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)

Administration of thymosin fraction V to NZB/NZW F1 mice, an animal model for human SLE, accelerated the appearance of proteinuria and anti-nDNA antibodies, increased deposition of immunoglobulins in kidneys, and significantly shortened survivals. Although the addition of thymosin to in vitro cultures of spleen and lymph node cells from thymosin-treated mice increased DNA synthesis in response to stimulation with Con A, in vivo treatment with thymosin did not affect the Con A response. There was no effect on in vitro responses to PHA or LPS, or on IgM antibody formation to SRBC (T cell dependent) or SSS III (T cell independent) immunizations. Antibodies to thymosin or contamination of our thymosin preparations with nucleic acids could not be demonstrated. The acceleration of autoimmune disease produced by thymosin treatment could not be explained by alteration of the T and B cell functions studied.
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PMID:Effect of altered lymphocyte function on immunologic disorders in NZB/NZW mice. III. Acceleration of disease by thymosin. 30 81

The presence of a serum factor secreted by the thymus has been demonstrated in the serum of mice and man using a rosette inhibition assay. This factor is a peptide with a molecular weight close to 1,000. Its level is age dependent, being stable until the age of 6 months in mice and until 20 years in man. New Zealand Black mice show a premature cessation of thymic hormone secretion preceeding the onset of other T cell abnormalities and auto-immunity. Before any treatment the serum thymic hormone level is abnormally low in most cases of SLE even in patients under 25, an age where control subjects still show high hormone levels. Conversely, normal or high levels are found in RA, PARTICularly in patients over 40 who showed in 60% of cases a hormone level significantly higher than normal controls of the same age. In keeping with this data T cells evaluated by SRBC spontaneous rosette formation show low figures in some patients with active SLE and normal or high values in most cases of RA.
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PMID:Evaluation of serum thymic hormone and of circulating T cells in rheumatoid arthritis and in systemic lupus erythematosus. 108 29

In murine models of systemic lupus erythematosus and in many humans with SLE, antibodies against native DNA (dsDNA) are a major contributor to the pathogenesis of the disease. Loss of self-tolerance to the DNA antigen may be associated with B-cell defects or regulatory cell dysfunction. We have developed B-cell lines with specificity for the antigen DNA, from both the autoimmune BWF1 mouse strain and from the non-autoimmune BALB/c strain, to use in the investigation of inherent B-cell defects in autoimmunity. Six BWF1 cell lines and five BALB/c cell lines which are free of Thy1.2+ cells and esterase positive cells, and have between 35 and 89% rosetting with dsDNA-SRBC targets, have been propagated in vitro for 24-36 months. The cells are non-malignant, growth-factor dependent and have no antigen or mitogen in the growth medium. Lyt-1 positive cells are found in the cell lines, but Lyt-1 negative cells are also present. They respond to the antigen DNA-HRBC when EL-4 supernatant is present in culture, and the peak of the plaque-forming cell (PFC) response is the same for both strains. When cells from both strains are cultured with varying amounts of T-cell factors, there is no difference in spontaneous antibody-forming cell (AFC) formation or in response to anti-mu stimulation between BWF1 and BALB/c strains. BALB/c spleen cells do not respond to DNA-HRBC in this culture system, but BWF1 spleen cells, as well as cell line cells from both strains, respond to this antigen. T cells from non-responding BALB/c spleen and responding BWF1 spleen are able to suppress the immune response to DNA-HRBC of cell line B cells from both strains. Propagating B-cell lines in the presence of DNA for 2 weeks stimulates BWF1 cell line cells, but suppresses the response of BALB/c cell lines to antigen.
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PMID:Investigations of intrinsic abnormalities in DNA-specific B lymphocytes from autoimmune mice. 252 8

