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)

Autoantibodies to the recombinant extracellular domain of epidermal growth factor receptor (exEGFR) were detected by ELISA in the serum of Fas-defective old MRL/MpJ/lpr and C3H/HeJ/gld mice, but not young mice from these strains, or nonautoimmune young and old BALB/c, MRL/MpJ/++, and C3H/HeJ/MMTV mice. Compared with control human subjects without autoimmune disease, the frequency of exEGFR-binding autoantibodies was increased in scleroderma (systemic sclerosis) patients and to a lesser extent in lupus patients. Phage autoantibodies (Fv fragments) isolated from a lupus library by selection on a linear epitope of EGFR (residues 294-310) displayed the ability to bind exEGFR. Treatment of EGFR-expressing A431 cells with autoantibodies purified by affinity chromatography on immobilized exEGFR resulted in specific staining of the cells. Short-lived but strong inhibition of cellular DNA synthesis was observed in the presence of the autoantibodies. We concluded that autoantibody responses to EGFR hold the potential of fulfilling a pathogenic role in autoimmune disease.
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PMID:Autoantibodies to the epidermal growth factor receptor in systemic sclerosis, lupus, and autoimmune mice. 1255 92

As in many humans suffering from lupus erythematosus, the development of systemic autoimmunity and inflammation in Fas-deficient MRL-lpr mice is accompanied by CNS dysfunction of unknown etiology. Experimental studies revealed infiltration of lymphoid cells into the choroid plexus, reduced neuronal complexity, retarded brain growth, and enlargement of cerebral ventricles. Moreover, an increased presence of cells with nicked-DNA (TUNEL+ cells) in the periventricular areas suggested accelerated apoptosis in brain cells of MRL-lpr mice. However, direct evidence that the dying cells were neurons was lacking. For this purpose, we presently use Fluoro-Jade B (FJB), a novel fluorescent dye which has high affinity for dying neurons (both apoptotic and necrotic). As expected, in comparison to the control groups, the brains of diseased, 5-month-old MRL-lpr mice showed increased numbers of FJB-positive (+) cells in cortical and periventricular regions. The FJB+ cells were significantly more numerous than TUNEL+ cells, and only approximately 7% co-localized with TUNEL. Immunostaining for CD4 and CD8 markers did not correlate with the number of FJB+ cells, suggesting that T-lymphocyte infiltration into the brain tissue is not a reliable predictor of neuronal demise. Conversely, indices of systemic autoimmunity (splenomegaly and high serum anti-nuclear antibody levels) were associated with increased FJB+ cell numbers in brains of autoimmune MRL-lpr mice, supporting the causal link between autoimmunity and neurodegeneration. Taken together, the above results suggest that factors other than T-cell infiltration and cell death mechanisms other than Fas-mediated apoptosis dominate neuronal degeneration in lupus-prone MRL-lpr mice.
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PMID:Neurodegeneration in autoimmune MRL-lpr mice as revealed by Fluoro Jade B staining. 1257 80

Peripheral T cell apoptosis is upregulated in active SLE, in parallel with high expression of both membrane-bound and soluble (s) Fas. Previous studies postulated that sFas down-regulates apoptosis in vitro through its blockade of the Fas-L of cytotoxic cells. We have investigated the extent of apoptosis and sFas levels in 14 patients with active (group A) and 11 with inactive SLE (group B). Fas was predominantly expressed by CD3+ cells from group A, whose increased serological levels of sFas were linearly correlated with the TUNEL positive cell population, whereas low titers paralleled a mild level of apoptosis in group B. This association was also investigated by measuring the effect of sFas on both cell proliferation and caspase activation. We found that incubation with sFas greatly suppressed proliferation of CD3+ cells, especially in group B, and in control cells from healthy donors whose content of CPP32 active products was significantly increased. We postulate that sFas promotes a pro-apoptogen effect, which would explain the high susceptibility to apoptosis in active lupus, and that the apoptosis program itself includes release of sFas to spread the death signal.
Lupus 2003
PMID:Enhancement of T cell apoptosis correlates with increased serum levels of soluble Fas (CD95/Apo-1) in active lupus. 1258 20

