BackgroundThe inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (MΦ) and dendritic cells (DC).MethodsMΦ and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, MΦ stimulated with GM-CSF (MΦGM-CSF, pro-inflammatory MΦ-1-model) or M-CSF (MΦM-CSF, immunomodulatory MΦ-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or MΦ polarization were investigated by flow cytometry. Furthermore, the impact of DC or MΦ on cHL cell proliferation was analyzed by BrdU/CFSE assay.ResultsIn cHL tissues mature myeloid (m)DC and MΦ predominated. High numbers of CD83+ mDC and low numbers of CD163+ MΦ were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory MΦ phenotype were promoted by SN derived from cHL cell lines. TNFα neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory MΦ inhibited the proliferation of cHL cells.ConclusionAdopting an immunomodulatory phenotype is a potential mechanism for how MΦ promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity.

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Epstein-Barr virus (EBV) replicates in superficial differentiated cells of oral hairy leukoplakia (OHL). Differentiation of squamous epithelial cells depends on B-lymphocyte-induced maturation protein 1 (Blimp1).Here we show that expression of the EBV immediate-early protein BZLF1 is restricted to Blimp1-positive epithelial cells in OHL. Luciferase assays revealed Blimp1-dependent induction of the BZLF1 promoter Zp in epithelial cell lines. Expression of ZEB1, a negative regulator of Zp, and of Xbp-1, which mediates the Blimp1 effect on Zp in B-cells, was not affected by enforced Blimp1 expression. Moreover, Xbp-1 protein expression was not detected in differentiated epithelial cells of OHL. Thus, Blimp1 induces BZLF1 expression in epithelial cells independently of ZEB1 and Xbp-1. In contrast to epithelial cells of OHL, BZLF1 expression was also observed in Blimp1-negative lymphoid cells in infectious mononucleosis tonsils, suggesting that EBV replication in B-cells may be induced independently of terminal differentiation.Epstein-Barr virus (EBV) is a B-lymphotropic human herpesvirus infecting .90 % of the adult population worldwide. Primary infection in childhood is usually asymptomatic but may cause a clinical syndrome, infectious mononucleosis (IM), when delayed into adolescence or early adulthood. Following primary infection, a lifelong persistent latent infection of memory B-cells is established. Infectious virus particles are released into the saliva, but their cellular source has been controversial (Niedobitek & Young, 1994). It is now clear that EBV may replicate in B-cells as well as in oral squamous epithelial cells. In both cellular compartments, the switch from latent to lytic infection is triggered by expression of the immediate-early gene BZLF1, which is necessary and sufficient to activate the EBV lytic cascade (Rooney et al., 1989;Miller, 1990). Various lines of evidence have indicated that EBV replication depends on cellular differentiation. Immunohistochemical analysis of B-cells in IM tonsils suggested a restriction of virus replication to cells with plasma-cell morphology (Crawford & Ando, 1986;Niedobitek et al., 1997). Furthermore, terminal differentiation of B-cells towards plasma cells initiates the lytic cycle in vivo (Laichalk & Thorley-Lawson, 2005). Similarly, it has been suggested that, in epithelial cells of oral hairy leukoplakia (OHL), an AIDS-associated lesion of the tongue mucosa, EBV replicates in a differentiation-dependent manner (Young et al., 1991).Plasma-cell differentiation is regulated by B-lymphocyteinduced maturation protein (Blimp)1 (Shapiro-Shelef et al., 2003). By repressing Pax5, Blimp1 indirectly activates the Xbox-binding protein Xbp-1 (Lin et al., 2002). Induction of BZLF1 expression by binding of Xbp-1 to the BZLF1 promoter Zp has been demonstrated in B-cells, but not in epithelial cells (Sun & Thorley-Lawson, 2007). In contrast, Bhende et al. (2007) showed that Xbp-1 transactivates BZLF1 only in combination with activated protein kinase D in B-lymphocytes and e...

Background:Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) up-regulates the human leukocyte antigen (HLA) class I antigen presentation machinery (APM). This appears counterintuitive with immune evasion in EBV-associated tumours like nasopharyngeal carcinoma (NPC).Methods:Latent membrane protein 1-transfected epithelial cell lines were used as a model system to study the impact of LMP1 and c-Myc on HLA class I components. The expression of components of the HLA class I APM, c-Myc and Ki-67 was analysed in LMP1+ and LMP1− NPC by immunohistochemistry.Results:In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. Studies of NPC biopsies revealed down-regulation of HLA class I APM expression. No difference was observed between LMP1+ and LMP1− NPC. However, expression of Ki-67 and c-Myc were up-regulated in LMP1+ tumours.Conclusion:These findings raise the possibility that c-Myc activation in NPC might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.