Epstein-Barr virus (EBV) is associated with a number of malignant lymphomas, including Burkitt lymphomas, Hodgkin lymphomas (HLS), immunodeficiency-associated lymphoproliferative disorders (LPDs), and subset of diffuse large B-cell lymphomas. We have recently identified a series of elderly patients afflicted with EBV-associated (EBV-positive) B-cell LPDs in the absence of predisposing immunodeficiencies ; we have named these neoplasms “senile” EBV⁺ B-cell LPDs. The large series of patients with this disease (n=76) provided additional evidence that this neoplasia, with a median age of onset of 71 years, has the highest incidence in elderly patients aged > 50 years, suggesting that this disease may be related to the immunological deterioration that occurs during the aging process. These lesions were pathologically characterized by varying numbers of Hodgkin and Reed-Sternberg (HRS)-like giant cells, often posing a diagnostic problem differentiating this condition from HL. Recent studies, however, have indicated that HL and non-Hodgkin lymphoma (NHL) may be more closely related than previously implied, promoting the general consensus that HRS cells are derived from B cells in most HL cases. The relationship between EBV⁺ HL and EBV⁺ B-cell LPDs remains to be clarified. This review provides a unique opportunity to highlight the gray areas between EBV⁺ HL and EBV⁺ B-cell LPDs. Further investigations are necessary to clarify the interrelationship, including their overlapping morphological and biological features.

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In Japan, EBV positive rate in immunocompetent patients with nodal lymphomas is less than 10% in B-cell and 20 - 50% in T cell lymphoma. Among extranodal lymphomas, EBV positive rate is higher in pyothorax-associated lymphoma (PAL), nasal NK/T-cell lymphoma, and adrenal lymphoma. PAL is non-Hodgkin's lymphoma that develops from chronic pyothorax resulted from artificial pneumothorax for the treatment of lung tuberculosis or tuberculous pleuritis. This disease was originally described by Dr. Aozasa as a distinctive clinicopathologic entity in 1987, and now listed as the disease entity in the WHO classification of Tumours, Pathology & Genetics, Tumours of the Lung, Pleura, Thymus and Heart (2004).

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Human Vγ2Vδ2 T cells recognize nonpeptide antigens derived from pathogenic microbes in a TCR-dependent manner, such as pyrophosphomonoester compounds from mycobacteria and malaria parasite and alkyl amines from Proteus, suggesting that this subset of γδ T cells is involved in infectious immunity. The precise recognition mechanism has been delineated using a site-directed mutagenesis strategy based on crystal structure of γδ TCR. On the other hand, several lines of evidence indicate that human γδ T cells are involved in tumor immunity. Although activated γδ T cells exhibit a cytolytic activity against most of tumor cells, only a small fraction of tumor cells, like Burkitt lymphoma cells and multiple myeloid cells, is recognized by human γδ T cells in a TCR-dependent manner. This implicates that human γδ T cells have two distinct pathways for anti-tumor immunity. One is a natural killer-like pathway and the other is a TCR-dependent pathway. Recently, it was shown that treatment of human tumor cells with nitrogen-containing bisphosphonates, therapeutic drugs for hypercalcemia in malignancy, generated antigenic structure on the surface of tumor cells, which could be recognized by human γδ T cells in a TCR-dependent manner. This tumor labeling system may lead to a novel strategy for cancer immunotherapy.

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We investigated the relationship of gastric mucosa-associated lymphoid tissue (MALT) lymphoma tumorigenesis to Helicobacter pylori infection, the t (11 ; 18) translocation, and alterations in cell cycle regulators. We sought to assess the implications of altered expression of p27^Kip1, a cyclin-dependent kinase inhibitor, on high-grade transformation and responsiveness to eradication therapy. We used immunohistochemistry to examine p27^Kip1, p53, and Ki-67 expression in 23 MALT lymphomas, five diffuse large B-cell lymphomas (DLBCLs), and four DLBCLs associated with MALT lymphoma. All of the MALT lymphomas were positive for p27^Kip1 expression and negative for p53 with a low Ki-67 index, regardless of the sensitivity of these cells to eradication. All DLBCLs were negative for p27^Kip1 and positive for p53, exhibiting a high Ki-67 index. In DLBCLs with MALT lymphoma, p27^Kip1 expression was absent from both the MALT and large cells components. In all of these lymphomas, the MALT components were negative for p53 and displayed a low Ki-67 index, while the large cell components were positive for p53 with a high Ki-67 index. The expression patterns of the DLBCLs differed significantly from those of the MALT lymphomas. p27^Kip1 was not detected in either component of DLBCL with MALT lymphoma, suggesting that decreased expression of p27^Kip1 in the MALT component may be related to high-grade transformation. Thus, p27^Kip1 expression in morphological MALT lymphomas could be useful tool to predict high-grade transformation to DLBCL.

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Dendritic cell (DC) activation is triggered by cytokines, including tumor necrosis factor (TNF)-α, and microbe components, including lipopolysaccharide (LPS). During the initial stage of infection, the microbe components appear to be present at low concentration. To determine the role of low-dose microbe-components in DC activation during the initial stage of infection, we examined the effects of low-dose LPS on cytokine-induced maturation and function of DCs. Low-dose LPS (1 ng/ml) treatment of DCs had only additive effects on the expression of CD86 and major histocompatibility complex class II induced by various cytokines, including interleukin (IL)-1β, TNF-α and interferon (IFN)-γ. IL-1β alone significantly induced IL-12 production in DCs, whereas TNF-α or IFN-γ induced modest levels of IL-12 production. When low-dose LPS (1 ng/ml), which only slightly induced IL-12 production, was added to the culture, only an additive effect was seen on IL-1β-induced IL-12 production. In contrast, low-dose LPS synergistically enhanced TNF-α- or IFN-γ-induced IL-12 production. SB203580, a specific inhibitor of p38 MAPK, markedly inhibited TNF-α- or IFN-γ-induced IL-12-production either in the absence or presence of LPS, but showed only modest effects on IL-1β-induced IL-12-production. These findings suggest that the p38 MAPK pathway is essential for the synergistic IL-12 production induced by TNF-α- or IFN-γ in combination with low-dose LPS in DC.

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