HIV-associated Hodgkin's lymphoma. Antiapoptotic pathways and mechanisms for immune escape by tumor cells in the setting of improved immunity.

Hodgkin’s lymphoma (cHL) are usually transformed B cells, gene expression analysis of RS cell lines using microarrays revealed that the RS cells have lost the expression of most B-cell markers (1). The alterations involved in the pathogenesis of Hodgkin’s lymphoma are still largely unknown. Escape from apoptosis is an important event in tumor-cell pathogenesis and this applies especially to RS cells. As RS cells are likely derived from preapoptotic germinal-center B cells (2), the rescue from apoptosis is a key event in the transformation process, leading to RS cell generation. Several aberrantly activated signaling pathways contribute to the survival of RS cells, nuclear factor kappa B (NFkB) being perhaps the most important one (3). The composition of the inflammatory-like cellular infiltrate in cHL-affected tissue is heterogeneous, consisting of lymphocytes, macrophages, eosinophils, plasma cells, stromal cells and fibroblasts. In primary cases of cHL, the CD4+ T lymphocytes represent the majority of the reactive cell population. RS cells and their reactive surrounding CD4+ T cells are able to cross-talk via a complex network of cytokines, chemokines, TNF-receptor family members, and cellcontact–dependent interactions. Several receptors which activate the classical NFkB pathway are expressed by RS cells, and ligands for these receptors are frequently expressed on activated CD4+ T cells and other bystander cells surrounding RS cells. RS cells of cHL typically express members of the TNF/NGF receptor superfamily (CD30, CD40, CD95/FAS, RANK, RANKL) as well as a number of adhesion receptors and T-cell costimulatory molecules (CD80) (4) . On the other hand, several of the TNF/NGF ligands, including CD40L, CD30L and CD95L, are expressed on activated CD4+ T cells and other bystander cells surrounding RS cells, including eosinophils, neutrophils and B-cell subsets (4). Because CD40 expression has been reported in primary cases of cHL (5) and CD40L is found on rosetting T cells in cHL-affected tissue (6), it can be assumed that the CD40/CD40L signaling pathway is important for the survival of RS cells in vivo. In Epstein-Barr virus (EBV)-positive cHL cases, the EBV-encoded latent membrane protein 1 (LMP1) gene also contributes to NFkB activation as it mimics an activated CD40 receptor (7). Several attempts have been made to explain the apparent inefficiency of the antitumoral immune response in cHL. Recently, the functional and molecular characterization of regulatory T cells (Treg) with the CD4+/CD25+ phenotype has been facilitated by the identification of markers that indentify specific subpopulations, such as FOXP3 (8). FOXP3 codes for a transcription factor known as Scurfin, expressed specifically by CD4+/CD25+ T cells, whose expression is independent of activation. These CD4+/CD25+ Treg exert immunosuppressive effects on the development of tumor-associated antigen-reactive lymphocytes, blocking the activation of CD8+ and natural killer cells to tumor antigens (9). The impact of HIV infection on CD4+/CD25+ Treg subpopulations was recently evaluated by FOXP3 quantitative reversetranscriptase polymerase chain reaction and by flow cytometry (10). FOXP3 mRNA was quantified in peripheral blood mononuclear cells or purified CD4+ lymphocytes from HIV-positive patients. The frequency of CD4+/CD25+ lymphocytes, measured by flow cytometry, was decreased in HIV+ patients compared with the group of uninfected subjects. Moreover, FOXP3 mRNA levels were found to be decreased in peripheral blood CD4+ lymphocytes from HIV+ patients compared with controls (10). Recent studies have demonstrated by immunohistochemistry that Treg are present in the reactive background of cHL (11). Moreover, we found FOXP3 expression on rosetting CD4+ T cells in primary cases of cHL-affected tissues (our unpublished observation; see Fig. 1). Thus, it can be assumed that the presence of Treg in the reactive background of cHL and, specifically, on CD4+ T cells rosetting RS cells, may explain the inhibition of the antitumoral host immune response observed in these patients. This constitutes an important mechanism for immune escape by tumor cells in cHL. HIV/AIDS-associated cHL (HIV-cHL) displays several peculiarities when compared with cHL of the HIV-seronegative population. In particular, the aggresThe International Journal of Biological Markers, Vol. 22 no. 2, pp. 161-163 © 2007 Wichtig Editore