A hemolytic assay was developed with the primary aim of being able to identify human lymphocytes producing anti-dsDNA antibodies found in patients with systemic lupus erythematosus (SLE). The coating of sheep red-blood cells with DNA was performed after precoating the cells with poly-L-lysine. The DNA-SRBC were lysed by anti-DNA antibodies from SLE sera, and the percent hemolysis was found to correlate with the anti-DNA activity demonstrated by the Farr assay (r = 0.87). Single-stranded DNA at the surface of the coated cells could be removed after digestion with nuclease S1. The effect of the digestion was verified by SLE serum specific for single-stranded DNA. With slight modifications, the target cells may be used to determine not only the titer of anti-DNA antibodies but also the complement-consumption and immunoglobulin classes of the anti-DNA antibodies.
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PMID:Immune hemolytic assay for identification of human anti-dsDNA antibodies with DNA-coated red blood cells as target cells. 283 17

Palmerston North (PN) mice spontaneously develop autoimmune disease resembling SLE. Because immune responsiveness has not been defined in this strain, a study was designed to assay primary splenic plaque-forming cell (PFC) responses to thymus-dependent (TD) and thymus-independent (TI) Ag. Initial surveys of PN mice inoculated with the TD Ag SRBC showed adequate production of IgM PFC, but small numbers of IgG PFC were developed with polyspecific antiserum. In contrast, H-2-compatible DBA/1 control mice gave the expected responses to SRBC (IgG plaques elevated twofold compared with IgM plaques). PN mice had the usual responses to Ag that are largely TI; both PN and DBA/1 mice had active IgM and modest IgG responses to TNP-LPS and TNP-Ficoll. Additional experiments determined that PN mice had similar patterns of defective IgG responses to several different TD Ag (SRBC, horse RBC, and DNP-keyhole limpet hemocyanin). In each instance, the usual predominance of IgG1 plaques was absent, and total numbers of plaques developed with antisera specific for IgG isotypes were suppressed. Defective PN IgG production was evident as early as 3 wk of age, was not influenced by aging to 43 wk, and was not corrected by increasing the antigenic challenge 10-fold. PN spleen cells treated with monoclonal anti-Thy-1.2 and C were injected with pools of DBA/1 T cells into 850-rad irradiated (DBA/1 x PN)F1 hybrids. These recipients expressed low IgG1 responses to SRBC, suggesting that the B cell-containing fraction that was not lysed by anti-Thy-1.2 transferred the PN defect. PN mice, which do not respond to TD Ag with active IgG production, contradict the proposal that autoimmunity is associated with hyper-responsiveness to TD and TI Ag.
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PMID:Defective primary and secondary IgG responses to thymic-dependent antigens in autoimmune PN mice. 328 33

Naturally occurring thymocytotoxic autoantibodies (NTA) have been described both in humans and in mice with SLE, and have been reported to be preferentially reactive with T suppressor as compared to T helper cells. However, although NTA has been shown by some groups of investigators to induce autoantibodies in normal strains of mice, other researchers have suggested that NTA has only a minor, if any, role in murine lupus. We have been studying the characteristics of a monoclonal antibody (TC-17) derived from the fusion of 4-mo-old NZB spleen cells with P3-X63-AG8.653 plasmacytoma cells. This monoclonal IgM reagent is cytotoxic for approximately 40% of total thymocytes, 50% of cortical thymocytes, less than 1% of cortisol-resistant thymocytes, 10% of splenocytes and lymph node cells, and less than 3% of bone marrow and fetal liver cells. The thymocytotoxicity can be absorbed by thymocytes but not by brain cells. Although NZB, NZW, NFS, and BALB/c thymocytes all manifest reactivity with TC-17, there was considerable difference between strains with respect to antigen density; NZB thymocytes have the highest density. By FACS analysis, TC-17 occurs independently of Lyt-1, Lyt-2, and T helper cell-specific antigens, and is more prevalent on larger proliferating thymocytes. TC-17 augments the response to SRBC but does not influence responses to TI-1 (TNP-BA) or TI-2 (DNP-Ficoll) antigen and production of LPS-induced B cell colonies. We believe that TC-17 recognizes a new T cell antigen, probably one involved in T cell differentiation. Because this monoclonal NTA reacts with only 40% of thymocytes, and is not absorbed with brain, it would not have been detected in mouse sera by using previously published methods. NTA are a heterogeneous group of autoantibodies; some specificities such as TC-17 went unrecognized in the past, and may be important either for disease pathogenesis or for secondary immunologic abnormalities.
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PMID:Characteristics of a spontaneous monoclonal thymocytotoxic antibody from New Zealand Black mice: recognition of a specific NTA determinant. 620 78

