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

We have studied the ability of the lupus prone MRL lpr/lpr (MRL/lpr) and (NZBxNZW)F1 (NZB/W) female mice to raise granulocyte mediated inflammatory responses. These autoimmune strains, known to exhibit severe anergy as concerns T cell dependent immune function, are not well analysed with respect to neutrophil-mediated inflammatory responses. An in vivo model of granulocyte mediated inflammation has been developed in our laboratory. A single intradermal injection of olive oil into mouse footpad induces massive infiltration of polymorphonuclear cells (PMNC) within 24 h. This extravasation of PMNC gives rise to a localized footpad swelling, which can be easily and reproducibly measured and relates to severity of the inflammatory process. T cell independence of this inflammatory model was ascertained by in vivo T cell depletion using monoclonal antibodies to CD4 and CD8 molecules. Olive oil triggered inflammation was inducible in both young and aged lupus mice. The intensity of footpad swelling upon olive oil injection was similar in lupus mice and in healthy control strains. In contrast, aged MRL/lpr and NZB/W mice showed severely depressed T cell dependent inflammatory responses as assessed by delayed type hypersensitivity reaction to sheep red blood cells. We conclude that the PMNC mediated inflammatory potential is not affected in severely diseased lupus mice. The increased numbers of circulating PMNC together with intact PMNC function may explain why severely immune deficient lupus mice seldom show clinical signs of bacterial infection.
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PMID:Neutrophil mediated inflammatory response in murine lupus. 832 62

A 34-year-old woman had suffered from systemic lupus erythematosus (SLE) and autoimmune hemolytic anemia (AIHA) in the teen age. She developed progressive ptosis of the eyelids, and difficulty in swallowing and speaking for several years. Endocrinological studies showed primary hypothyroidism. A serum IgG level was elevated (1,973 mg/dl), and antinuclear antibody, thyroid test and microsome test were positive. A muscle biopsy showed massive inflammatory cell infiltrates in the perivascular area in addition to some myopathic change; some variation in fiber size. Immunological staining demonstrated most of these inflammatory cell infiltrates were CD3+ cells and CD4+ cells were counted more than CD8+ cells (CD4/CD8 = 2.3). The diagnoses were confirmed as oculopharyngeal myopathy and Hashimoto's disease. In addition, she had suffered from SLE and AIHA. Therefore we conclude that manifestation of this myopathy may be associated with some autoimmune process.
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PMID:[Oculopharyngeal myopathy with autoimmune disease]. 833 98

Relative reactivity of anti-lymphocyte autoantibodies (ALA) from patients with systemic lupus erythematosus (SLE) against CD4+ and CD8+ T cells was studied using C-dependent microcytotoxicity assay. Of 46 SLE sera screened for anti-T cell autoantibodies, 27 sera (59%) showed significant cytotoxic reactivity. Of these, positive correlation between the titer of anti-T cell antibody and CD4/CD8 killing ratio (p < 0.01) was demonstrated. In time course study of individual patients, the CD4/CD8 killing ratio increased and decreased as the disease flared and subsided and was accompanied by parallel changes in the titer of anti-T cell antibody titer. Moreover, as sera were serially diluted, the CD4/CD8 killing ratio decreased in 5 out of 10 sera. These results suggest that discrepancy among reports concerning the subset specificity of anti-T cell antibodies may be due, in part, to differences in the titer of ALA in the sera studied and to the dilution of serum used.
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PMID:Changes in subset specificity of anti-T cell autoantibodies in systemic lupus erythematosus. 834 69

We estimated the concentration of soluble IL-2R (sIL-2R) in the serum of patients with systemic lupus erythematosus (SLE) and examined the relationship between the serum levels of sIL-2R and clinical features or laboratory data. We found that elevated levels of sIL-2R were present in the serum of SLE patients with discoid rash, and sIL-2R concentrations were correlated with the soluble CD4 and soluble CD8 concentrations but not with classical serological marker, anti-DNA antibody or complement titer.
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PMID:Increased soluble IL-2 receptor in serum of patients with systemic lupus erythematosus. 835 79

