Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three independent mutations involving the apoptosis-1 (APO-1)/Fas receptor or its putative ligand have led to lupuslike diseases associated with lymphadenopathy in different strains of mice. To determine whether humans with SLE also have a defect in this apotosis pathway, we analyzed the expression of APO-1 on freshly isolated blood mononuclear cells and on lymphocytes activated in vitro using flow cytometry and the monoclonal antibody anti-APO-1. Significantly higher level of APO-1 expression were detected on freshly isolated peripheral B cells and both CD4+ and CD8+ T lymphocyte populations obtained from lupus patients when compared with normal controls (P < 0.001). Almost 90% of the cells that stained positive for APO-1 also expressed the CD29 antigen, suggesting that APO-1 was upregulated after lymphocyte activation in vivo. No defect in APO-1 regulation was detected after activation of SLE T (with anti-CD3) or B (with Staphylococcus aureus Cowan 1) lymphocytes in the presence of IL-2 in vitro. Similarly, the anti-APO-1 antibody induced apoptosis in 74 +/- 5% of activated SLE T cells in vitro compared with 79 +/- 6% of the normal controls (P > 0.05). These results reveal that, while APO-1/Fas may play an important role in the regulation of lymphocyte survival in SLE, no consistent defect in the expression or function of the receptor could be detected in these studies.
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PMID:The apoptosis-1/Fas protein in human systemic lupus erythematosus. 751 Jul 16

Fast antigen is a cell surface protein that mediates apoptosis. Using immunohistological, flow cytometry and electron microscopic analyses, we investigated the expression of Fas antigen on various skin tissues, and on cultured SV40-transformed human epidermal keratinocyte cell line KJD and human skin squamous cell carcinoma cell line HSC. The Fas antigen was widely distributed in skin components such as the keratinocytes in the lower portion of the epidermis, epidermal dendritic cells, endothelial cells, fibroblasts, apocrine glands, eccrine sweat glands, sebaceous glands, some normal melanocytes and infiltrating lymphoid cells. It was also strongly expressed on the keratinocytes of lichenoid eruptions seen in lupus erythematosus and lichen planus, and on the spongiotic or acanthotic epidermis seen in chronic eczema, adult T-cell leukaemia/lymphoma (ATLL) and atopic dermatitis. Its expression was closely correlated with lymphoid infiltrating cells and it was strongly expressed in lymphoid neoplastic cells, particularly ATLL cells, and fibroblasts seen in dermatofibroma. However, the antigen was not detected on basal cell epithelioma cells, some malignant melanomas or any junctional naevi. The cell lines KJD and HSC strongly expressed the Fas antigen, and crosslinking of the Fas antigen by an anti-Fas monoclonal antibody induced apoptosis of these cell lines. These results indicate that the apoptosis-mediating Fas antigen may play an important role in normal skin turnover and cell differentiation, in immune regulation of skin tumours, and in the pathogenesis of various skin diseases.
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PMID:Distribution of apoptosis-mediating Fas antigen in human skin and effects of anti-Fas monoclonal antibody on human epidermal keratinocyte and squamous cell carcinoma cell lines. 752 80

Cells of the immune system are, most likely, programmed to die unless recruited into an immune response. An active cell death program may also be induced by a variety of soluble and surface signals, many of which have only recently been recognized. The importance of these pathways in maintaining tolerance is highlighted by the development of lupus-like diseases in three different mouse strains that have spontaneous mutations in the Fas/APO-1 receptor or its ligand. The known function of Fas/APO-1 in signalling apoptosis explains the persistence of self reactive cells in lpr mice although it is unclear, at present, whether Fas defects effect both central and peripheral tolerance. Whereas Fas/APO-1 receptor expression appears to be normal in humans with SLE, other defects in the Fas/APO-1 pathway or other key molecules in the cell death survival require further study.
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PMID:Apoptosis in SLE--too little or too much? 753 Nov 24

To define age-associated alterations in the immune system at the molecular level, we have analyzed TCR V beta gene expression patterns at the fetal, neonatal, adult, and advanced ages of mice. In contrast to V gamma and VH genes, V beta genes rearranged without any preference related to their chromosomal organization. Endogenous superantigen-mediated clonal deletions were registered for the first time at the neonatal stage, presumably reflecting the late developmental appearance of these molecules. Such deletions, once established, were maintained throughout life with little, if any, leakage in this process. Furthermore, bone marrow transplantation and other studies indicated that an involuted thymus maintained its capacity to perform both its functions, i.e. positive and negative selection. Although overall V beta repertoires showed remarkable stability with advanced age, modifications in expression levels for some V beta, particularly those associated with the CD8 subset and presumably reflecting antigenic stimulation, were recorded. Mice with lupus and early-life thymic involution were fully capable of deleting endogenous superantigen-reactive V beta clones, and even lupus mice with a genetic defect in the apoptosis-promoting Fas gene were normal in this regard. The results indicate that, aside from some anticipated clonal expansions induced by antigenic stimulation, age-associated alterations in immune functions are not caused by any profound changes in the overall TCR repertoire.
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PMID:V beta gene repertoire in the aging mouse: a developmental perspective. 759 12