By induction of a graft-vs.-host reaction (GVHR) in nonirradiated H-2-different F1 mice, one can induce stimulatory pathological symptoms, such as lymphadenopathy and hypergammaglobulinemia, combined with the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). Alternatively, the GVHR can lead to the suppressive pathological symptoms, such as pancytopenia and hypogammaglobulinemia, characteristic of acute GVH disease (GVHD). Whether stimulatory or suppressive symptoms are induced by a GVHR depends, in our view (2-4), on the functional subset of donor T cells activated in the F1 host. The purpose of the present study was to investigate whether class I and/or class II H-2 alloantigens can selectively trigger, out of a pool of unselected donor T cells, those subpopulations of T cells responsible for the stimulatory and suppressive GVH symptoms, respectively. For the induction of the GVHR, 10(8) lymphoid cells from C57BL/6 (B6) donors were injected into three kinds of F1 hybrid mice, which had been bred from H-2 mutant strains on a B6 background. Whereas the I-A-disparate (B6 X bm12)F1 recipients exclusively developed stimulatory GVH symptoms, including SLE-like autoantibodies and immune complex glomerulonephritis, the K locus-disparate (B6 X bm1)F1 recipients showed neither clearly stimulatory nor clearly suppressive GVH symptoms. In marked contrast, the (bm1 X bm12)F1 recipients, which differ from the B6 donor strain by mutations at both K and I-A locus, initially developed stimulatory GVH symptoms, but rapidly thereafter showed the suppressive pathological symptoms of acute GVHD and died. Moreover, spleen cells obtained from (B6 X bm12)F1 mice injected with B6 donor cells helped the primary anti-sheep erythrocyte (SRBC) response of normal (B6 X bm12)F1 spleen cells in vitro, whereas spleen cells (bm1 X bm12)F1 mice injected with B6 donor cells strongly suppressed the primary anti-SRBC response of normal (bm1 X bm12)F1 spleen cells. Spleen cells from the K locus-disparate (B6 X bm1)F1 recipients also suppressed the primary anti-SRBC of normal (B6 X bm1)F1 spleen cells; this suppression, however, was weak when compared with the suppression induced by spleen cells from GVH (bm1 X bm12)F1 mice. Taken together, these findings indicate that a small class II (I-A) antigenic difference suffices to trigger the alloreactive donor T helper cells causing SLE-like GVHD. In contrast, both class I (H-2K) and class II (I-A) differences are required to trigger the subsets of donor T cells responsible for acute GVHD. It appears that alloreactive donor T helper cells induce the alloreactive T suppressor cells, which then act as the suppressor effector cells causing the pancytopenia of acute GVHD. These findings may help to understand the variability of GVH-like diseases caused by a given etiologic agent, their cellular pathogenesis, and association with certain HLA loci.
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PMID:Allosuppressor and allohelper T cells in acute and chronic graft-vs.-host disease. II. F1 recipients carrying mutations at H-2K and/or I-A. 621 18