To further understand the contribution of I-A to the development of disease in murine lupus, we compared the incidence and/or titers of natural thymocytotoxic autoantibodies (NTAs), autoantibodies to red blood cells, gp70 immune complexes (gp70), antibodies to Sm, and rheumatoid factor in NZB (H-2d), NZB.H-2b and NZB.H-2bm12 mice. There were striking and significant differences among the three NZB strains in several of these parameters. NZB (H-2d) and NZB.H-2bm12 mice had a 100% incidence of NTA. In contrast, NZB.H-2b mice were found to have NTA in only 36% of animals at 8-10 months of age. Furthermore, the NTA titers of NZB.H-2bm12 mice were relatively low. There were also distinct differences between these strains with respect to the presence of antibodies to anti-erythrocytes (positive Coombs' test). NZB (H-2d) and NZB.H-2bm12 both had high titers of anti-erythrocyte autoantibodies (AEAs), whereas there was a delayed onset and lower titers in NZB.H-2b mice. Additionally, there was a dramatic increase in gp70 IC levels in NZB.H-2bm12 mice. In previous studies, NZB.H-2bm12 as well as NZB.H-2bm12 x NZB.H-2b F1 mice were found to produce high autoantibody titers to single-stranded (ss) and double-stranded (ds) DNA. Using unfractionated or fractionated splenic T cells (CD4+ CD8-, CD4- CD8+, or CD4-CD8-) from NZB.H-2b or NZB.H-2bm12 mice, we compared their relative abilities to cooperate with T-depleted splenocytes from NZB.H-2bm12 x NZB.H-2b F1 mice to produce antibodies to ss- and ds-DNA. Only T cells, including both CD4+ CD8- and CD4- CD8- populations, from NZB.H-2bm12 mice, were able to induce such autoantibody production among F1 splenocytes. Finally, marked alterations in splenic T cell subsets were found in NZB.H-2bm12 mice compared to NZB.H-2b mice, and to a lesser extent, in B6.C-H-2bm12 mice compared to C57BL/6 (H-2b) mice. These data further highlight the influence of I-A on autoimmunity and in particular the influence of the bm12 mutation on altering the natural history of disease expression in NZB mice.
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PMID:The contribution of I-Abm12 to phenotypic and functional alterations among T-cell subsets in NZB mice. 838 89

Necrotizing leucocytoclastic vasculitis is the histopathological hallmark of the small vessel systemic vasculitides (SV), a group of human diseases commonly associated with anti-neutrophil cytoplasm autoantibodies (ANCA). Necrotizing vasculitis is seen in a number of experimental systems, but none of these provide an ideal animal model for human SV. Vasculitis occurs in serum sickness reactions; in murine models of systemic lupus erythematosus; in association with infection, particularly chronic viral infections; and after treatment with certain drugs or inflammatory mediators. 'Spontaneous' vasculitis has been reported in specific mouse strains, especially with ageing, and in some larger species. The size of vessel involved and the type of inflammatory cells predominating are variable in these experimental situations, and none of these models feature antibodies analogous to ANCA. We have recently reported that Brown Norway rats treated with mercuric chloride (HgCl2) develop necrotizing leucocytoclastic vasculitis, especially in the gut, and also develop antibodies to myeloperoxidase (MPO) which recognize similar determinants on MPO to those bound by a subset of ANCA. Transfer of serum from HgCl2-treated rats to naive animals does not induce tissue injury. Preliminary experiments using pooled immunoglobulin or an anti-CD4 monoclonal antibody did not show useful therapeutic benefit from these treatments. HgCl2-induced vasculitis has weaknesses as an animal model of human SV, but is the only experimental model in which anti-MPO autoantibodies have so far been demonstrated, and therefore may be of particular relevance to ANCA-associated SV.
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PMID:Animal models of systemic vasculitis. 838 93