Type I Interferons (IFN-I) are immunoregulatory cytokines that enhance activation and survival of many cellular components of the immune system. In the present work, we evaluated the effect of IFN-I on the development of the lymphoproliferative disorder in Fas-defective lpr mice. We report that sustained injection of polyinosinic:polycytidylic acid, a potent inducer of IFN-I, in B6 lpr mice resulted in a dramatic aggravation of the renal disease, higher titers of autoantibodies, a 10-fold increase in serum Ig and accumulation of activated lymphocytes. Moreover, introducing a null mutation for the IFN-I-Receptor gene into the lpr background resulted in dramatic decrease of immune complexes deposition in the kidney and reduced lymphadenopathy. While several recent reports correlated serum levels of IFN-alpha with disease activity in systemic Lupus erythematosus patients, our findings establish a causal link from IFN-I production to the onset and severity of another related autoimmune syndrome.
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PMID:Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. 1260 9

Autoimmune disease in MRL-Fas(lpr) mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-gamma-secreting T cells, and 2) MRL-Fas(lpr) mice deficient in the IFN-gamma receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas(lpr) mice reduces IFN-gamma-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Fas(lpr)(IL-12(-/-)) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12(-/-) mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4(+), CD8(+), CD4(-)CD8(-)B220(+)) and macrophages was dramatically reduced in IL-12(-/-) MRL-Fas(lpr) kidneys. We determined that there were fewer IFN-gamma transcripts (>70%) in the IL-12(-/-) protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12(-/-) MRL-Fas(lpr) kidneys generated substantially less IFN-gamma when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-gamma in these IL-12(-/-) MRL-Fas(lpr) kidneys. Of note, survival was modestly extended in the IL-12(-/-) MRL-Fas(lpr) mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12(-/-) MRL-Fas(lpr) mice, renal pathology and IFN-gamma expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.
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PMID:IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. 1264 61

The immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) was cleaved by purified IgG from Fas-defective C3H/gld mice, lupus patients, and autoimmune thyroiditis patients. No VIPase activity was detected in IgG from control mice and humans. Kinetic analyses of VIPase IgG preparations suggested low-affinity recognition of VIP. Yet the VIPase activity was VIP selective, judged by lack of correlation with other protease activities expressed by the IgG and by noninterference of unrelated peptides in the activity. Recombinant Fv constructs selected from a human lupus phage show library displayed VIPase activity, confirming that the active site is located in the V domains. Inhibition of the VIPase activity by di-isopropylfluorophosphate suggested a serine protease-like mechanism of catalysis. Irreversible binding of a biotinyated phosphonate diester by the IgG and Fv preparations was observed, consistent with the presence of activated nucleophiles similar to those in enzymes capable of covalent catalysis. These observations show that VIP is a target for specific catalytic autoantibodies in autoimmune disease.
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PMID:VIPase autoantibodies in Fas-defective mice and patients with autoimmune disease. 1266 75

The sympathetic nervous system is one of the major pathways involved in immune-neuroendocrine interactions. Disturbances in these interactions are likely to have consequences during lymphoproliferative diseases. Work derived from our group as well as from several others led us to the hypothesis that the overstimulation of the immune system that characterizes this type of pathology results in decreased sympathetic nerve activity in lymphoid organs. To explore this possibility, we used as a model lpr/lpr mice, which develop a genetically determined autoimmune, lupus-like lymphoproliferative disease. We show that 18-week-old female C57Bl/6J lpr/lpr mice, which do not show overt symptoms of the disease but already have increased IgM and IgG2a levels in the blood, have decreased noradrenaline (NA) concentration and content in the spleen, but not in the kidney, as compared to normal C57Bl/6J littermates. Lpr/lpr mice do not express normal Fas, and therefore apoptosis cannot be triggered through this receptor. The defects in sympathetic innervation in the spleen of lpr/lpr mice prompted us to evaluate whether NA could influence lymphoid cell mass by inducing apoptosis. We found that NA can directly induce apoptosis in normal lymphoid cells via beta-adrenergic receptors. From the reported results we propose that reduction in sympathetic nerve function in lpr/lpr mice contributes to aggravation of the disease and suggest that in addition to the incapacity to mount Fas-mediated apoptosis, a second proapoptotic mechanism, namely, that triggered by NA, is defective in these animals because of reduced availability of the neurotransmitter.
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PMID:Sympathetic abnormalities during autoimmune processes: potential relevance of noradrenaline-induced apoptosis. 1279 55

