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Introduction to lymphotoxin-a
Click on links to see definitions...

        Lymphotoxin-a, or simply lymphotoxin (LT) is a cytokine secreted by activated TH1 cells, fibroblasts, endothelial and epithelial cells (Ibelgauft, TNF-beta, 1999).  LT (a.k.a. Tumor Necrosis Factor-b) is a member of the Tumor Necrosis Factor (TNF) family of cytokines, so named so named because such cytokines were observed to cause necrosis of tumor cells by attacking the surrounding blood vessels, effectively starving the tumor to death (Sompayrac 1999).  LT was first defined by its cytotoxicity to fibroblasts, hence the name “lympho-toxin” (De Togni et al. 1994).  Among the diverse immune functions of LT are the activation and recruitment of effector cells to infection sites, facilitation of leukocyte adhesion to endothelial cells, participation in peripheral lymphoid organogenesis, stimulation of B-cells, and inhibition of tumor angiogenesis.  Lymphotoxin is a proinflammatory cytokine because of its important role in the migration of effector cells to infection sites and has been implicated as a cause of tissue damage in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (Körner et al. 1995, Suen et al. 1997)

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         LT is a b-structural cytokine, meaning that its secondary structure is completely b-sheet (Figure 1) (Ibelgauft, Cytokines, 1999).  The lymphotoxins are found as either homotrimers of LT-a (LT-a3) or as heterotrimers of one LT-a subunit and two LT-b subunits (LT-a,b2).  While the homotrimer lacks a transmembrane domain, LT-b is a type II transmembrane protein, so LT-a,b2 is anchored to the expressing cell’s surface (von Boehmer 1997).  The trimeric structure is characteristic of all members of the TNF cytokine family and seems to be crucial for initiation of signaling (Janeway et al. 1999).  The receptors of LT-a3 are the same as those of TNF-a, which are expressed in a variety of tissues including epithelial cells; the receptor for LT-a,b2 binds to the LT-b receptor, which is found in primary and secondary lymphoid tissues (von Boehmer 1997).  Thus, the main role of LT-b is in lymphoid organogenesis rather than inflammation, while the LT-a subunit is crucial to both processes as part of both LT-a3 and LT-a,b2 (Suen et al. 1997).

Figure 1:  This interactive figure shows the crystal structure of lymphotoxin (tumor necrosis factor-b) complexed with the extracellular domain of Tumor Necrosis Factor Receptor P55.

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Role in autoimmune diseases and tumor necrosis

        The growth and survival of metastatic tumor cells depends upon successful angiogenesis and the tumor cells’ ability to evade detection by the host organism’s immune system (Borgström et al. 1997).  In order to respond to tumor cells, leukocytes must be able to interact with the endothelial cells of the tumor blood vessels (tumor microvessels) and reach the tumor stroma.  The inefficiency of leukocyte recruiting to the stroma of tumor cells could be a contributing factor in the extreme difficulty with which metastatic tumors are treated.  In 1997, Borgström et al. investigated the role of LT in leukocyte recruiting through experiments with Lewis lung carcinoma-induced tumor microvessels in nude mice.  They found that gene trasfer of plastocytomas using human LT-expressing plasmids to the nude mice resulted in tumor growth inhibition due to infiltration by granulocytes and macrophages (Borgström et al. 1997).  Thus, the efficiency of leukocyte recruitment into tumor cell stroma was greatly enhanced in nude mice with the introduction of functional LT, which has far-reaching implications in the treatment of malignant tumors (Borgström et al. 1997).
        Since LT is a leukocyte-recruiting cytokine, which is beneficial in the presence of tumors, it can also contribute to autoimmune pathogenesis by causing chronic inflammation.  Research has shown that treatment of experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis) with anti-TNF/LT antibody results in the virtual disappearance of central nervous system inflammation (Körner et al. 1995).  EAE can be induced in mice by immunizing them myelin oligodendrocyte glycoprotein (MOG).  Suen et al. (1997) showed that wild type mice developed central nervous system inflammation and demyelination upon immunization with MOG, while LT-a-deficient mice (LT-a-/-) were very resistant to EAE.  In addition, EAE was transferred to LT-a-/- mice via wild type T-cells.  These results indicate that T-cell production of  LT-a3 plays a major role in the pathogenesis of neurologic inflammatory diseases (Suen et al. 1997).

