B Cell Growth and Differentiation Factors (also known as BCGF and BCDF) are two important groups of soluble factors controlling the life cycle of B cells (also referred to as B lymphocytes, cells which perform functions including: antibody secretion, antigen presentation, preservation of memory for antigens, and lymphokine secretion).[1] BCGFs specifically mediate the growth and division of B cells, or, in other words, the progression of B cells through their life cycle (cell cycle stages G1, S, G2). BCDFs control the advancement of a B cell progenitor or unmatured B cell to an adult immunoglobulin (Ig) secreting cell. Differentiation factors control cell fate and can sometimes cause matured cells to change lineage. Not all currently known BCGFs and BCDFs affect all B cell lineages and stages of the cell cycle in similar ways. Both BCGFs and BCDFs work on cells previously "activated" by factors such as anti-immunoglobulin (anti-Ig). BCGFs cause activated B cells to enlarge, express activation markers (ex. transferrin receptor) and enter the S phase (DNA synthesis phase) of the cell cycle. Meanwhile, BCDFs stimulate these cells to differentiate to mature Ig-secreting B cells.[2][3]
An important note is that B cell Proliferation Factors (BCPFs) also exist and are different from BCGFs. BCPFs make cells, which are not necessarily activated, more responsive to BCGFs and help maintain cell viability, whereas BCGFs direct and stimulate growth and division.[3] This article will mention BCPFs and factors that induce proliferation, yet the main focus will remain on BCGFs and BCDFs.
Human B Lymphocyte
General Overview
The currently known BCGFs and BCDFs are BCGF I (also called B cell Stimulating Factor 1 (BSF1)), BCGF II, BCDF, IL-1 (interleukin-1), IL-2,[4] IL-3, IL-4, IL-5, IL-6 (BSF-2), IFN-alpha, beta 2, and gamma, neuroleukin, TGF-beta (Transforming Growth Factor-beta), LP1 (Lymphopoetin 1),[5] BCGFLOW, TNF-alpha (Tumor Necrosis Factor alpha),[6] TRF (T cell Replacing Factor), CSF (colony-stimulating factors), MAF (macrophage activation factors),[7][1] and lymphotoxin.[8] Most factors act in many points throughout the B cell lifecycle, activation, growth, differentiation, and maturation, making this a complex pathway for study.[6] Provided here is a list of these with some more detailed descriptions about their origins and functions.
BCGF I (BSF1 or BSFp1) - secreted by activated T cells. BCGF I induces "resting" cells to become susceptible to stimulation by ligands. Both anti-Ig and BCGF I are required for a cell to enter S and G2 phase. It is not clear if BCGF I acts on memory B cells specifically, but it appears to induce growth in the continuous presence of anti-Ig in all other lineages.[4] BCGF is uninhibited by anti-Tac (T cell activation antigen), whereas other factors, such as IL-2 are.[9]
BCDF - causes calcium influx in cells, critical for differentiation. It is the only factor which can achieve this effect.[10] Induces differentiation in late-stage activated cells.[11] BCDF subclasses are associated with the secretion of specific subclasses of Ig, for example BCDF(γ) with IgG and BCDF(μ) with IgM.[8]
IL-1 - a cytokine derived from macrophages, this factor drives cells into S phase, usually working after BCGF I.[4] IL-1 weakly co-stimulates even resting B cells in the presence of anti-Ig and can enhance BCDF function.[2]
IL-2 - a cytokine key activating factor for T cells and B cells secreted by T cells.[4] Cells in early-stage activation differentiate in response to IL-2 and all B cells proliferate in the presence of IL-2.[11] IL-2 exhibits an additive affect to BCGF when both are present.[9] Yet the magnitude of its effect is much less than BCGF and BCDF in both growth and differentiation.[12]
IL-3 - cytokine associated with the differentiation of more mature B cells.[5]
IL-4 - cytokine associated with the differentiation of mature T cells, which some B cell precursors are also responsive to.[5]
IL-5 - cytokine that acts like IL-6, except it can also induce proliferation in B cells, and its effect on differentiation is partially inhibited by IL-4. IL-5 cannot induce differentiation in cells activated by anti-Ig.[13]
IL-6 (BSF-2) - cytokine that acts exclusively as a B cell differentiation factor, stimulating increase in levels of Ig, J-chain mRNA, and proteins.[13]
IFN-alpha, beta 2, and gamma (interferons alpha, beta 2, and gamma) - IFN-gamma in combination with IL-2 also induces early-stage differentiation.[11] Interferon-gamma has previously been reported as a requirement for plaque-forming cell response. Interferon-alpha can either enhance or suppress differentiation by controlling responsiveness of human peripheral blood B cells to B-cell helper factors, depending on certain environment and context-specific conditions, as its signaling is likely mediated by other cell types.[12]
TRF - induced primarily IgM secretion from B cells, thus constituting a differentiation factor.[7] Various sources disagree as to whether TRF can induce proliferation.[14][15]