Lymphocyte development, selection, and education are strictly controlled to prevent autoimmunity, with potentially autoreactive cells being removed by apoptosis. Dysregulation of apoptosis is a central defect in diverse murine autoimmune diseases. In murine models of autoimmune lupus, for example, mutations in the death receptor Fas (CD95) or in its ligand, FasL (CD95L), have been identified and shown to render lymphoid cells resistant to apoptosis. In contrast, select lymphoid subpopulations of mice with autoimmune diabetes manifest an increased susceptibility to apoptosis as a result of impaired activation of the transcription factor nuclear factor-kappa B (NF-kappaB), which normally protects cells against tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. The genetic basis of this defect in NF-kappaB activation is a mutation in the promoter-enhancer region of a gene that encodes an essential subunit (LMP2) of the proteasome. Although no specific genetic defects have been identified in most common forms of human autoimmune disease, functional assays consistently demonstrate heightened apoptosis attributable to multiple death signaling pathways.
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PMID:Role of defective apoptosis in type 1 diabetes and other autoimmune diseases. 1279 17

MRL/MpTn-gld/gld (MRL/gld) mice, which are deficient in a functional Fas ligand (FasL), spontaneously develop autoimmune diseases involving both lethal glomerulonephritis and systemic arteritis, while MRL/Mp-+/+ (MRL/+) and C3H/HeJ-gld/gld (C3H/gld) do not. To determine the cells responsible for the development of glomerulonephritis and arteritis, we transferred bone marrow cells from MRL/gld mice to undiseased MHC-compatible gld/gld or +/+ mice. In bone marrow irradiation chimeras, MRL/gld bone marrow cells were transferred to lethally irradiated MRL/+ or C3H/HeJ-+/+ (C3H/+) mice, and both recipients developed glomerulonephritis associated with hypergammaglobulinemia without causing graft-versus-host (GVH)-like diseases. However, a striking difference between them was that MRL/+ recipients developed arteritis, but C3H/+ recipients did not. In bone marrow mixed chimeras formed by transferring MRL/gld bone marrow cells to unirradiated mice, the MRL/gld bone marrow cells induced glomerulonephritis in C3H/gld mice, but not in C3H/+ and MRL/+ mice. These results indicate that bone marrow cells from MRL/gld mice can cause glomerulonephritis in mice, even in those with a C3H background, possibly if they survive longer by escaping from Fas-mediated apoptosis, while the development of arteritis requires the MRL genetic background in the recipients. This is the first report of the transfer of arteritis in lupus mice to undiseased recipients.
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PMID:Bone marrow cell transfer of autoimmune diseases in a MRL strain of mice with a deficit in functional Fas ligand: dissociation of arteritis from glomerulonephritis. 1289 30

The expression of muH chain is an important checkpoint in B cell development. In mice deficient for IgM transmembrane tail exons (muMT mice) B cell development is blocked at the pro-B stage. However, we showed that Fas-deficient muMT mice (muMT/lpr) develop a very small population of isotype-switched B cells and produce high titers of self-reactive serum antibodies. In addition, muMT/lpr mice develop severe lymphoproliferation and both pathologic processes occur at young ages. This may suggest that lack of Fas-Fas ligand signaling exacerbates murine lupus in B cell lymphopenic mice. To test this we analyzed antibody and plasma cell formation, and accumulation of abnormal T cells in muMT/lpr mice. Our results show that the muMT/lpr mouse is particularly permissive for the development and accumulation of antibody-producing cells, thereby explaining the high titers of serum antibodies in these mice. In addition, we found that accumulating cells in spleen and lymph nodes of muMT/lpr mice are alphabeta T cells expressing the abnormal B220+/CD3+ surface markers, a phenotype also described for other Fas-deficient mouse models. Strikingly, we found that accumulating cells in muMT/lpr mice express the membrane proteoglycan syndecan-1, a known plasma cell marker. Development of these cells is blocked in mice deficient for TCRbeta and TCRdelta. We also found that both antibody production and lymphoproliferation in muMT/lpr mice are Th1 regulated. Our results, therefore, suggest that in the muMT/lpr mouse model a small population of isotype-switched B cells is sufficient for the initiation and propagation of Th1-regulated murine lupus.
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PMID:Increased plasma cell frequency and accumulation of abnormal syndecan-1plus T-cells in Igmu-deficient/lpr mice. 1291 56


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