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.
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).
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.
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 p27Kip1, a cyclin-dependent kinase inhibitor, on high-grade transformation and responsiveness to eradication therapy. We used immunohistochemistry to examine p27Kip1, 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 p27Kip1 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 p27Kip1 and positive for p53, exhibiting a high Ki-67 index. In DLBCLs with MALT lymphoma, p27Kip1 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. p27Kip1 was not detected in either component of DLBCL with MALT lymphoma, suggesting that decreased expression of p27Kip1 in the MALT component may be related to high-grade transformation. Thus, p27Kip1 expression in morphological MALT lymphomas could be useful tool to predict high-grade transformation to DLBCL.
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.