Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.
Lupus 1999
PMID:Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. 1002 1

Among various rheumatic diseases, systemic lupus erythematosus and Behcet's disease are frequently complicated with serious neurological involvement, called CNS lupus and neuro-Behcet's syndrome (NB), respectively. CNS lupus includes lupus psychosis, such as organic brain syndrome and non-organic psychosis, as well as non-psychotic CNS lupus, such as epilepsy and focal lesions. Anti-ribosomal P antibody is closely associated with lupus psychosis, whereas anti-phospholipid antibodies appear to be involved in some manifestations of non-psychotic CNS lupus. NB includes acute type and chronic progressive type. Acute NB is characterized by acute meningoencephalitis with focal lesions, which respond to steroid therapy. By contrast, chronic progressive NB is characterized by intractable slowly progressive dementia and/or psychosis with persistent elevation of cerebrospinal fluid IL-6 activity, which is resistant to conventional steroid therapy. However, recent studies suggest the efficacy of low dose methotrexate in chronic progressive NB.
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PMID:[Central nervous system involvement in rheumatic diseases]. 1007 15

The aim of this study was to determine whether the levels of serum cytokines IL-6 and TNFalpha and of the soluble receptors p55 srTNFalpha, p75 srTNFalpha and srIL-2ac are valuable markers of disease activity in patients with systemic lupus erythematosus (SLE) compared with the established parameters of anti-dsDNA, C3, C4 and CH50. Forty patients with SLE, 19 ambulatory and 21 hospitalised, were included in this study. On the day of blood sampling a clinical examination was performed and SLEDAI and ECLAM disease activity scores were used to assess disease activity. Nineteen patients had inactive disease and 21 patients had active disease. Thirteen patients from the second group developed nephritis. In these patients the blood sampling and disease activity assessment were performed twice (at presentation and 6 months after treatment). Serum levels of cytokines and soluble receptors were measured by ELISA. Serum levels of cytokines and soluble receptors of patients with active disease were significantly higher than in patients with inactive disease (IL-6 p = 0.0004, TNFalpha p = 0.0015, srIL-2c p<0.0001, p55 srTNFalpha p<0.0001, p75 srTNFalpha p<0.0001). Serum soluble receptor levels of patients with inactive disease were higher than those of healthy controls (p55 srTNFalpha p<0.0001, p75 srTNFalpha p = 0.0002, srIL-2alpha p = 0.0012). No significant difference was found for TNFalpha and IL-6 (TNFalpha p=0.015, IL-6 p=0.019). Serum TNFalpha levels and especially srIL-2alpha, p55 srTNFalpha( and p75 srTNFalpha levels correlated strongly with SLEDAI and ECLAM disease activity scores, anti-dsDNA, C3, C4 and CH50 (p<0.0001). Serum soluble receptor (srIL-2alphac, p55 srTNFa, p75 srTNFalpha) levels were higher in patients with nephritis before treatment and decreased significantly 6 months after treatment (p=0.005). The same trend was noticed with SLEDAI and ECLAM disease activity scores (p = 0.005) and anti-dsDNA (p = 0.008). In contrast, no significant differences were observed for C3 and C4 levels before and after treatment, which suggests that soluble receptors of cytokines are more sensitive markers of disease activity than C3 or C4 in predicting improvement. Serum levels of srIL-2alpha, p55 srTNFalpha and p75 srTNFalpha could provide useful information about disease activity in SLE patients, especially in cases where the other markers do not.
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PMID:Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. 1008 43

Intraperitoneal injection of pristane induces a lupus-like disease in BALB/c and other non-autoimmune mice characterized by autoantibody production and the development of immune complex disease closely resembling lupus nephritis. Two subsets of autoantibodies are induced by pristane: IgG anti-DNA DNA and -chromatin autoantibodies are strongly IL-6-dependent, whereas IgG anti-nRNP/Sm and -Su antibodies are not. The present studies were carried out to examine the role of T cells in establishing this dichotomy between the production of anti-nRNP/Sm/Su versus anti-DNA/chromatin autoantibodies. Autoantibody production and renal disease were evaluated in athymic (nude) mice treated with pristane. BALB/c nu/nu mice spontaneously developed IgM and IgG anti-single-stranded (ss)DNA and -chromatin, but not anti-nRNP/Sm or -Su, autoantibodies. Pristane treatment increased the levels of IgG anti-chromatin antibodies in nu/nu mice, but did not induce production of anti-nRNP/Sm or -Su antibodies. In contrast, BALB/c nu/+ and +/+ control mice did not spontaneously produce autoantibodies, whereas anti-nRNP/Sm and -Su autoantibodies were induced by pristane in approx. 50% of nu/+ and +/+ mice and anti-DNA/chromatin antibodies at lower frequencies. Nude mice spontaneously developed mild renal lesions that were marginally affected by pristane, but were generally milder than the lesions developing in pristane-treated nu/+ and +/+ mice. The data provide further evidence that two distinct pathways with different cytokine and T cell requirements are involved in autoantibody formation in pristane-induced lupus. This dichotomy may be relevant to understanding differences in the regulation of anti-DNA versus anti-nRNP/Sm autoantibodies in systemic lupus erythematosus, as well as the association of anti-DNA, but not anti-nRNP/Sm, with lupus nephritis.
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PMID:Disparate T cell requirements of two subsets of lupus-specific autoantibodies in pristane-treated mice. 1019 32

