The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately 1 percent of the world population, are not well understood [1][2][3] . Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1) and leukocyte integrins α4β1 and αLβ2. Inhibition of leukocytevascular interactions either with blocking antibodies, or in mice genetically deficient in functional PSGL-1, dramatically reduced seizures. Treatment with blocking antibodies following acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with potential leukocyte involvement in the human, leukocytes were more abundant in brains of epileptics than of controls. Our results Correspondence should be addressed to: P.F.F (E-mail: paolo.fabene@univr.it) or G.C. (E-mail: gabriela.constantin@univr.it). Author contribution G.N.M., D.B., A.C., L.Z., F.S. performed epilepsy experiments, telemetry and open field behavior. M.M., B.R., L.O., S.B., S.A., performed intravital microscopy, in vivo staining for adhesion molecules, adhesion assays and contributed to the obtainment of behavioral data. A.O. provided the human samples. F.M., A.C. and F.O. performed immunohistochemistry on human and animal samples. P.M., E.N. and A.S provided MRI expertise. J.W.H., L.X., J.B.L., R.P.M provided vital reagents and mice. E.C.B contributed experimental suggestions, reagents and assistance with writing. P.F.F and G.C. designed the study, analyzed the data and wrote the paper NIH Public Access suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.Experimental data from animal models as well as human evidence indicate that seizures can lead to neuronal damage and cognitive impairement 2, 3 . However, the molecular mechanisms leading to seizures and epilepsy are not well understood. Recent data suggests that inflammation may play a role in the pathogenesis of epilepsy 4, 5 . For instance, elevation in inflammatory cytokines are seen in the central nervous system (CNS) and plasma in experimental models of seizures and in clinical cases of epilepsy 4, 5 . Moreover, CNS inflammation is associated with breakdown in the blood-brain barrier (BBB), and BBB leakage has been implicated both in the induction of seizures and in the progression to epilepsy 6-9 . Leukocyte recruitment is a hallmark of and a point of therapeutic intervention in tissue inflammation 10,11 , but a role for leukocyte-endothelia...
Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated a4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that a4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS. STEM CELLS
Regulatory T cells (Tregs) maintain tolerance toward self-antigens and suppress autoimmune diseases, although the underlying molecular mechanisms are unclear. In this study, we show that mice deficient for P-selectin glycoprotein ligand-1 (PSGL-1) develop a more severe form of experimental autoimmune encephalomyelitis than wild type animals do, suggesting that PSGL-1 has a role in the negative regulation of autoimmunity. We found that Tregs lacking PSGL-1 were unable to suppress experimental autoimmune encephalomyelitis and failed to inhibit T cell proliferation in vivo in the lymph nodes. Using two-photon laser-scanning microscopy in the lymph node, we found that PSGL-1 expression on Tregs had no role in the suppression of early T cell priming after immunization with Ag. Instead, PSGL-1-deficient Tregs lost the ability to modulate T cell movement and failed to inhibit the T cell–dendritic cell contacts and T cell clustering essential for sustained T cell activation during the late phase of the immune response. Notably, PSGL-1 expression on myelin-specific effector T cells had no role in T cell locomotion in the lymph node. Our data show that PSGL-1 represents a previously unknown, phase-specific mechanism for Treg-mediated suppression of the persistence of immune responses and autoimmunity induction.
Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) are virulent intracellular pathogens that invade and multiply within macrophages. The effect of M. tuberculosis on HIV-1 infection and replication was analyzed in vitro using human monocyte-derived macrophages (MDM) isolated from peripheral blood mononuclear cells by countercurrent centrifugal elutriation. Preinfection of MDM with M. tuberculosis followed by HIV-1 infection resulted in an increase in p24 release, reverse transcriptase activity, and infective virus production. In contrast, no increase in HIV-1 production was observed when MDM were infected with Mycobacterium avium complex or heat-killed M. tuberculosis. Coinfected MDM were potent stimulators of T cell proliferation, while HIV-1-infected MDM failed to present exogenous tuberculin to T cells. Furthermore, coinfected MDM showed an increased capacity to transmit HIV-1 to activated T cells. These results suggest that M. tuberculosis infection can both up-regulate HIV-1 infection and replication within MDM and increase the efficiency of virus transmission from infected MDM to T cells.
SUMMARYHeat-shock proteins (hsp) represent a highly conserved family of proteins, normally localized in the cytoplasm and nucleus, whose expression is induced in situations involving cell stress. This paper reports the unusual translocation of hsp to the cell membrane of T cells undergoing apoptosis. We observed that glucocorticosteroid-induced thymocyte death is associated to the surface expression of hsp 60 and hsp 70 in a discrete fraction of apoptotic cells. hsp surface expression is closely related to a thymic subset of immature CD3 low/7 T cells. The expression of surface hsp 60 appears early after treatment with dexamethasone (3 hr) whereas the membrane expression of hsp 70 follows different kinetics and peaks later. Morphological analysis of the hsp + apoptotic cells suggest that this subset represents late-stage apoptotic cells at their minimal volume before fragmentation into apoptotic bodies. Membrane expression of hsp is also associated with apoptosis in peripheral blood mononuclear cells from AIDS patients cultured in vitro. Altogether, we show that a discrete fraction of cells undergoing apoptosis expresses membrane hsp 60 and hsp 70, supporting the hypothesis that apoptosis causes a radical alteration in the expression of cell surface molecules. Surface hsp expressed during apoptosis may constitute a novel immune-context able to generate packages of self-and exogenous antigens, originating from degradation of altered cells.Heat-shock proteins (hsp) belong to a highly conserved family of proteins normally localized in the cytoplasm and nucleus.
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