Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F(1) model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F(1) mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F(1) splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.
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PMID:Apoptotic splenocytes drive the autoimmune response to poly(ADP-ribose) polymerase 1 in a murine model of lupus. 1718 44

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that are predominantly localized in the bone marrow (BM). Mesenchymal stromal cells (MSCs) give rise to most BM stromal cells that interact with MM cells. However, the direct involvement of MSCs in the pathophysiology of MM has not been well addressed. In this study, in vitro and in vivo migration assays revealed that MSCs have tropism toward MM cells, and CCL25 was identified as a major MM cell-produced chemoattractant for MSCs. By coculture experiments, we found that MSCs favor the proliferation of stroma-dependent MM cells through soluble factors and cell to cell contact, which was confirmed by intrafemoral coengraftment experiments. We also demonstrated that MSCs protected MM cells against spontaneous and Bortezomib-induced apoptosis. The tumor-promoting effect of MSCs correlated with their capacity to enhance AKT and ERK activities in MM cells, accompanied with increased expression of CyclinD2, CDK4, and Bcl-XL and decreased cleaved caspase-3 and poly(ADP-ribose) polymerase expression. In turn, MM cells upregulated interleukin-6 (IL-6), IL-10, insulin growth factor-1, vascular endothelial growth factor, and dickkopf homolog 1 expression in MSCs. Finally, infusion of in vitro-expanded murine MSCs in 5T33MM mice resulted in a significantly shorter survival. MSC infusion is a promising way to support hematopoietic recovery and to control graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation. However, our data suggest that MSC-based cytotherapy has a potential risk for MM disease progression or relapse and should be considered with caution in MM patients.
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PMID:Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo. 2210 54