B cell hyperactivity, a feature common to all lupus-prone murine strains, may be caused by hyperresponsiveness to, overproduction of, or bypassing of certain signals required for B cell activation, proliferation, and differentiation. In this study, we have compared the responses of B cells from three lupus-prone strains of mice (BXSB males, MRL and NZB/W females) and normal strains in a number of assays for which two or more signals are required to obtain a response. In medium to low density cultures of B cells from BXSB and NZB/W but not MRL/l lupus mice, the cells' proliferation induced by bacterial lipopolysaccharide (LPS) or anti-mu antibody was much higher than that of B cells from normal controls. At low B cell density, polyclonal activation by these substances and subsequent Ig secretion were dependent on accessory signals present in supernatants of concanavalin A-treated normal lymphocytes (CAS) or on the MRL/l proliferating T cell-derived B cell differentiation factor (L-BCDF) in both lupus-prone and immunologically normal mice. However, the responses of B cells from BXSB and NZB/W, but not MRL/l, mice to these accessory signals were higher than those of normal mice. Ig synthesis by fresh B cells of BXSB and NZB/W mice cultured in the absence of mitogens but in the presence of CAS or L-BCDF was higher than by similar cells from other strains, suggesting an increased frequency of B cells activated in vivo in these two autoimmune strains of mice. The patterns of IgG subclass secretion in response to LPS (without added CAS or L-BCDF) were abnormal in all lupus strains, with a predominance of IgG2b and/or IgG2a and low levels of IgG3, contrary to normal B cells for which IgG3 synthesis predominated. However, IgG1 synthesis in vitro by autoimmune and normal B cells alike was highly dependent on T cell-derived soluble mediators. Antigen-specific responses to SRBC in vitro of B cells from all lupus strains, like those of B cells from normal strains, required a minimum of three signals (antigen, LPS, T cell-derived antigen nonspecific helper factors). Yet, once triggered, B cells of BXSB and NZB/W mice gave higher responses than those of the other strains. We conclude that B cells of lupus mice have signal requirements similar to those of normal mice. Nevertheless, B cells of BXSB and NZB/W, but not MRL/l, lupus mice hyperrespond or process some accessory signals abnormally.
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PMID:B cell dependence on and response to accessory signals in murine lupus strains. 640 39

Induced IgM anti-ss-DNA antibodies in NZB/W female mice did not alter the time of onset nor the course of nephritis. Monthly pulse doses of cyclophosphamide suppressed the mortality of these mice, and also prevented a switch of anti-ss-DNA from IgM to IgG class. The production of IgM anti-SRBC was markedly reduced in old NZB/W mice, but IgG anti-SRBC was only moderately reduced and this hyporesponsiveness towards SRBC could be reversed by CPA treatment. These observations are discussed in relation to cyclophosphamide as an effective therapeutic agent for the murine lupus syndrome.
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PMID:Effects of pulse cyclophosphamide on NZB/W disease. 645 49

Antibodies to the nuclear antigen SM are specific for systemic lupus erythematosus in humans and mice. In order to study the cellular mechanisms of anti-Sm generation, a hemolytic plaque assay to identify and enumerate lymphocytes secreting anti-Sm has been developed by using SRBC coated with purified Sm by a modified carbodiimide technique. Anti-Sm-specific PFC were found in MRL/Mp-Ipr/Ipr and MLR/Mp- +/+ mice whose sera contained anti-Sm, but were never detected in anti-Sm-negative MRL mice or in normals. Spleen cells from anti-Sm-positive MRL/Mp-Ipr/Ipr mice generated anti-Sm PFC spontaneously after 4 days of in vitro culture, whereas cells from normal mice or anti-Sm-negative MRL mice were never observed to produce spontaneous anti-Sm, even when cultured in the presence of bacterial lipopolysaccharide. The generation of anti-Sm by MRL cells in vitro was found to be dependent on the presence of T cells, but the ability of cells from individual MRL mice to generate anti-Sm appeared to be limited by the availability of Sm-specific B cell precursors and not due to a relative absence of T cells capable of providing help for the anti-Sm response. Analysis at the cellular level of the in vitro generation of a disease-specific autoantibody by using the methods described should facilitate understanding of mechanisms of autoreactivity.
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PMID:Anti-Sm autoantibodies in MRL mice: in vitro detection and generation of antibody-forming cells. 698 38


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