Extranodal Nasal NKTcell Lymphoma

This rare and highly malignant lymphoma occurs mainly in Asia. The tumor cells are intermixed with inflammatory cells in a necrotic tissue with obvious vascular damage [54]. These lymphomas are regularly EBV-positive, with some variation in the expression of the virally encoded genes, the tissue contains both Type I and Type II cells, the latter with high variation in the level of LMP-1 [55, 56]. EBV-negative and EBV-positive cell lines have been established, and, except for one, that is Type I, the EBV carrier ones maintained the Type II pattern. In contrast to the in vivo tumor the level of LMP-1 in the cell lines is homogeneous, though it differs in the various cell lines. Importantly, these tumor-derived lines with the NK phenotype require IL-2 for in vitro proliferation, thus in this respect they resemble normal NK cells. LMP-1 expression is coupled to cell proliferation, it is dependent on the supply of IL-2 [57]. We demonstrated that in absence of IL-2 cells treated with the cytokines IL-10 and IFN-gamma expressed LMP-1, but cell proliferation was not sustained [57]. Thus the LMP-1 protein in the NK tumor cells was not sufficient for induction of proliferation. However it modified the growth potential of the cells indirectly because the requirements for IL-2 were changed in the cytokine-treated cells. Concomitantly with the induction of LMP-1 the expression of CD25, the high affinity component of the IL-2 receptor, increased and this led to lower IL-2 concentration requirement for growth [57]. We concluded therefore that while the EBV-encoded proteins expressed in the NK-lymphoma do not induce proliferation, LMP-1 can contribute to the pathogenesis of the NK-lymphoma, by potentiating the response of the malignant NK-cells to growth-promoting cytokines.

The following sequence of events may thus contribute to the development of NK/T lymphomas. This malignancy is confined to the nasal area, a site where inflammation is frequent. In the inflammatory tissue B, T and NK lymphocytes are activated. For the part of B lymphocytes, the ones carrying the EBV genome may be induced for virus production. Through direct contact, the otherwise rare event, NK-cells may be infected with the virus and the cells exhibit the Type Ila protein pattern (Fig. 10.2) Activated T-cells in the tissue produce IL-2, and IL-10. Activated NK-cells express IL-2 receptors and respond with proliferation. The sensitivity to the effect of IL-2 is potentiated by the influence of IL-10 that is also provided by the T lymphocytes, and by macrophages as well. In addition the tumor cells are induced to produce IL-10 exhibiting thus autocrine upregulation of LMP-1. By concomitantly up-regulating the expression of CD25 (IL-2R-alpha), IL-10 may have a key role in the proliferation of the malignant cells because it may be responsible for efficient exploitation of the available amount of IL-2.

Fig. 10.2 Contributing factors to the development of nasal NK-lymphoma, emphasizing the role of EBV. In the inflammatory tissue NK-, B-, T-cells and macrophages are activated. Occasional EBV-carrying B-cells produce viral particles and infect NK-cells through direct contact. In these, the EBV-encoded protein expression is Type Ila. Activated NK-cells express the IL-2-receptor, consequently they can respond to the growth-promoting stimulus of IL-2 that is produced by T-cells. IL-10 and IL-15 is secreted by macrophages that elevate the level of LMP-1 that may directly increase CD25 expression. Consequently these cells can be stimulated for division by relatively lower level of IL-2. The assignment of cytokines to a particular cell type is not exclusive, e.g. IL-10 can be produced by T-cells and by the tumor cells as well. The circles in the nucleus of the cells represent the viral episome

Fig. 10.2 Contributing factors to the development of nasal NK-lymphoma, emphasizing the role of EBV. In the inflammatory tissue NK-, B-, T-cells and macrophages are activated. Occasional EBV-carrying B-cells produce viral particles and infect NK-cells through direct contact. In these, the EBV-encoded protein expression is Type Ila. Activated NK-cells express the IL-2-receptor, consequently they can respond to the growth-promoting stimulus of IL-2 that is produced by T-cells. IL-10 and IL-15 is secreted by macrophages that elevate the level of LMP-1 that may directly increase CD25 expression. Consequently these cells can be stimulated for division by relatively lower level of IL-2. The assignment of cytokines to a particular cell type is not exclusive, e.g. IL-10 can be produced by T-cells and by the tumor cells as well. The circles in the nucleus of the cells represent the viral episome

Table 10.2 The role of EBV in lymphomagenesis

Malignancy

Key factors for in vitro proliferation

The role of EBV

Burkitt lymphoma

Ig-myc translocation

Anti-apoptosis?

Hodgkin lymphoma

Constitutive NF-kappa

Rescue of faulty GC B-cells from

B activity

apoptosis

Nasal NK/T-cell

ExogeneousIL-2

IL-2R-alpha (CD25) upregulation

lymphoma

AIDS-lymphomas

EBV-encoded, growth

Induction of proliferation

and PTLD

promoting genes

Thus unlike B lymphocytes in which LMP-1 together with other EBV-encoded proteins (particularly EBNA-2) drives cell proliferation, the role of EBV in the NK/T lymphomas is confined to potentiate the sensitivity to growth promoting cytokines received from the components of the inflammatory tissue. Whether LMP-1 is directly involved in the expression of the IL-2R alpha (CD25), or its regulation of expression is concomitant, remains to be seen.

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