A cell death pathway induced by antibody-mediated cross-linking of CD45 on lymphocytes.

The protein tyrosine phosphatase CD45 is a highly expressed glycoprotein present on all nucleated cells of hematopoietic origin. To date, all the functions attributed to CD45 are inherently coupled to its phosphatase activity. For instance, the regulation of lymphocyte antigen receptor signaling is mediated through the dephosphorylation, and hence activation, of Src-family kinases by CD45. Moreover, signaling via cytokine receptors is negatively modulated by CD45 by dephosphorylation of Janus kinase family members. Recently, another function for CD45, unrelated to regulation of surface receptor signaling, has been unraveled. Specific engagement of CD45 by monoclonal antibodies at the surface of lymphocytes induced their death, through an alternative caspase-independent pathway. In striking contrast to all other previously reported functions for CD45, its phosphatase activity is completely dispensable for the induction of cell death. This article reviews the current knowledge on the death pathway triggered by CD45 ligation on lymphocytes. In an attempt to better elucidate the mechanism of cell death induction through CD45, we also provide original data regarding the susceptibility of various subsets of immature and mature T and B cells to death induced by CD45 engagement. The physiological significance and therapeutic potential of CD45-induced death are also discussed.

Cellular specificity related to monoglyceride-induced cell death.

We have recently observed that monoglycerides (MGs), a family of lipids consisting of a single fatty acid moiety attached to a glycerol backbone, induce rapid dose-dependent apoptosis in murine thymocytes. In this work, we evaluated the sensitivity of various normal and malignant immune and non-immune cells to MGs. We demonstrate that the propensity to MG-induced death displayed by both T and B lymphocytes is clearly modulated according to their differentiation and activation status. For instance, the earliest T and B cell precursors are refractory to MG-mediated cell death. In the T-cell lineage, immature thymocytes are the most susceptible to MG treatment, while B cells from peripheral lymphoid organs appear more sensitive than B-cell subsets from the bone marrow. On the other hand, both activated T and B cells are more resistant to MG exposure than their non-activated counterparts. In addition, other hematopoietic lineages such as natural killer cells, macrophages, and erythroid cells are quite resistant to MG-induced death. Furthermore, using various immortalized cell lines from different tissues, we found that lymphomas and thymomas are the most sensitive among all lineages tested, while epithelial cells and fibroblasts are unaffected by MG treatment. Finally, MG-induced death was shown to be independent of Fas/Fas ligand (FasL) interactions. Altogether, our findings indicate that there is a cellular specificity related to MG-mediated cell death biased towards T and B lymphocytes. This suggests that MGs could potentially be used in the treatment of specific lymphoid disorders by bypassing the requirement for the Fas/FasL system.

Concentrations of alpha-fetoprotein, insulin-like growth factor binding protein-3, c-erbB-2, and epidermal growth factor in serum of patients with endometriosis.

OBJECTIVE: Endometriosis, although it is a benign disorder, shares many similarities with cancer. There is increasing levels of evidence suggesting that some circulating factors involved in gynecologic cancers, such as alpha-fetoprotein (AFP), insulin-like growth factor binding protein-3 (IGFBP-3), c-erbB-2 (HER-2/neu), and epidermal growth factor (EGF), could also play a role in endometriosis. Hence, the present study was aimed at evaluating whether the levels of these molecules are modulated in the serum of patients with endometriosis. METHODS: Levels of AFP, IGFBP-3, c-erbB-2, and EGF were determined by enzyme-linked immunosorbent assay in serum from 36 subjects with surgically confirmed endometriosis and 36 controls with no surgical evidence of the disease. In addition, information such as demographic characteristics, personal habits, menstrual characteristics, and clinical profile was collected from each participating subject. RESULTS: No significant difference was found between serum levels of AFP, IGFBP-3, c-erbB-2, and EGF in patients with endometriosis and controls, even when we adjusted for potential confounders and took into account the menstrual cycle. Moreover, no correlation was observed between the serum concentrations of these molecules and the stage of the disease. However, a correlation was detected between soluble levels of IGFBP-3 and presence of uterine leiomyoma. CONCLUSION: Although AFP, IGFBP-3, c-erbB-2, and EGF are not altered in the circulation of patients with endometriosis, their involvement in the development of endometriotic lesions cannot be excluded.

Monoglycerides induce apoptosis in human leukemic cells while sparing normal peripheral blood mononuclear cells.

A major drawback of the current antineoplastic treatments is their lack of specificity toward cancer cells, because they are most often cytotoxic to normal cells, thus creating related side effects. Hence, the identification of new apoptosis-inducing agents, specifically targeting malignant cells while sparing their normal counterparts, is of crucial interest. We show here that monoglycerides, a family of lipids consisting of a single fatty acid attached to a glycerol backbone, induce cell death in several human leukemic cell lines. Importantly, treatment of primary leukemic cells, obtained from B-cell chronic lymphocytic leukemia patients, resulted in rapid apoptosis. In striking contrast, resting or activated human peripheral blood mononuclear cells from healthy individuals were resistant to the same treatment. Therefore, these compounds could represent potential antileukemic drugs or could allow for the design of novel therapeutic agents applied to leukemia.