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Role in lymphoid organogenesis

        Using gene targeting in embryonic stem cells to render mice LT-a-deficient, De Togni et al. (1994) found that the mice developed an apparently normal thymus but no morphologically detectable lymphnodes or Peyer’s patches.  While this result indicates the importance of LT in peripheral lymphoid organogenesis, the mechanism by which LT contributes to lymphoid organ development is unknown.  A hypothesis based on the known leukocyte adhesion-inducing action of LT and TNF-a is that an essential interaction between bone marrow-derived lymphoid cells and lymphoid stromal cells requires the presence of LT (De Togni et al. 1994).  A few years ago, it was suggested that LT and TNF-a were functionally redundant for the most part.  However, the abnormal lymphoid development in LT-/- mice even in with functional TNF-a expression indicates that LT has a specific function that is not duplicated by TNF-a or that LT and TNF-a are produced at different stages in development (De Togni et al. 1994).  In 1996, Matsumoto et al. showed that lethally irradiated LT-a-deficient mice were able to form germinal centers (GC) and organized follicular dendritic cells (FDC) in the spleen after bone marrow transfer from normal mice (Matsumoto et al. 1997).  On the other hand, lethally irradiated normal mice that received a bone marrow transfer from LT-a-deficient mice were unable to generate GC or FDC.  These results indicate that the LT-a-expressing cells that are necessary for the development of organized FDC and GC are bone marrow-derived, i.e. non-bone marrow-derived LT-a is insufficient for or does not contribute to lymphoid organogenesis (Matsumoto et al. 1997).

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(for those who aren't quite so immuno-literate...)

Cytokines – (1) proteins made by cells that affect the behavior of other cells by acting on specific receptors on the cells they affect (Janeway et al. 1999).  (2) Cytokines are a diverse group of soluble proteins and peptides that act as humoral regulators by modulating the functional activities of individual cells and tissues (Ibelgauft, Cytokines, 1999).

Link to cool cytokines website....

Inflammation – general term for the local accumulation of fluid, plasma proteins, and white blood cells that is initiated by physical injury, infection, or local immune response (a.k.a. inflammatory response).   Chronic inflammation occurs when the infection if persistent or in autoimmune responses (Janeway et al. 1999).

Lymphoid organs - organized tissues characterized by very large numbers of lymphocytes interacting with non-lymphoid stroma.  The thymus and bone marrow are the primary lymphoid organs, where lymphocytes are generated.  Adaptive immune responses are initiated in the secondary (peripheral) lymphoid organs, which are the lymph nodes, spleen, tonsils, and Peyer's patches (Janeway et al. 1999).

Necrosis – the death of cells or tissues due to chemical or physical injury, as opposed to apoptosis, in which cell death is biologically programmed.  Necrosis leaves cellular debris that is later phagocytosed, while apoptosis does not (Janeway et al. 1999).

Nude mice – mice that are homozygous for the nude mutation, which causes hairlessness and the inability to produce any mature T-cells (Janeway et al. 1999).

Tumor angiogenesis – directed sprouting of new blood vessels in the direction of the tumor mass.  This facilitates blood supply to the tumor, without which the tumor cells would die by necrosis (Ibelgauft, Angiogenesis, 1999).

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Borgström P, Hughes GK, Hansell P, Wolitzky BA, Sriramarao P.  1997.  Leukocyte Adhesion in Angiogenic Blood Vessels.  J. Clin. Invest. 99: 2246-2253.

De Togni P, Goellner J, Ruddle NH, Streeter PP, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, Russel JH, Karr R, Chaplin DD.  1994.  Abnormal Development of Peripheral Lymphoid Organs in Mice Deficient in Lymphotoxin.  Science 264: 703-707.

Ibelgauft H.  1999 Aug.  Angiogenesis.  Cytokines Online Pathfinder Encyclopedia.
<http://www.copewithcytokines.de/cope.cgi?000343>  Accessed 2000 Feb 27.

---------------.  1999 Aug.  Cytokines.  Cytokines Online Pathfinder Encyclopedia. <http://www.copewithcytokines.de/cope.cgi?001668>  Accessed 2000 Feb 27.

---------------.  1999 Aug.  TNF-beta.  Cytokines Online Pathfinder Encyclopedia. <http://www.copewithcytokines.de/cope.cgi?6079>  Accessed 2000 Feb 26.

Janeway C, Travers P, Walport M, Capra JD.  1999.  Immunobiology:  The Immune System in Health and Disease.  New York, NY: Elsevier Science Ltd./Garland Publishing.  p 292, 598-608.

Körner H, Goodsall AL, Lemckert FA, Scallon BJ, Ghrayeb AF, Sedgwick JD.  Unimpaired autoreactive T-cell traffic within the central nervous system during tumor necrosis factor receptor-mediated inhibition of experimental autoimmune encephalomyelitis.  Proc. Natl. Acad. Sci. 92: 11066-11070.

Matsumoto M, Fu Y, Molina H, Huang G, Kim J, Thomas DA, Nahm MH, Chaplin DD.  1997.  Distinct Roles of Lymphotoxin a and the Type I Tumor Necrosis Factor (TNF) Receptor in the Establishment of Follicular Dendritic Cells from Non-Bone Marrow-derived Cells.  J. Exp. Med. 186: 1997-2004.

Sompayrac, L.  1999.  How the Immune System Works.  Malden, MA: Blackwell Science, Inc.  p 100.

Suen WE, Bergman CM, Hjelmström P, Ruddle NH.  1997.  A Critical Role for Lymphotoxin in Experimental Allergic Encephalomyelitis.  J. Exp. Med. 186: 1233-1240.

von Boehmer, H.  1997.  Lymphotoxins:  From cytotoxicity to lymphoid organogenesis.  Proc. Natl. Acad. Sci. 94: 8926-8927.

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