Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow failure has been regarded as one of the triad of clinical manifestations of paroxysmal noctumal hemoglobinuria (PNH), and PNH in turn has been described as a late clonal disease evolving in patients recovering from aplastic anemia. Better understanding of the pathophysiology of both diseases and improved tests for cell surface glycosylphosphatidylinositol (GPI)-linked proteins has radically altered this view. Flow cytometry of granulocytes shows evidence of an expanded PNH clone in a large proportion of marrow failure patients at the time of presentation: in our large NIH series, about 1/3 of over 200 aplastic anemia cases and almost 20% of more than 100 myelodysplasia cases. Clonal PNH expansion (rather than bone marrow failure) is strongly linked to the histocompatability antigen HLA.-DR2 in all clinical varieties of the disease, suggesting an immune component to its pathophysiology. An extrinsic mechanism of clonal expansion is also more consistent with knock-out mouse models and culture experiments with primary cells and cell lines, which have failed to demonstrate an intrinsic proliferative advantage for PNH cells. DNA chip analysis of multiple paired normal and PIG-A mutant cell lines and lymphoblastoid cells do not show any consistent differences in levels of gene expression. In aplastic anemia/PNH there is surprisingly limited utilization of the V-beta chain of the T cell receptor, and patients' dominant T cell clones, which are functionally inhibitory of autologous hematopoiesis, use identical CDR3 regions for antigen binding. Phenotypically normal cells from PNH patients proliferate more poorly in culture than do the same patient's PNH cells, and the normal cells are damaged as a result of apoptosis and overexpress Fas. Differences in protein degradation might play a dual role in pathophysiology, as GPI-linked proteins lacking an anchor would be predicted to be processed by the proteasome machinery and displayed in a class I H.A. context, in contrast to the normal pathway of cell surface membrane recycling, lysosomal degradation, and presentation by class II HLA. The strong relationship between a chronic, organ-specific immune destructive process and the expansion of a single mutant stem cell clone remains frustratingly enigmatic but likely to be the result of interesting biologic processes, with mechanisms that potentially can be extended to the role of inflammation in producing premalignant syndromes.
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PMID:The relationship of aplastic anemia and PNH. 1243 Sep 20

Severe aplastic anemia (SAA) is an autoimmune disease with destruction of hematopoietic cells by activated T lymphocytes. However, the precise mechanism of cytotoxicity T cells recognizing and attacking CD34(+) cells remains unclear. Here, we investigated the proteome of CD34(+) cells in SAA patients to further explore the pathogenesis of SAA. CD34(+) cells from 29 SAA patients and 20 health controls were isolated by magnetic activated cell sorting. The protein of CD34(+) cells were examined by iTRAQ labeling combination of multidimensional liquid chromatography and tandem mass spectrometry. A total of 156 differential expression proteins in CD34(+) cells were identified. Compared with health controls, 53 proteins were up-regulated and 103 proteins were down-regulated in SAA patients. Specifically, abnormal expression of proteasome subunits, histone variants, dolichyl-diphosphooligosaccharide-protein glycosyltransferase subunit (DAD1) and ATPase inhibitor, mitochondrial isoform 1 precursor(IF1) may relate to the hyperfunction of immune responses and excessive apoptosis of SAA CD34(+) cells.
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PMID:Comparative proteomic analysis of CD34(+) cells in bone marrow between severe aplastic anemia and normal control. 2708 42