The objective of this study was to determine the extent of interleukin (IL)-6, -10 and/or LIF involvement in systemic lupus erythematosus (SLE). Specific ELISA were used to measure cytokines in the supernatants of 48 hours cultures of whole blood stimulated or not by lipopolysaccharide and phytohemagglutinin, from controls (n = 10) or SLE patients divided according to the median of the SLE activity measurements (SLAM): < 9, group 1 (n = 11), and 9, group 2 (n = 10). Comparing median basal and stimulated cytokine concentrations from patients and controls, IL-6 was significantly higher in all SLE patients, IL-10 was significantly higher in both non- and stimulated situations only for SLE group 1 patients. With regard to LIF, it was significantly enhanced only in stimulated cultures of whole blood from group 2 patients as compared to control subjects. In conclusion, the production of cytokines involved in B-cell regulation and inflammation was altered in SLE, and LIF appears to be a potential marker of disease activity.
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PMID:Analysis of interleukin-6, interleukin-10 and leukemia inhibitory factor (LIF) production by peripheral blood cells from patients with systemic lupus erythematosus identifies LIF as a potential marker of disease activity. 1021 Jul 68

The elevated expression of IL-6 and IL-10 may have an important role in SLE pathogenesis. IL-6 production by normal monocytes can be inhibited by IL-10, and it has been suggested that SLE monocytes are refractory to this negative signal. To examine this possibility, the effects of regulatory factors on IL-6 expression by SLE PBMC (N = 51) were compared to effects on control PBMC (N = 21). We found that (1) exogenous rIL-10 and rIL-4 mediated reduction of constitutive and lectin-induced IL-6 in monocytes of SLE patients as effectively as that of controls; (2) IL-6 mRNA decay was significantly delayed in SLE with active disease (P < 0.001); (3) adding rIL-10 or neutralizing endogenous IL-1 beta and TNF-alpha down-regulated IL-6 mainly by destabilizing IL-6 transcripts, whereas exogenous IL-4 and TGF beta 1 down-regulated IL-6 transcriptionally; (4) time kinetics and levels of IL-10 were lower than those of IL-6 and IL-1 beta. Thus, contrary to a previous report, IL-6 production by SLE PBMC responds normally to regulatory signals, and the IL-6 overexpression in SLE may be due, at least in part, to the kinetics and availability of regulatory cytokines.
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PMID:Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC. 1021 49

The toxic oil syndrome (TOS) represents an exogenously induced autoimmune disease with acute or chronic symptoms similar to systemic lupus erythematosus or scleroderma. When genetically different mouse strains were exposed to oleic acid anilide (OAA), it was possible to mimic the different syndrome manifestations. The aim of the present study was to examine the role of NF-kappaB/Rel transcription factors in the development of the severe acute wasting disease observed in A/J mice. Within a week of OAA exposure, the A/J, but not B10.S strain, displayed weight loss, cachexia, apathy, reduced activity, and breathing difficulties. In affected A/J mice we observed a marked increase in NF-kappaB activation (p50/p65 dimers) both in splenic T cells and peritoneal macrophages as well as in tissue from aorta and gut. Incubation of splenocytes with OAA in vitro induced a dose-dependent removal of IkappaB-alpha, accompanied by NF-kappaB activation, whereas Sp-1 binding was not affected. Furthermore, we demonstrated the increased expression of the two NF-kappaB target genes IL-6 and IL-1beta in OAA-exposed mice and a transient OAA-induced accumulation of TNFalpha in vitro. This is the first report which implicates NF-kappaB/Rel in acute forms of chemically induced autoimmune-like disease and may serve as a paradigm for the involvement of this transcriptional system in acute processes associated with autoimmunity, suggesting possible avenues of therapeutic intervention.
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PMID:Involvement of nuclear factor-kappaB in a murine model for the acute form of autoimmune-like toxic oil syndrome. 1037 5