The lymphoproliferation (lpr) mutation in the MRL strain of mice is caused by the insertion of the early transposable element ETn in the Fas gene. The insertion causes a striking decrease in Fas mRNA expression and is associated clinically with marked acceleration of the lupus-like disease. To further explore the role of the Fas protein in T-cell selection in the thymus and tolerance in the peripheral immune system, we produced a monospecific polyclonal anti-murine Fas antibody that binds to a polymorphic region of the protein. Fas protein expression was detected on approximately 90% of BALB/c and MRL +/+ thymocytes, and the expression was highest on CD4+CD8+ thymocytes, the stage at which most thymocytes die by apoptosis. In contrast to the high level of expression of Fas on thymocytes, Fas was detected on < 10% of normal splenic T cells. After activation of splenic T cells with Con A or anti-CD3 and interleukin 2, Fas expression increased approximately 10-fold. Fas expression on splenic B cells was also markedly up-regulated after activation with lipopolysaccharide or anti-mu antibodies. The Fas protein was not detected on resting or activated lymphocytes obtained from MRL lpr/lpr mice. Together, these findings suggest that Fas plays a role in both thymic selection and T-cell survival in the periphery and that the accelerated autoimmunity in MRL lpr/lpr mice results from a defect in both of these pathways.
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PMID:The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. 769 92

Human systemic lupus is a heterogeneous disorder characterized by multisystem inflammatory disease and the production of a variety of autoantibodies. For many years, in our ignorance, we had the freedom to imagine numerous abnormalities which might give rise to lupus: defects of the immune system, viruses, major histocompatibility driven predispositions, complement or complement receptor defects, biochemical abnormalities, impaired DNA repair, sex hormone imbalances, and many others. Now, the basis for lupus in lpr/lpr mice has been uncovered: a mutation in fas. The normal Fas cell surface molecule is important in programmed cell death, apoptosis. The lpr-associated defect in Fas interferes with normal apoptosis, allowing persistence of self-reactive lymphocytes. This finding is especially exciting to those of us who have stressed lupus-associated defects in tolerance. It also illustrates the apparent antigen-nonspecific nature of an etiologic abnormality leading to lupus. The multigenic NZB disorder is less well dissected. Recent work points to defects in an unusual bone marrow progenitor population. Patients with systemic lupus erythematosus may have different and multiple pathogenic factors, including those listed above. We recently have found that some patients with lupus have persistence of T cells with random mutations, consistent with prior abnormal activation and, perhaps, impaired apoptosis. Future therapies of patients must consider both the heterogeneity and the multifactorial pathogenesis of the syndrome we call "lupus."
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PMID:Systemic lupus erythematosus: theories of pathogenesis and approach to therapy. 805 Jan 89

Fas, a member of the tumor necrosis factor receptor family, can induce apoptosis when activated by Fas ligand binding or anti-Fas antibody crosslinking. Genetic studies have shown that a defect in Fas-mediated apoptosis resulted in abnormal development and function of the immune system in mice. A point mutation in the cytoplasmic domain of Fas (a single base change from T to A at base 786), replacing isoleucine with asparagine, abolishes the signal transducing property of Fas. Mice homozygous for this mutant allele (lprcg/lprcg mice) develop lymphadenopathy and a lupus-like autoimmune disease. Little is known about the mechanism of signal transduction in Fas-mediated apoptosis. In this study, we used the two-hybrid screen in yeast to isolate a Fas-associated protein factor, FAF1, which specifically interacts with the cytoplasmic domain of wild-type Fas but not the lprcg-mutated Fas protein. This interaction occurs not only in yeast but also in mammalian cells. When transiently expressed in L cells, FAF1 potentiated Fas-induced apoptosis. A search of available DNA and protein sequence data banks did not reveal significant homology between FAF1 and known proteins. Therefore, FAF1 is an unusual protein that binds to the wild type but not the inactive point mutant of Fas. FAF1 potentiates Fas-induced cell killing and is a candidate signal transducing molecule in the regulation of apoptosis.
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PMID:A Fas-associated protein factor, FAF1, potentiates Fas-mediated apoptosis. 852 70

