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)

It has been proposed that interleukin-6 may play a role in the pathogenesis of autoimmune diseases like lupus erythematosus. We have therefore investigated the immunoreactivity of IL-6 in 32 skin biopsies of 23 patients suffering from chronic discoid lupus erythematosus (n = 16), subacute cutaneous lupus erythematosus (n = 5) and systemic lupus erythematosus (n = 5) as well as in uninvolved skin (n = 6) and in normal skin from healthy volunteers (n = 3). Increased immunohistochemical staining was detectable in 14 of 26 biopsies from lesional skin. The remaining biopsies from lesional, non-lesional and normal skin displayed only minimal or no reactivity, but 8 out of 12 lupus erythematosus patients had been pretreated with local or systemic antiinflammatory drugs. Irrespective of the LE subtype, immunolabelling was generally most intense in the basal layer of the epidermis, with additional intense suprabasal staining in sections from 2 of 5 SLE patients. Preferential production of IL-6 in the lower parts of the epidermis was confirmed by RNA in situ hybridization. No correlation was found between the deposition of immunoglobulins and complement at the dermo-epidermal junction and IL-6 expression in keratinocytes. These data suggest that IL-6 may be involved in LE although its exact role in the pathogenesis of the disease needs to be further elucidated.
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PMID:Interleukin-6 expression in the skin of patients with lupus erythematosus. 775 33

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

When measured serially by Farr assay at a frequency of approximately once a month, changes in levels of anti-dsDNA appear to be a good predictor of clinical disease activity. Although the role of antibodies to the RNA component of snRNP awaits further studies, measurement of anti-UsnRNP antibody levels seems to be of limited value in monitoring lupus patients in clinical practice. The same holds for antibodies to SSA (Ro) and anti-histone antibodies. More recently described antibodies to C1q are probably useful in the follow-up of SLE patients suspected of proliferative renal involvement. The best alternative to measuring levels of the antibodies mentioned before is probably serial analysis of activation of the complement cascade. Levels of complement factors like C3, C4 and, functionally, CH50 remain a useful parameter for monitoring disease activity in SLE, although fluctuations in anti-dsDNA as measured by Farr assay seem superior with respect to sensitivity and specificity for an ensuing relapse. Despite the problems in sampling, measuring levels of activated split products of complement factors like C3a, C3d or C5a may prove to be a valuable tool in the follow-up of lupus patients. The involvement of the endothelial surface is illustrated by rising sVCAM-1 levels prior to relapses in SLE. Although one could expect that subsequent inflammation should be reflected by increased levels of inflammatory molecules like CRP and IL-6, the use of these molecules as predictors of lupus activity seems limited. Interferon-alpha as a direct reflector of the effector phase seems, however, rather promising in this respect and awaits longitudinal studies to analyse the possible relation with clinical disease activity and other serological parameters.
Lupus 1995 Apr
PMID:Serological markers of disease activity in systemic lupus erythematosus. 779 29

Cytokines are important in developmental and effector pathways of lymphocyte function. Our objective was to elucidate the profile of cytokines produced by circulating mononuclear cells from patients with systemic lupus erythematosus as estimated from studies of cytokine-gene activation. cDNA prepared by reverse transcription of lymphocyte mRNA was amplified using the polymerase chain reaction and normalized on the basis of beta-actin gene expression. Of 10 cytokines investigated in 16 individuals, differences between SLE and controls were found in only three. IL-2 transcripts were detected in four of six cases of subjects hospitalized for active SLE, but in only one of seven healthy controls, and none of three cases with pulmonary tuberculosis. By contrast, IL-4 transcripts were decreased compared with healthy controls and patients with tuberculosis. Also, TGF beta transcripts appeared to be decreased in SLE. All individuals studied regularly demonstrated high levels of transcripts for IL-1 beta, IL-6 and TNF alpha and transcripts for IFN gamma, TNF beta, IL-5 and IL-10 were variably expressed. In a second group of six SLE patients with less active disease, there was also a decrease in IL-4 expression compared with six healthy controls. Moreover, assays performed on sera from patients with active SLE revealed that IL-4 levels were not increased. Although in mice this cytokine has a well documented role in supporting antibody production, this study provides no evidence that IL-4 is involved in the B cell hyperactivity characteristic of human SLE.
Lupus 1994 Oct
PMID:Cytokine gene profile in circulating blood mononuclear cells from patients with systemic lupus erythematosus: increased interleukin-2 but not interleukin-4 mRNA. 784 98

The MRL-lpr/lpr and MRL-(++) mice were studied for the expression of cytokines in the spleen, lymph node, thymus, kidney and brain through the reverse transcription-polymerase chain reaction (RT-PCR). The frequencies of IL-4 and TNF-alpha expression in the thymus and spleen were significantly higher in MRL-lpr/lpr mice than in MRL-(++) mice from the age of 17 to 32 weeks. More importantly, IL-4 transcript was demonstrated in the early rather than in the terminal stage of the lupus disease. At the 20th week, MRL-lpr/lpr mice with active disease exhibited higher concentrations of IL-1 alpha, IL-6 and TNF-alpha in serum than MRL-(++) mice. Interestingly, in MRL-lpr/lpr but not MRL-(++) mice, the IL-6 concentration in cultured supernatants of the thymic cells was significantly higher than that of the splenic or lymph node cells. On the other hand, IL-6 and IL-1 beta were expressed in the brain and kidney of MRL-lpr/lpr mice but not of MRL-(++) mice. Cultured MRL-lpr/lpr mesangial cells could also express IL-6 but to a lesser extent. These results suggest that the abnormal splenic and thymic IL-4 and TNF-alpha expression may predispose the development of autoimmune reactions. The expression of IL-1 beta and IL-6 in the brain and kidney may be implicated in the damage of these two organs in MRL-lpr/lpr mice.
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PMID:Abnormal splenic and thymic IL-4 and TNF-alpha expression in MRL-lpr/lpr mice. 786 62