The CD4 molecule represents a major functional T-cell surface molecule, defining an important T-cell subset, which also is expressed on monocyte, dendritic, and Langerhans cells. Various in vivo studies have demonstrated its implication in various steps of physiological T-cell activation: 1. CD4 interacts with its physiological ligand, the class II molecules, thus increasing the affinity of the conjugation between CD4+CD(3+)-TCR+ and class II+ antigen-presenting cells. 2. Through CD4, the signal transduction machinery is stimulated via its association with p56lck. In addition, CD4 has proved to be the receptor for gp120, the surface glycoprotein of HIV, that allows the virus to penetrate the CD4+ T cells and monocytes. Based on in vitro studies in various animal models, CD4 mAbs have proved to be efficient in the prevention and/or therapy of a variety of immunologically based diseases: 1. When injected early in the prodromic phase of autoimmune diseases (AID) such as diabetes, either delay or prevention is achieved with or without maintenance after therapy. 2. These mAbs have proved to be self-tolerogenic, thus allowing prolonged in vivo therapy and suppression of immunogenicity of mAb of a distinct specificity. In humans, CD4 mAbs are, or could be, used and evaluated in AID (lupus, diabetes, rheumatoid arthritis, etc.), transplantation, leukemias and lymphomas expressing CD4, and, finally, in AIDS patients, in whom CD4 mAbs can block HIV-CD4 binding and deliver a negative signal to T cell, thus blocking T-cell activation and HIV transcription. CD4 mAbs at least provide evidence that the CD4 molecules are suitable for immunomodulation and could be the target for a new pharmacological antagonist.
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PMID:Therapeutic applications of anti-CD4 antibodies. 847 11

MRL/Mp-lpr/lpr (MRL/lpr) mice develop a syndrome similar to systemic lupus erythematosus in humans. This strain of mice is characterized by the progressive accumulation of CD4-CD8- (double-negative; DN) T cells which express increased levels of cell adhesion molecules such as CD44 and heat stable antigen (HSA). The DN T cells exhibited a higher level of spontaneous cytolytic activity and contained a higher level of serine esterase as compared with T cells of MRL/Mp-+/+ (MRL/+) mice. We also found that mAbs against CD44, Mel-14, CD45R, and HSA could augment the cytolytic activity of DN T cells of MRL/lpr mice. Antibody-mediated augmentation of cytolytic activity of DN T cells was due to conjugate formation in which the Fc portion of mAb bound to the Fc gamma receptor on target cells and the Fab portion of mAb bound to corresponding cell surface antigens on DN T cells. The antibody-mediated augmentation of cytolytic activity was not detected in T cells of MRL/+ mice and lymphokine activated killer (LAK) cells of C57BL/6 mice. In contrast, anti-CD3 mAbs could augment the cytolytic activity of DN T cells, T cells as well as LAK cells. mAbs against LFA-1 and VLA-4 failed to augment the cytolytic activity of three different effector cells. It should be noted that anti-CD3 mAb-mediated cytolytic activity of DN T cells was substantially reduced by anti-LFA-1 mAb. However, CD44, Mel-14, CD45R as well as HSA-mediated cytolytic activity of DN T cells was not inhibited by anti-LFA-1 mAb.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Spontaneous and antibody directed cytotoxicity of double-negative T cells from autoimmune mice. 849 23

This study attempted to estimate soluble CD4(sCD4)/CD8(sCD8) molecules in active systemic lupus erythematosus (SLE) patients. Measurements were made by solid-phase enzyme-linked immunosorbent assay. sCD8 or sCD4 molecules were significantly increased in the patients as compared to control subjects. sCD8 correlated with the erythrocyte sedimentation rate. sCD4 correlated with the anti DNA antibody titer, the IgG concentration, and negatively with the complement titer. An association of these molecules with immunologic abnormalities and disease activity exists in SLE patients.
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PMID:Immunologic significance of increased soluble CD8/CD4 molecules in patients with active systemic lupus erythematosus. 850 43

Induction of an experimental disease resembling systemic lupus erythematosus (SLE) has been achieved in mice by immunization with a human monoclonal anti-DNA antibody, bearing a common idiotype, designated 16/6 Id. In the present study we used anti-CD4 and anti-CD8 antibodies to modulate the induction and development of the experimental disease. Thus, depletion of CD4+ T cells prior to the immunization with the 16/6 inhibited the induction of experimental SLE. In contrast, injection of anti-CD4 antibodies to mice that were already immunized with the 16/6 Id did not prevent the development of the disease. Furthermore, administration of anti-CD8 antibodies either before or after priming with the 16/6 Id increased the serological and clinical manifestations of the disease. These results demonstrate the pathogenic role of CD4+ and CD8+ T cells in the induction and development of the experimental SLE.
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PMID:Effect of injection of anti-CD4 and anti-CD8 monoclonal antibodies on the development of experimental systemic lupus erythematosus in mice. 854 42


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