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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant tumor necrosis factor alpha (TNF-alpha) administration significantly delayed the development of lupuslike nephritis in the New Zealand black x New Zealand white (NZB x NZW)F1 and to a lesser extent in the MRL-lpr/lpr model systems. TNF-alpha treatment was effective when treatment was initiated at 2, 3, or 4 months of age but was ineffective if initiated as late as 6.5 months of age. Treatment of (NZB x NZW)F1 mice for 3 months was more effective than treatment continued for 6 months. Anti-TNF-alpha antibodies did not develop in these mice. Flow microfluorometry analysis showed no major effects on B, T, or monocyte cell population in cells from the peritoneum, spleen, lymph node, and thymus. A decrease in class II Ia expression on macrophages in the peritoneum of TNF-alpha-treated mice was noticed. A correlation between the level of TNF-alpha inducibility in vitro and the effect of TNF-alpha administration in vivo could be shown. Although a limited polymorphism could be shown by restriction fragment length polymorphism, using an amplified (AC)n microsatellite located in the 5' regulatory region of TNF-alpha, a much more extensive interallelic polymorphism was found. The AC microsatellite allele found in NZW mice was unique and different from other lupus strains and nonautoimmune strains. These results have possible implications to the pathogenesis of systemic lupus erythematosus.
Cytokine 1991 Nov
PMID:Tumor necrosis factor alpha in murine systemic lupus erythematosus disease models: implications for genetic predisposition and immune regulation. 168 13

Autoimmunity (AI) exemplifies the potent and destructive activity expressed by the immune system when normal constraints against self-reactivity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) from young AI-prone mice [1-3]. There are two points in particular that we believe speak to the importance of this observation: (i) Cytokine dysregulation is distinguished from many of the aberrancies reported in AI-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarkably consistent characteristic of M phi from strains that develop manifestations of systemic AI, including MRL/+, NZB, NZB/W F1, BXSB, and NOD, and distinguishes these strains from mice whose disease is predicated on defects in apoptosis (e.g., the lpr and gld mutations). The multigenic basis for disease and renal pathology in the former strains more closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key mediators of lymphocyte growth and function, a defect in the cytokine network has the potential to disrupt the normal regulation of self-reactivity, leading to the initiation of systemic AI.
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PMID:Cytokine dysregulation and the initiation of systemic autoimmunity. 773 85

The nature of the stimuli driving autoantibody production in systemic lupus erythematosus (SLE) is unclear, but cytokines are believed to play an important role. Since cytokines primarily appear to act locally at the tissue level, we analysed mRNA expression of several cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IFN gamma, TNF alpha, TNF beta and TGF beta 1) in the lymph nodes of lupus-prone mice, in models of early onset disease. We constructed a multispecific competitor fragment that allowed quantification of these cytokine transcripts by competitive PCR assay. The results reveal considerable overexpression of IL-1 beta, IL-10 and IFN gamma transcripts in SLE-prone MRL-lpr/lpr (MRL/l) and BXSB male (BXSBm) mice, but with some strain differences. IFN gamma was most markedly augmented in MRL/l mice (in some cases over 100-fold greater than control mice), IL-1 beta was most severely overexpressed in BXSBm mice while IL-10 was equally increased in both strains. In addition, TGF beta 1 expression was moderately elevated in the lymph nodes of BXSBm (but not MRL/l) mice. We found no abnormality in the expression of the other cytokines. Cytokine transcript levels were only slightly altered at 4 weeks of age, but were elevated from 10 to 22 weeks of age. The latter phase corresponds to a period where lupus-like disease escalates, resulting in frequent mortality. Interestingly, our results do not reveal a clear Th1 or Th2 cytokine expression pattern in these lupus-prone mice. IL-1 beta, IFN gamma and IL-10 are pleiotropic cytokines with pro-inflammatory and B-cell stimulatory effects. These results point to certain cytokines as potential targets for immunotherapy in lupus.
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PMID:Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. 778 52

Previous work showed that IFN-alpha induced the autoimmune-associated lupus inclusions (LI) in all 16 umbilical cord mononuclear cell samples from healthy mothers. In contrast, IFN-alpha induced LI and the LI-associated protein, p36, in only 2 of 16 human B lymphoblastoid cell lines. Resistance of these 14 cell lines to form LI and p36 may be due to their stage of development or differentiation or their transformed state. We sought to determine whether aging, neoplastic transformation, and HIV infection affected the observed IFN-alpha induction of LI in cord blood mononuclear cells. Expression of LI and p36 was investigated in PBMC on IFN-alpha chemotherapy and on culturing IFN-alpha with PBMC samples prepared from healthy adults and AIDS patients. The IFN-alpha induction of LI (detected by electron microscopy) or p36 (detected by two-dimensional gels) in all of the PBMC samples from these individuals was indistinguishable from the cord blood mononuclear cell response. Furthermore, induction of p36 and LI was not a good indicator of effective IFN-alpha chemotherapy. It may be consequential for autoimmunity induced by IFN-alpha in cancer, AIDS, and systemic lupus erythematosus (SLE). An essential biologic role for p36 and LI is suggested by a highly homologous p36 gene in the invertebrate Caenorhabditis elegans.
J Interferon Cytokine Res 1996 Sep
PMID:Interferon-alpha-induced human lupus inclusions and p36 protein in cancer and AIDS. 888 55