CSF
MAF
Lymphotoxin
Discovery
The identification and classification of B cell growth and differentiation factors was primarily conducted in the 1980s-1990s, though it had begun to spark interest of the scientific community in the 1970s. It began with the creation of T cell hybridomas - immortal cells that could be selected to produce only one factor. This allowed the study of B cells exposed to only one soluble factor at a time, enabling the identification of that factor's direct effects on the cells. Previously, it was believed that B cell growth was induced exclusively by the presence of antigen. Some major questions that researchers attempted to answer were which cells and specifically cell types secreted these factors, and in which conditions, as well as if and how these factors differed from T Cell Growth and Differentiation Factors (TCGFs and TCDFs) such as IL-2. Additionally, it was established early on that several compounds could mediate B cell growth and differentiation, some of them working only when encountered together (synergistically). So, researchers also attempted to identify how many BCGFs and BCDFs exist and classify the varieties of these factors.[14]
A major early challenge was the inability of culturing one distinctive T cell line or the isolation of thereof to analyze its effects. T cell factors that induced B cell activation, proliferation, growth, and differentiation were frequently generated by mixed populations of T cells. When the first immortalized T cell lines began to emerge, it became possible to observe which T cells had specific effects on B cells. Various T cell types secreted factors that induced Ig production, in some cases only of specific kinds or only in the presence of antigen. Some IgG classes secreted by B cells are exclusively T cell dependent.[7]
Another major advance was the declaration that BCGF and BCDF were indeed two different entities. It was determined that T cell secreted factors and anti-Ig were necessary for the proliferation of activated B cells, while the addition of a differentiation factor was required to induce Ig production (ie. differentiation). So, it was determined that these two factors were separate entities. Isolating the two types of BCGF and BCDF was difficult as it required purification from IL-2. A key difference between the two variants of BCGF was that only one could induce growth in colony-forming B cells.[16]
Later, difficulties with the subject B cell populations began to emerge, as there wasn't yet a stable long-term method of culture or isolation of individual subtypes. The difficulty of obtaining populations of viable B cell precursors was resolved by the design of a long-term bone marrow culture system, which secreted LP1 growth factor.[5] In given populations, it was determined that B cells could be sorted into groups of "activated" and "resting" cells by their size, enabling the study of factors on these two distinct subgroups. As not all cell lines responded to the factors listed in the above section in similar ways (and some were completely irresponsive), a model cell line that could respond to various factors was necessary to compare the resulting responses and study in more detail the pathways of each lymphokine or factor's signal. Researchers identified several such cell lines that were guaranteed to have receptors for or respond to groups of factors. For example, in CH12 B cell lymphoma, cells differentiate in response to both IL-5 and IL-6 in the presence of other costimulatory cytokines, while in other cell lines IL-5 is only effective in a narrow window of time right after activation.[13]
BCGFs and BCDFs were originally sought after for research purposes. Previously identified similar factors for T cells allowed T cells to be "immortalized" or kept alive in the research setting for prolonged periods of time. This permitted the extensive study of T cells and their functioning. It also permitted the modelling of the immune response, such as studying the activated T cell state. Finding factors that would enable a similar closer study of B cells would greatly benefit science.
B cell differentiation pathways
The most common simplified overview description of the B cell differentiation pathway involves the following steps: an antigen interacts with the corresponding surface membrane immunoglobulin after which the B cell begins expressing receptors for growth factors secreted by T cells (BCGFs and IL-2), after these factors bind, the lymphocytes enter S phase, and subsequent binding with BCDFs differentiates B cells into Ig secreting cells.[8] This model quickly grows more complex as individual resting B cells receive multiple varying sequential signals that determine future cell fate and functions that will be performed by those cells.[12] Depending on this sequence of BCDFs, B cells may achieve different "fates" which can constitute the types of Ig they secrete or even their destiny with a specialized lineage (such as Memory B cells or plasma cells).