Interleukin-10 (IL-10) is produced at a high level by B lymphocytes and monocytes of patients with systemic lupus erythematosus (SLE). In the present work, we analyzed whether this increased production of IL-10 contributed to the abnormal production of immunoglobulins (Ig) and of autoantibodies in SLE. The role of IL-10 was compared with that of IL-6, another cytokine suspected to play a role in these abnormalities. The spontaneous in vitro production of IgM, IgG, and IgA by peripheral blood mononuclear cells from SLE patients was weakly increased by recombinant IL (rIL)-6, but strongly by rIL-10. This production was not significantly affected by an anti-IL-6 mAb but was decreased by an anti-IL-10 mAb. We then tested the in vivo effect of these antibodies in severe combined immunodeficiency mice injected with PBMC from SLE patients. The anti-IL-6 mAb did not significantly affect the serum concentration of total human IgG and of anti-double-stranded DNA IgG in the mice. In contrast, the anti-IL-10 mAb strongly inhibited the production of autoantibodies, and, to a lesser extent, that of total human IgG. These results indicate that the Ig production by SLE B lymphocytes is largely IL-10 dependent, and that the increased production of IL-10 by SLE B lymphocytes and monocytes may represent a critical mechanism in the emergence of the autoimmune manifestations of the disease.
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PMID:Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. 786 46

IL-6, soluble IL-6 receptor and IgG with anti-IL-6 activity were measured in the plasma of 14 lupus patients and 10 normal subjects. The capacity of peripheral blood mononuclear cells to spontaneously produce IL-6 in vitro was also measured. Our results indicate that IL-6 plasma levels in patient plasma as measured by ELISA were not different from normal but that supernatant levels were significantly lower than normal (P < 0.05). In vitro IgG production was comparable for all lupus patients' cells irrespective of the in vitro IL-6 levels. Plasma soluble IL-6 receptor levels directly correlated with IL-6 production capacity of SLE cells and the ratio of soluble receptor to anti-IL-6 directly correlated with IL-6 production in patients but not in normals. Inhibition assays demonstrated competition between anti-IL-6 and soluble receptors for IL-6 and the inhibition by plasma of IL-6 binding to monoclonal anti-IL-6. We believe the interaction of anti-IL-6 and IL-6 receptor with IL-6 may contribute to the homeostasis in IL-6 activity in vivo and skewing of the soluble receptor/anti-IL-6 ration may contribute to the lupus disease process.
Lupus 1994 Jun
PMID:Anti-interleukin-6 and soluble interleukin-6 receptor in systemic lupus erythematosus. 795 1

Thymopentin (TP-5) is a synthetic pentapeptide that corresponds to the active 32-36 amino acid sequence of the thymic hormone thymopoietin, of which it retains all the immunomodulatory properties. In this study, we have evaluated the effects of long term prophylactic treatment with TP-5 on the clinical, immunological and histological parameters of the SLE-like syndrome that spontaneously occurs in MRL/lpr-lpr (MRL-lpr) mice. TP-5, administered (s.c.) to these mice at the doses of 1, 10 and 100 mg/kg, was given daily, five times a week, from the 9th to the 26th weeks of life. The prophylactic treatment with TP-5 prolonged in a clear dose-dependent fashion the lifespan of MRL-lpr mice as compared with PBS-treated control mice, and the effect reached statistical significance at the doses of 10 and 100 mg/kg. In parallel ex vivo studies, this clinical effect was associated with multiple profound modifications of the immune system including: (i) the reduction of the spontaneous and Con A-induced release of interleukin-4 (IL-4); (ii) the increased secretion of interferon-gamma (IFN-gamma) and IL-6 upon polyclonal mitogenic stimulation, and (iii) the amelioration of the defective Con A-induced lymphoproliferative response. In contrast, although the drug diminished the severity of proteinuria in MRL-lpr mice, it neither reduced histological signs of lupus nephritis nor diminished the serum titres of anti-native DNA and anti-histone autoantibodies. These results indicate that TP-5 displayed powerful immunodulatory activities in a well known model of human SLE.
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PMID:The effects of thymopentin on the development of SLE-like syndrome in the MRL/lpr-lpr mouse. 797 60

We report on a patient with splenic lymphoma of B-cell origin who developed autoimmune hemolytic anemia (AIHA). IgM lambda M-protein, IgM anticardiolipin antibody (ACA), and lupus anticoagulant (LA) were detected in the serum, and direct Coombs' test showed autoantibodies of the IgG1 and IgG2 subclasses on red blood cells (RBC). In in vitro culture, tumor cells isolated from the spleen produced only IgM ACA, which was enhanced by IL-6 but not by IL-4 or IL-5. The levels of ACA and LA decreased after splenectomy and chemotherapy; the strength of the direct Coombs' test, however, did not change. These findings indicated that in this patient the lymphoma cells produced IgM lambda ACA, but not autoantibodies of the IgG1 and IgG2 subclasses against RBC. It was also suggested that IL-6 might at least partially stimulate the production of ACA.
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PMID:Multiple autoantibody production in a patient with splenic lymphoma. 801 67

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.
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PMID:Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. 804 Mar 14


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