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For the wikipedia project, I want to explore the function of lymphotoxin-alpha and its role in immune regulation. There are various aspects of lymphotoxin-alpha that I would like to discuss, all of which is outlined below.

Here is an outline of what I plan to add/contribute to the page of lymphotoxin-alpha.

Background information of lymphotoxin

  • Cytotoxic proteins secreted by peripheral blood leukocytes and cell lines of hematopoetic cell lines; LT is a cytokine.
  • Cause the cytolysis of tumor cell lines and have anti-proliferative activity
  • Kill transformed cells that are cancerous
  • Secreted from T-lymphocytes.
    • Can exist in two forms: a membrane bound LT-alpha-beta heterotrimers, where LT-beta is anchored in the cell membrane or soluble LT-alpha homotrimers.
    • Gene is encoded by chromosome 6
    • Is crucial to the transport of LT-beta to cell surface, thus resulting in the formation of the LT-alpha-LT-beta complex.
    • Is not produced by macrophages after LPS. It is still pro-inflammatory (cellular inflammation) with effects on chemokine induction and changes in endothelial cells; similar to TNF-alpha.

·     Reference: OLD PAPER and Traveler’s guide

Effects of no lymphotoxin present

  • Knock out mice were created with no presence of LT.
  • Results: Had lots of biological differences.
  • Major defects in DSLOs with no lymph nodes, no Peyer’s patches, and the presence of a disorganized spleen, and defective nasal lymphoid tissues
    • LT is important for secondary lymphoid organ development.
    • LT regulates lymphoid organs by its production by lymphoid tissue inducer cells acting on stromal lymphoid tissue organizer cells.
    • o  LT maintains lymphoid organs through its production by T cells, B cells, and dendritic cells.

·     Reference: Traveler’s guide

Anti-LT-alpha antibody

  • Jane Grogan developed a humanized antibody that reacts with both LT-alpha 3 and LT-beta3 (Pateclizumab or MLTA3698A). Ref: Traveler’s guide
  • Prolonged inflammatory signals can lead to the formation of granulomas and the generation of tertiary lymphoid organs (TLOs) at the infection site, thus leading to obesity, chronic obstructive pulmonary disease, autoimmune pancreatitis, type 2 diabetes, atherosclerosis, and cancer. Ref: dark side of cytokines.

Relevance/Impact of Cancer Research

  • Some cytokines have been shown to either have procarcinogenic or anticarcinogenic, depending on the type of organ, time of action, gender, and cellular environment.
  • The cell types and cytokines expressed in the tumor microenvironment decided whether tumor growth suppression or progression occurs.
  • Since LT belongs the TNF family, LT-alpha binds and activates TNFRI and TNFRII, thus activating the NF-kB pathway and affecting cell survival, proliferation, differentiation, and apoptosis.
  • LT plays a beneficial role in immune regulation by activating the innate immunity response.
  • LT mediated signaling has been linked to cancer development; Table 2 of dark side. LOTS OF EXAMPLES
  • MOSTLY ABOUT lymphotoxin-beta receptor causes cell proliferation. HOWEVER, lymphotoxin beta receptors’ ligands are membrane form of lymphotoxin heterotrimer (lymphotoxin-alpha-beta complex). Thus, like mentioned previously, LT-alpha is essential for the survival of LT-beta and they can form to make the complex; no LT-alpha means no LT-beta.
  • Unregulated NF-kB signaling due to mutations in its regulators can be seen in different forms of B-cell lymphoma.
  • Constant activation of the NF-kB pathway such as through the constant binding to LT-betaR results in multiple myeloma.
  • After LT-betaR activation, other NF-kB pathways can lead to the formation of NF-kB p50/p65 heterodimers through the production of IKK-alpha, beta, and gamma. IKK allows for degradation of I-kB (inhibitor of NF-kB), thus upregulating gene transcription that promote other forms of cytokines and lead to inflammation (since it’s constantly activated, it can lead to cancer!!!) In other words, lymphotoxin plays a role in the organization of tumor tissue during tumor development.
  • Thus, removal of LT-beta receptor signaling(ablation) can increased tumor growth inhibition and decrease angiogenesis.  
  • Lymphotoxin and its downstream signaling through the NF-kB pathway have illustrated the ability to influence tumor development and metastasis.