Further investigations have been conducted since the identification of BCGFs and BCDF to determine what receptors they bind to and outline their pathways. There is evidence that CD23 is the receptor for BCDF.[17] It was concluded that neither BCGF nor BCDF shared a receptor with IL-2.[18] At least one pathway of B cell maturation via 446-BCDF, derived from anti-CD3 peripheral blood T cells, may involve reduction of intracellular cAMP.[19] Stimulation by 446-BCDF causes an influx of calcium.[10]
Immune system interactions
BCGFs and BCDFs primarily travel through the body intravenously but tend to be more concentrated in sites most critical to the human immune system - the lymph nodes, thyroid, spleen, bone marrow, and liver. The environments in all of these areas are complex ecosystems of various cell types, states, and concentrations of factors. So, in general, B cell activation, proliferation, and differentiation appears to be a complex process dependent on many cell and factor interactions as well as the state of activation of the cell.[12]
The interconnected nature of the immune system has caused many complications, for when looking at cells in model systems, it has often been unclear which, if any, factor actually exerted their effects directly on the B cells themselves as opposed to acting via accessory cells or in conjunction with other factors.[12]
Related diseases
Common diseases associated with the dysregulation of B cells are autoimmunity, immune deficiency, and various blood-associated cancers. BCGFs and BCDFs are associated with these diseases because they control crucial parts of the B cell life cycle - the cell's growth and identity. For example, if BCGFs are present at an extremely high concentration, cells may multiply very quickly exhibiting cancer-like behavior or extreme levels of immune response. Similarly, extreme differentiation towards a specific lineage may make the immune system weakened in some areas or too powerful and cause immune-related disease.
Different lineages or states of T cells secrete various BCDF subgroups. Maintaining the balance of the number and proportion of these cells is critical, as deficiencies in one or more subgroups cause disease, such as common variable immunodeficiency and chronic lymphocytic leukemia.[3]
Dysregulation of growth factor production is a characteristic of some diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, and traumatic joint injury, where high levels of BCDF and IL-2 are present in the synovial fluid, resulting in increased differentiation of B lymphocytes into plasma cells and Ig secreting cells that secrete so many antibodies that they generate an immune response and inflammation in locations where they accumulate.[8]
Related Research Articles
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.
Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Cellular immunity, also known as cell-mediated immunity, is an immune response that does not rely on the production of antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.
Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells. Put shortly the function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells.
The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.
Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: after removal of the signal peptide sequence, the mature protein contains 133 amino acids in its polypeptide chain. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.
Interleukin-1 alpha also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases.
Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.
Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.
Interleukin 24 (IL-24) is a protein in the interleukin family, a type of cytokine signaling molecule in the immune system. In humans, this protein is encoded by the IL24 gene.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.
T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.
The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Lymphocyte-variant hypereosinophilia is a rare disorder in which eosinophilia or hypereosinophilia is caused by an aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-eosinophils or CFU-Eos.
Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.
Th22 cells are subpopulation of CD4+ T cells that produce interleukin-22 (IL-22). They play a role in the protective mechanisms against variety of bacterial pathogens, tissue repair and wound healing, and also in pathologic processes, including inflammations, autoimmunity, tumors, and digestive organs damages.
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1 2 Huang R, Cioffi J, Kimberly R, Edberg J, Mayer L (September 1995). "B cell differentiation factor-induced human B cell maturation: stimulation of intracellular calcium release". Cellular Immunology. 164 (2): 227–233. doi:10.1006/cimm.1995.1165. PMID7656331.
↑ Gordon J, Webb AJ, Walker L, Guy GR, Rowe M (December 1986). "Evidence for an association between CD23 and the receptor for a low molecular weight B cell growth factor". European Journal of Immunology. 16 (12): 1627–1630. doi:10.1002/eji.1830161225. PMID3028819. S2CID24348097.
↑ Kehrl JH, Grove JH, Goldsmith PK, Fauci AS (July 1986). "B cell growth and differentiation factors interact with receptors distinct from the interleukin 2 receptor". European Journal of Immunology. 16 (7): 761–766. doi:10.1002/eji.1830160708. PMID3013645. S2CID33699736.
↑ Huang R, Cioffi J, Berg K, London R, Cidon M, Maayani S, Mayer L (April 1995). "B cell differentiation factor-induced B cell maturation: regulation via reduction in cAMP". Cellular Immunology. 162 (1): 49–55. doi:10.1006/cimm.1995.1050. PMID7704910.
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