B cell
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B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by T cells). The principal function of B cells is to make antibodies against soluble antigens. B cells are an essential component of the adaptive immune system.
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[edit] Development of B cells
Immature B cells are produced in the bone marrow of most mammals. Rabbits are an exception; their B cells develop in the appendix-sacculus rotundus. After reaching the IgM+ immature stage in the bone marrow, these transitional B cells migrate to the spleen where they mature into B lymphocytes[1]. 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 light (L) and two heavy (H) chains, and the genes specifying them are found in the 'H' chain locus and the 'L' chain locus. In the H chain loci there are three regions, 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 L chain locus except there are only two regions, namely V and J. The list below describes the process of immunoglobulin formation at the different stages of B cell development.
- Progenitor B cells - Contains Germline H genes, Germline L genes
- Early Pro-B cells - undergoes D-J rearrangement on the H chains
- Late Pro-B cells - undergoes V-DJ rearrangement on the H chains
- Large Pre-B cells - the H chain is VDJ rearranged, Germline L genes
- Small Pre-B cells - undergoes V-J rearrangement on the L chains
- Immature B cells - VJ rearranged on L chains, VDJ rearranged on H chains. There is start of expression of IgM receptors.
- Mature B cells - There is start of expression of IgD
When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis, here called clonal deletion.[1] If it recognizes self-antigen during the maturation process, the B cell will become suppressed (known as anergy) or undergo apoptosis (also termed negative selection). B cells are continuously produced in the bone marrow, but only a small portion of newly made B cells survive to participate in the long-lived peripheral B cell pool.
B cell membrane receptors on which drugs may be active evolve during the B cell life span [2]. CD20 is present on preB cells, but disappears in mature B cells. TACI, BCMA and BAFF-R are present on immature B cells and mature B cells. The agonist of these 3 receptors is inhibited by Belimumab.
[edit] Functions
The human body makes millions of different types of B cells each day that circulate in the blood and lymph 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 listed below (plasma B cells and memory B cells). The B cell may either become one of these cell types directly or it may 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.
[edit] Clonality of B cells
B cell exist as clones, meaning, all the B cells derived from a particular cell, and thus, the antibodies their differentiated progenies (see below) produce can recognize and/or bind the same components (epitope) of a given antigen. This has important consequences, most notably, the phenomenon of immunogenic memory relies on this clonality of B cells. The great diversity in immune response comes about because there are up to 109 clones with that many specificities for recognizing antigens. A single B cell or a clone of cells with shared specificity upon encountering its specific antigen (rather, the epitope), divides many times to produce many B cells, most of which differentiate into Plasma cells that can secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place, while a very small minority survive as memory cells that can again recognize only the same epitope, and when that happens would divide further to produce more plasma and memory cells. However, with each such cycle, the number of surviving memory cells increases. This also is accompanied by affinity maturation that increases the sum total of epitopes that can be recognized by the related clones through random mutations in the epitope binding (and recognizing) portions of these cell. This subsequent amplification with improved specificity of immune response is known as secondary immune response. If the cell that encountered the epitope to subsequently proliferate did so for the first time, it would be known as a naive cell, i.e., neither it nor any of its predecessors ever encountered this epitope.
[edit] B cell types
- Plasma B cells (also known as plasma cells) are large B cells that have been exposed to antigen and are producing and secreting 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 required for survival.
- Memory B cells are formed from activated B cells that 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 its receptors show polyspecificity, meaning that they have low affinities for many different antigens, but 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.[2][3]
- B-2 cells are the conventional B cells most texts refer to.
[edit] Recognition of antigen by B cells
A critical difference between B cells and T cells is how each lymphocyte "sees" 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.
[edit] Activation of B cells
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 that have not been exposed to antigen, also known as Naive B cells, can be activated in a T-cell dependent or independent manner.
[edit] T-cell dependent activation
When a macrophage ingests a pathogen, it attaches parts of the pathogen's proteins to a class II MHC protein. This complex is moved to the outside of the cell membrane, where the epitope on the antigen can be recognized by a T cell, which is compatible with similar structures on the cell membrane of a B cell. If the B cell and T cell structures match, the T cell will activate the B cell, which starts producing antibodies in large scale against the bits of pathogen, called antigen, it has found with its B cell receptor (a membrane bound antibody). Since, many clones of B memory/naive cells can recognize the same antigen, the response is polyclonal.
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 cross linking the B cell receptor (BCR) and the second signal comes from co-stimulation provided by a T cell. T dependent antigens contain proteins that are presented on B cell Class II MHC to a special subtype of T cell called a 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 can no longer make the earlier isotypes, IgM or IgD.
[edit] T-cell independent activation
Many antigens are T-independent, meaning 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. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, by cross-linking the IgM antigen receptors in the B-cell,responding with IgM synthesis in the absence of T cell help. There are two types of T-cell independent activation; Type 1 T cell-independent (polyclonal) activation, and type 2 T cell-independent activation (in which macrophages present several of the same antigen in a way that causes cross-linking of antibodies on the surface of B cells).
[edit] The ancestral roots of B cells
In an October 2006 issue of Nature Immunology, it was reported that certain B-cells of primitive vertebrates (like fish and amphibians) are capable of phagocytosis, a function usually associated with cells of the innate immune system. The authors of this article 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[4].
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.
[edit] Origin of the word B cell
The abbreviation "B" in B cell originally came from Bursa of Fabricius, an organ in birds in which avian B cells mature.[5] 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. The fact that bone and bursa both start with the letter 'B' is a coincidence.
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[edit] References
- ^ Parham, P. (2005). The Immune System, Garland Science Publishing, New York, NY.
- ^ Montecino-Rodriguez, Encarnacion'''''''; Kenneth Dorshkind (2006-09). "New perspectives in B-1 B cell development and function". Trends in Immunology' 27 (9): 428-433. Elsevier B.V.. doi:
doi:[http://dx.doi.org/10.1016/j.it.2006.07.005 10.1016/j.it.2006.07.005]. - ^ [[James W Tung'''''''|Tung, James]]; Leonore A Herzenberg''''''' (2007-04). ""Unraveling B-1 progenitors"". Current Opinion in Immunology 19 (2): 150-155. Elsevier B.V.. doi:doi:[http://dx.doi.org/10.1016/j.coi.2007.02.012 10.1016/j.coi.2007.02.012].
- ^ J. Li, D.R. Barreda, Y.-A. Zhang, H. Boshra, A.E. Gelman, S. LaPatra, L. Tort & J.O. Sunyer (2006). "B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities". Nature Immunology 7: 1116–1124. doi:. PMID 16980980.
- ^ Bursa
- ^ Goldsby, Richard; Kindt, TJ; Osborne, BA; Janis Kuby (2003). Immunology Fifth Edition. New York: W. H. Freeman and Company, 119-120. ISBN 0-07167-4947-5.
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