LT and Its Relevance to the Development of Gastrointestinal Immune System

  • During the embryonic development, LT signaling contributes to the formation of mLN(ASK!) and peyer’s patches.
  • Both of these intestinal lymphoid follicles are part of the immune system of the digestive tract, thus containing up to 70-80% of the antibody producing immune cells of the body.
  • Peyer’s patches are highly specialized lymphoid nodules located in the intestine.
  • PP are surrounded by follicle-associated epithelium and through mediation of M cells, it is able to communicate with the underlying immune cells via transcytosis of bacteria, viruses, or luminal antigens,
  • PP development requires interaction between the membrane-associated ligand LT-alpha-beta and LT-beta receptor.
  • Thus, mice that do not have the LT-alpha gene is not able to form PP or any other lymph nodes.
  • In addition to peyer’s patches, isolated lymphoid follicles (ILF) which are located in the small intestine, forms only in the first 2 weeks after birth.     
  • Studies has shown that ILFs could only start developing when LT-alpha was expressed on donor hematopoietic cells and LT-betaR on host cells.
  • Under normal conditions, IgA, which is the most abundantly produced immunoglobulin, provides protection against mucosal pathogens by regulation of bacterial growth and prevention of adhesion the intestine. Reaction with IgA involves migration from the PP to the mLN and then differentiation to IgA-secreting cells.
    • Thus, mice without LT-alpha will display reduced amounts of IgA (studies have shown this). Therefore, it suggests that the interaction between LT-alpha-beta and LT-betaR is essential for IgA expression.

Lead Section

Lymphotoxin-alpha (LT-alpha), also known as tumor-necrosis factor beta, is a lymphokine cytokine that is secreted by peripheral blood leukocytes.[1][2] Belonging to the hematopoietic cell line, LT-alpha exhibit anti-proliferative activity and causes the cellular disruption of tumor cell lines.[1] As a cytotoxic protein, LT-alpha performs a variety of important roles in immune regulation depending on the form that it is secreted as. Thus, LT-alpha can exist in either two forms: as a membrane-bound LT-alpha-beta heterotrimers or as soluble LT-alpha homotrimers.[3]

The roles of LT-alpha have been studied extensively and have shown significant impact on the maintenance of the immune system. Studies involving transgenic mice revealed insight into LT-alpha's effect on the development of secondary lymphoid organ development.[3] It was seen that the absence of LT-alpha led to the disruption of normal gastrointestinal development, lack of Peyer's patches, and the presence of a disorganized spleen.[4]

Furthermore, studies have also shown the importance and roles of LT-alpha in the field of cancer research. As a signaling molecule, LT-alpha is responsible for activating signaling pathways thus affecting cellular survival, proliferation, differentiation, and apoptosis.[5] LT-alpha plays an important role in innate immune regulation and its presence have been shown to prevent tumor growth and destroy cancerous cell lines.[6] However, unregulated expression of LT-alpha can lead to a constitutively active signaling pathway of cellular division, which may lead to the creation of tumors.[5] In other words, LT-alpha is known to be a pro-carcinogenic and an anti-carcinogenic factor. The role that LT-alpha can take on in regards to cancer is dependent on the type of organ it affects, type of cancer cells, cellular environment, gender, and time of affect.[7] Thus, further research is continued into investigating and understanding the complex interaction and mechanism of LT-alpha with other cells in the development and suppression of cancerous cell lines.[6]

Actual Wikipedia Assignment

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Lymphotoxin-alpha (LT-α), also known as tumor-necrosis factor beta, is a lymphokine that is secreted by peripheral blood leukocytes.[2] Belonging to the hematopoietic cell line, LT-α can inhibit cell division activity and causes the cellular destruction of tumor cell lines.[1] LT-α has both a membrane-bound and soluble form that perform distinct roles in immune regulation, hence performing a variety of important roles in immune regulation depending on the form that it is secreted as.

The roles of LT-α have been studied extensively and have shown significant impact on the maintenance of the immune system, such as their effects on the development of secondary lymphoid organ development.[3] Absence of LT-α leads to the disruption of normal gastrointestinal development, prevents Peyer's patches, and results in a disorganized spleen.[4]

Furthermore, studies have also shown the importance and roles of LT-α in the field of cancer research. As a signaling molecule, LT-α is responsible for activating signaling pathways thus affecting cellular survival, proliferation, differentiation, and apoptosis.[5] LT-α is known to be a pro-carcinogenic and an anti-carcinogenic factor. The role that LT-α can take on in regards to cancer is dependent on the type of organ it affects, type of cancer cells, cellular environment, gender, and time of affect.[7] Thus, further research is being continued into investigating and understanding the complex interaction and mechanism of LT-alpha with other cells in the context of cancer.[6]

Gene

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The human gene encoding for LT-α was cloned in 1985.[1] The gene of LT-α is located on chromosome 6 and is in close proximity of the gene encoding major histocompatibility complex.[8][9]

Structure

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LT-α is translated as a 25 kDa glycosylated polypeptide with 171 amino acid residues.[2] Furthermore, human LT-α is 72% identical to mouse LT-α at the protein's primary sequence.[10] LTα expression is highly inducible and when secreted, forms a soluble homotrimeric molecule. LT-α can also form heterotrimers with lymphotoxin-beta, which anchors lymphotoxin-alpha to the cell surface. The interaction between LT-α and LT-β results in the formation of a membrane bound complex (LT-α1-β2).[11]

Function

[edit]

LT-α is secreted as a cytotoxic protein and as a cytokine. Similar to many cytokines, LT-α induces pro-inflammatory responses which affect the activity of chemokines and promotes changes in the surrounding endothelial cells.[5] As a cytotoxic protein, LT-α causes the dissociation of cancerous cell lines, activates signaling pathways, and effectively kills transformed tumor cells.[3] After stimulation of a particular antigen, LT-α is produced and secreted by blood leukocytes, such as a T-cell.[3]

Relevance/Impact on Cancer Research

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            Studies have shown that some cytokines can promote or suppress tumor activity based on the type of affected organ, type of cancer, time of action, gender, and cellular environment.