It is controversial whether mixed connective tissue disease (MCTD) should be regarded as a distinct disease entity. In the present study, we investigated immunological parameters in patients with MCTD by studying serum levels of immunoglobulins, C-reactive protein (CRP) and cytokines and compared the results to the corresponding values in systemic lupus erythematosus (SLE), in rheumatoid arthritis (RA) patients and in healthy controls. Using the ELISA technique, serum levels of the cytokines interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha) were investigated. Cytokine levels in SLE and MCTD were correlated to disease activity as assessed by systemic lupus activity measure (SLAM). They were also correlated to serum levels of CRP, IgG, IgA and IgM in the three patient groups. The MCTD patients had the highest levels of immunoglobulins, followed by the SLE patients. In contrast, the highest CRP levels were observed in RA patients, followed by the MCTD patients. The MCTD patients had the highest serum levels of IL-10, but also had elevated IFN-gamma and TNF-alpha levels similar to the RA patients. There was no correlation between the investigated cytokine levels and disease activity, as assessed by SLAM. We conclude that MCTD patients have high immunoglobulin levels as well as high CRP levels and that this situation is compatible with the observed increase in both type 1 and type 2 cytokine levels. The findings imply that MCTD shares some distinct immunological properties with both RA and SLE and that MCTD may also be considered as a separate disease entity according to these properties.
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PMID:Increased serum levels of immunoglobulins, C-reactive protein, type 1 and type 2 cytokines in patients with mixed connective tissue disease. 980 36

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

Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th(2)cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4(-)CD8(-)T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-gamma level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th(1). The clinical implications of this suppression of autoimmune disease are also discussed.
Cytokine 2000 Jul
PMID:IL-12-encoding plasmid has a beneficial effect on spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. 1088 Feb 49

The apoptosis-defective lpr (fas) mutation in MRL mice causes the early onset of a lupus-like autoimmune disease with concomitant inflammation. In order to analyse the consequences of the impaired Fas-dependent apoptosis on inflammation, the susceptibility to apoptosis of polymorphonuclear leukocytes (PMN), obtained from MRL lpr/lpr mice, has been studied. Peritoneal PMN from lpr/lpr and control (+/+) mice were recruited with a mild inflammatory stimulus. The number of cells collected from the peritoneal cavity of young lpr/lpr mice was comparable to that obtained from age-matched control mice, indicating that PMN homeostasis is maintained regardless of the loss-of-function Fas mutation. Recruited neutrophils were exposed in culture to apoptosis-inducing stimuli. Treatment with agonist anti-Fas antibody increased apoptosis of +/+ PMN, but did not affect lpr/lpr PMN which do not express Fas on their surface. However, lpr/lpr PMN could undergo both spontaneous and stimulus-induced apoptosis in a fashion comparable to or higher than that of control +/+ mice. Analysis of mRNA expression revealed that lpr/lpr PMN have reduced expression of IL-18, whereas IL-1beta, IFNgamma, caspase 1 and caspase 3 are expressed at levels comparable to those of +/+ cells. However, caspase-3-like activity was higher in PMN from lpr/lpr mice than in +/+ cells, and correlated with enhanced apoptosis. It could be concluded that in young, uncompromised lpr/lpr mice, PMN homeostasis is still fully regulated through the involvement of Fas-independent, compensatory, apoptotic mechanisms. This could include an increased participation of caspase 3 in the apoptotic pathway, consequent to enhanced activation of the enzyme and to the decreased production of IL-18, which acts as a competitive caspase 3 substrate.
Eur Cytokine Netw
PMID:Neutrophil apoptosis in autoimmune Fas-defective MRL lpr/lpr mice. 1156 32

We have developed a panel of murine monoclonal antibodies that recognize human interferon alpha. One of these mononclonal antibodies binds and neutralizes, with high affinity, all of seven tested recombinant human interferon alphas. This mononclonal antibody also neutralizes the interferon activity present in two independent pools of interferon alphas prepared following stimulation of human peripheral blood leukocytes. The complementary determining regions from this murine mononclonal antibody were transferred to a human IgG2 heavy chain and to a human kappa1 light chain. In addition, six (heavy chain) and two (light chain) amino acids were transferred from the framework regions. This generated a humanized mononclonal antibody that retained the specificity of the mouse parent. The humanized anti-interferon alpha antibody is a candidate therapeutic for those diseases, such as insulin-dependent diabetes, systemic lupus erythematosis, psoriasis and Crohn's disease, which are all characterized by pathological expression of interferon alpha.
Cytokine 2001 Sep 07
PMID:Characterization and humanization of a monoclonal antibody that neutralizes human leukocyte interferon: a candidate therapeutic for IDDM and SLE. 1159 89

To analyze the Th1 and Th2 paradigm of peripheral T helper cells in patients with systemic lupus erythematosus (SLE). The intracellular Th1 and Th2 cytokines were analyzed in fresh blood T cells from 20 SLE patients who had not yet received any treatment. Th1 and Th2 cells were quantitated based on their intracellular cytokine content as assessed by flow cytometry. Cytokine expressions were correlated with clinical features, laboratory findings, and disease activities. There was no difference in the expression of intracellular IFN-y, or IL-4 between SLE patients and healthy controls. However, the IL-2 and IL-10 levels were significantly higher and lower respectively in the lupus patients than in the control group. In addition, patients with arthritis had higher IFN-gamma expression than patients without arthritis. Moreover, patients with serositis or CNS involvement had higher IL-4 expression than in patients without these manifestations. There was no correlation between the SLEDAI scores and the cytokine expression levels. However, patients with serum anti-ds DNA antibodies had higher IL-10 levels than in those without these antibodies. The present study demonstrates that a Th1 pattern of intracellular cytokines predominates in patients with SLE prior to treatment. The pattern of particular intracellular T cell cytokines may suggest specific clinical manifestations and disease progression of SLE.
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PMID:The expression and significance of intracellular T helper cytokines in systemic lupus erythematosus. 1199 Apr 59


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