPCR. They found that methamphetamine, a potent TAAR1 agonist, signals PKA and PKC activation following ligand binding to TAAR1.[15] Although it is largely recognized as an important regulator of monoaminergic systems, TAAR1 has only recently been characterized as being important for T cell-independent lymphocyte activation.

The ancestral roots of B cells[edit]

In an October 2006 issue of Nature Immunology, certain B cells of basal vertebrates (like fish and amphibians) were shown to be capable of phagocytosis, a function usually associated with cells of the innate immune system. The authors postulate that these phagocytic B cells represent the ancestral history shared between macrophages and lymphocytes. B cells may have evolved from macrophage-like cells during the formation of the adaptive immune system.[16]

B cells in humans (and other vertebrates) are nevertheless able to endocytose antibody-fixed pathogens, and it is through this route that MHC Class II presentation by B cells is possible, allowing Th2 help and stimulation of B cell proliferation. This is purely for the benefit of MHC Class II presentation, not as a significant method of reducing the pathogen load.

Etymology[edit]

The abbreviation "B" in B cell originally came from Bursa of Fabricius, an organ in birds in which avian B cells mature.[1] When it was discovered that in most mammals immature B cells are formed in bone marrow, the word B cell continued to be used, although other blood cells also originate from pluripotent stem cells in the bone marrow.[17]

B cell-related pathology[edit]

Aberrant antibody production by B cells is implicated in many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. B cells are also susceptible to malignant transformation.

Additional image[edit]

Figure 1: Schematic diagram to explain mechanisms of clonal selection of B cell, and how secondary immune response is stronger, quicker and more specific in comparison with the primary one.[18]

See also[edit]

References[edit]

  1. ^ a b Bursa of Fabricius
  2. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts k, Walter P (2002) Molecular Biology of the Cell. Garland Science: New York, NY pg 1367. "T cells and B cells derive their names from the organs in which they develop. T cells develop in the thymus, and B cells, in mammals, develop in the bone marrow in adults or the liver in fetuses."
  3. ^ Mauri, Claudia; Bosma, Anneleen (2012). "Immune Regulatory Function of B Cells". Annual Review of Immunology 30: 221–41. doi:10.1146/annurev-immunol-020711-074934. PMID 22224776. 
  4. ^ Rossi B, Espeli M, Schiff C, Gauthier L (July 2006). "Clustering of pre-B cell integrins induces galectin-1-dependent pre-B cell receptor relocalization and activation". J. Immunol. 177 (2): 796–803. doi:10.4049/jimmunol.177.2.796. PMID 16818733. 
  5. ^ "B Cell Development". Archived from the original on 2008-05-30. Retrieved 2008-09-20. 
  6. ^ "Immunology, Biology 328". Archived from the original on 6 October 2008. Retrieved 2008-09-20. 
  7. ^ Parham, P. (2005). The Immune System, Garland Science Publishing, New York, NY.[page needed]
  8. ^ "Hyperactive_Blymphocytes_lifespan_receptors". Retrieved 2008-09-16. 
  9. ^ Bona, Constantin; Francisco A. Bonilla (1996). "5". Textbook of Immunology. Martin Soohoo (2 ed.). CRC Press. p. 102. ISBN 978-3-7186-0596-5. 
  10. ^ Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2006). "New perspectives in B-1 B cell development and function". Trends in Immunology 27 (9): 428–33. doi:10.1016/j.it.2006.07.005. PMID 16861037. 
  11. ^ Tung, James W; Herzenberg, Leonore A (2007). "Unraveling B-1 progenitors". Current Opinion in Immunology 19 (2): 150–5. doi:10.1016/j.coi.2007.02.012. PMID 17303402. 
  12. ^ Yang, M.; Rui, K.; Wang, S.; Lu, L. (2013). "Regulatory B cells in autoimmune diseases". Cellular and Molecular Immunology 10 (2): 122–132. doi:10.1038/cmi.2012.60. PMID 23292280.  edit
  13. ^ Immune regulatory function of B cells, Claudia Mauri and Anneleen Bosma
  14. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524781/
  15. ^ Panas, Michael W.; Xie, Zhihua; Panas, Helen N.; Hoener, Marius C.; Vallender, Eric J.; Miller, Gregory M. (2011). "Trace Amine Associated Receptor 1 Signaling in Activated Lymphocytes". Journal of Neuroimmune Pharmacology 7 (4): 866–76. doi:10.1007/s11481-011-9321-4. PMC 3593117. PMID 22038157. 
  16. ^ Li, Jun; Barreda, Daniel R; Zhang, Yong-An; Boshra, Hani; Gelman, Andrew E; Lapatra, Scott; Tort, Lluis; Sunyer, J Oriol (2006). "B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities". Nature Immunology 7 (10): 1116–24. doi:10.1038/ni1389. PMID 16980980. 
  17. ^ http://www.albrecht-kossel-institut.de/en/4_publications/2006/Mix_J_Neurol_2006.pdf page V/12 top-left column
  18. ^ Goldsby, Richard A.; Kindt, Thomas J.; Osborne, Barbara A.; Kuby, Janis (2003). "Somatic Hypermutation Adds Diversity in Already-rearranged Gene Segments". Immunology (5th ed.). New York: W. H. Freeman. pp. 199–20. ISBN 978-0-7167-4947-9. 

Activation of B Lymphocytes by T-Independent Antigens. Gary Kaiser. American Society for Microbiology. July 2005.

External links[edit]