LT-α mediated Signaling Pathway

As a member of the TNF family, LT-α binds to various receptors and activates the alternative NF-kB pathway, thus promoting immune regulation through the innate immune response.[5] In order for activation to occur, LT-α must form a complex with LT-β to form the LT-α1-β2 complex. Formation of LT-α1-β2 complex enables binding to LT-β receptors and subsequent activation of signaling pathways. Activation of signaling pathways such as NF-kB ultimately leads to various cellular fates, including cell proliferation and cell death. After LT-β receptor activation, IKK-α, β, and γ are produced, which increases degradation of I-kB, an inhibitor of NF-kB, and produce NF-kB1 (p50) and ReIA (p60). The production of NF-kB1 and ReIA ultimately increases gene transcription of cytokines and inflammatory molecules.[12]

Anti-Carcinogenic Properties

Activation of LT-β receptors is capable of inducing cell death of cancerous cells and suppressing tumor growth.[13][14] The process of cell death is mediated by the presence of IFN-gamma and can involve apoptotic or necrotic pathways. It appears that LT-β receptors facilitate the upregulation of adhesion molecules and recruit lymphocytes to tumor cells to combat tumor growth.[1][5] In other words, LT-α interactions with LT-β receptors can increase anti-tumor effects through direct destruction of tumor cells.

Pro-carcinogenic Properties

However, recent studies have shown the contribution of LT mediated signaling to the development of cancer.[3][5][6][14] As mentioned previously, LT signaling can promote inflammatory responses, but prolonged inflammation can cause serious cellular damage and increase the risk of certain diseases including cancer.[6] Thus, mutations in regulatory factors in LT signaling pathways can promote disruptions in the signaling pathway and encourage the creation of cancerous cell lines. One of these mutations include constant binding of LT-α1-β2 complex to LT-β receptors, which results in the constant activation of the NF-kB (alternative) pathway.[5] Presence of a constitutively active NF-kB pathway manifests in multiple myeloma and other cancer-related diseases. Removal of LT-β receptors has been shown to inhibit tumor growth and decrease angiogenesis.[4] Thus, lymphotoxin and its downstream signaling via the NF-kB pathway illustrates its influence on tumor development and metastasis.

Developed by Jane Grogan, a fully humanized anti-LT-α antibody (Pateclizumab or MLTA3698A) has been shown to react with both LT-α and LT-β.[3] Clinical trials involving this antibody have yet to be employed, but the creation of this antibody offers alternative inhibitory methods for the NF-kB pathway.

Relevance to Gastrointestinal Immune System Development

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            The gastrointestinal immune system contains up to 70-80% of the antibody producing cells of the body.[6] During embryonic development, LT-α signaling plays an active part in the formation of the gastrointestinal immune system.[6] In particular, LT-α mediated signaling is responsible for the development of intestinal lymphoid structures such as Peyer’s patches. This intestinal lymphoid follicle plays an important in the immune system of the digestive tract.

            Peyer’s patches are highly specialized lymphoid nodules located in the intestine.[15][16] They are surrounded by follicle-associated epithelium and are able to interact with other immune cells through the transcytosis of foreign antigens.[17] In addition to this function, Peyer’s patches facilitate the production Ig-A producing immunocytes, thus increasing the efficacy of the adaptive immune system.[18]

The development of Peyer’s patches requires the binding and activation of LT-β receptor with LT-α1-β2 complex. Experiments involving transgenic mice have shown that the absence of LT-α resulted in the lack of Peyer’s patches and other lymph nodes.[6] The lack of Peyer’s patches and other lymph nodes have also been shown to reduce levels of Ig-A. Being the most produced immunoglobulin, Ig-A protects against mucosal pathogens by regulating bacterial growth and inhibiting antigen adhesion to the intestine under normal conditions.[19] Reduced levels of Ig-A greatly diminishes gut immune regulation and deregulates protection against microbes, thereby emphasizing the importance of LT-mediated response for the expression of Ig-A.

Nomenclature

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Discovered by Granger and his research group in 1960, LT-α was known as lymphotoxin.[20] As years progressed, its name was changed to tumor necrosis factor-beta (TNF-β).[21] Later discovery of LT-β and LT-α1-β2 complex prompted the disposal of TNF-beta and the subdivision of LT into two classes: LT-α and LT-β.[22][23]

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