New Zealand Black (NZB) mice spontaneously develop autoimmune disease, usually characterized by an autoimmune hemolytic anemia, and NZB genes are essential for a severe systemic lupus-like disease in (NZB x NZW)F1 mice. We have found that resting B cells from NZB mice demonstrate a pronounced defect, compared with five normal strains, in apoptosis induction after cross-linking with anti-IgM Abs. In contrast, spontaneous apoptosis of NZB B cells in culture was similar to normal strains. B cells from young (NZB x SM/J)F1 and (NZB x NZW)F1 mice underwent apoptosis normally, indicating that the NZB defect in apoptosis is a recessive trait. However, older (8-32 wk) predisease (NZB x NZW)F1 mice manifested a similar defect in apoptosis induction. The analysis of NXSM recombinant inbred mice derived from NZB and SM/J, in addition to backcross mice, suggested that the NZB apoptosis defect is a multigenic trait. Interestingly, resting B cells form B6.lpr and B6gld mice underwent apoptosis following anti-IgM treatment at a level similar to that of the C57BL/6 parental strain. Thus, the induced apoptosis of resting B cells and the NZB defect are likely not related to either Fas or Fas ligand. We propose that this phenotypic defect in apoptosis induction, or the biochemical alteration that underlies the defect, may be casually related to autoimmune disease in NZB mice and its contribution to lupus-like disease in (NZB x NZW)F1 mice.
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PMID:Resting B cells from New Zealand Black mice demonstrate a defect in apoptosis induction following surface IgM ligation. 866 26

Apoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the thymuses enlarged until in 5-month-old females the average weight was three times that at 1 month, and spleen and kidney weights also increased in size disproportionately. At light microscope level apoptotic cells in tissue sections were counted using both routine eosin and haematoxylin staining (to identify them by their morphology) and in situ end-labelling of cells with DNA strand breaks; their presence was further confirmed by electron microscopy. As the mice aged, the numbers of apoptotic cells in thymic cortex, thymic medulla and spleen white pulp areas reduced significantly (P < 0.01-0.001), whereas in BALB/c normal controls they increased significantly (P < 0.05). These changes were coincident with the development of severe lupus, whose activity was assessed by measuring serum anti-ssDNA and anti-dsDNA antibody titres and urinary protein (albumin) level which were elevated significantly by 5 months of age (P < 0.001 for both ssDNA and dsDNA and P < 0.01 for urine albumin) compared with their younger counterparts. Thus, lymphoid organ enlargement, decrease in apoptotic indices, elevated serum anti-ssDNA and anti-dsDNA antibody levels, and impaired renal function coincided with the onset and severity of lupus disease in lpr mice. It seems likely that there is a causal relationship between defective deletion of autoreactive lymphoid cells, imperfect Fas-mediated apoptosis and development of murine SLE.
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PMID:An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE). 870 39

Studies from our laboratory indicate that n-3 (fish oil, FO) lipids at 10% (w/w) in a nutritionally adequate, semipurified diet, and supplemented with equal levels of antioxidants, extended the life span of lupus-prone (NZB/NZW)F1 (B/W) female mice as compared to n-6 (corn oil, CO) lipids. The early rise of autoimmune disease in CO-fed mice was closely linked to the loss of T-cell function. Both IL-2 production and IL-2 receptor expression were reduced due to the loss of naive T-cells and a rise in memory T-cells. Proliferative response to both mitogens and superantigens (staphylococcal enterotoxins A and B) was higher in FO-fed 6.5-mon-old mice. These changes paralleled decreased PGE2 production by splenic cells from FO-fed mice. Analysis of mRNA expression in different organs revealed differential effects of dietary lipids. In FO-fed mice, transforming growth factor beta 1 (TGF beta 1) expression was decreased in kidneys, but splenic tissues had higher expression of TGF beta mRNA. As TGF beta promotes programmed cell death (PCD), we studied the effects of CO and FO on PCD rates in lymphocytes. Both propidium iodide staining and DNA fragmentation were elevated in lymphocytes of FO-fed mice when compared to CO-fed mice of similar age. Also, increased PCD correlated closely with increased Fas gene expression. Thus, in addition to various other antiinflammatory effects, dietary FO appears to increase PCD and prevent accumulation of self-reactive immune cells in lymphoid organs. Further studies are required to dissect the pro- and antiinflammatory mechanisms associated with dietary n-3 and n-6 lipids in modulating autoimmune disorders or malignancy during aging.
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PMID:Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids. 872 1


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