Systemic lupus erythematosus (SLE) is an autoimmune disease most prevalent in women between the ages of twenty and sixty. Successful treatment remains challenging due to a lack of understanding of the underlying mechanisms and multiple symptoms ranging from skin rashes to glomerulonephritis. The pathogenesis of SLE has been linked to a B-cell hyperproliferation unique to afflicted patients. These B-cells generate large quantities of IgG autoantibodies, ultimately capable of leading to lupus nephritis and renal failure. The significance of cytokines in SLE and in murine lupus, a related disease in mice, has been debated, particularly with respect to B-cell activity. Potential roles of auto-regulatory and inflammatory cytokines have been investigated. In particular, IL-6 and IL-10 have been shown to be key factors in regulating autoantibody-secreting B-cell activity in lupus. Here, we will provide a critical overview of our current knowledge of the regulatory roles of these two cytokines in SLE.
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PMID:The roles of interleukin-6 and interleukin-10 in B cell hyperactivity in systemic lupus erythematosus. 1039 Nov 13

Juvenile rheumatoid arthritis (JRA) and juvenile systemic lupus erythematosus (JSLE) are the most common autoimmune rheumatic diseases in children associated with high levels of autoantibodies and immune reactivity. JRA and JSLE are more common in girls. Disease activity is worse in the morning, improves during the daytime and worsens at night suggesting that neuroendocrine immune mechanisms are involved in disease pathophysiology. Adult patients with RA and SLE have excessive levels of prolactin (PL) while cortisol (CS) production is down-regulated for the degree of ongoing inflammation. PL has potent proinflammatory properties. Normal to low levels of cortisol have been observed in children with active JRA despite the high serum levels of IL-6, IL-1 beta, and TNF-alpha, which activate the hypothalamic-pituitary-adrenal axis (HPA). The CS levels are in fact subnormal because inflammatory stress activates the HPA. Normal serum PL levels were seen in children with JRA, most of whom were not active with higher levels in those with active ANA +ve JRA complicated by uveitis. A trend toward high PL levels was seen in 33 children with JSLE. High serum PL levels are seen in patients with active juvenile ankylosing spondylitis (JAS) only. Growth retardation is a feature of JRA. Patients with JRA have low to normal levels of growth hormone (GH) and low levels of insulin-like growth factor 1 (IGF-1). IGF-1 mediates the effects of GH. The observation of low IGF-1 in JRA raises the therapeutic possibility with IGF-1. Overall, high levels of follicle stimulating hormone and luteinizing hormone are found in children with JSLE while the levels in JRA tend to be normal. Testosterone levels are low in patients with JRA. No significant differences in estrogen levels have been found between patients with JRA and those with JSLE and matched controls. There is evidence that the autonomic nervous function is defective in patients with JRA.
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PMID:Neuroendocrine immune features of pediatric inflammatory rheumatic diseases. 1041 95

Prolactin (PL) is a mammotropic neuropeptide produced by the pituitary and extrapituitary cells existing as several isoforms and belongs to the growth and lactogenic hormone family, which includes growth hormone and placental lactogens. The secretion of pituitary PL is under hypothalamic control. The cytokines IL-1, IL-2, and IL-6 also stimulate production, while IFN-gamma and endothelin-3 are inhibitory. PL exerts its effects via PL receptors (PLr) which exist as three isoforms. PL regulates reproduction, osmoregulation, and behavior and has potent immunomodulatory effects. PL is structurally related to members of the cytokine/hematopoietic family such as erythropoietin, GM-CSF, growth hormone, and IL-2 to IL-7. The PLr is a member of the cytokine/hematopoietic receptor family. Interaction of PL with PLr activates the Jak kinases which phosphorylate latent STAT proteins resulting in the activation of transcription. PL counteracts the effects of corticosteroids by enhancing Th1 cellular responses. Perturbations of PL physiology have significant immunologic effects. Hypoprolactinemia impairs immune function while hyperprolactinemia enhances active systemic lupus erythematosus, Reiter's disease, juvenile and adult rheumatoid arthritis (RA), autoimmune thyroiditis, multiple sclerosis, and cardiac allograft rejection. PL gene polymorphisms have now been shown to be linked to RA. Thus, manipulation of PL may have significant clinical utility. Further study of the relationship of the PL/PLr complex, other hormones, and the immune system will provide further insights into the potential therapeutic utility of this complex in immune diseases.
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PMID:Prolactin and neuroimmunomodulation: in vitro and in vivo observations. 1041


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