Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune MRL-lpr/lpr and NZB/W mice spontaneously secrete large quantities of pathogenic IgG1 and IgG2a autoantibodies. NZB mice also produce autoantibodies but these tend to be of the IgM H chain class. This work examines whether differences in the isotype of autoantibody produced by lupus-prone mice reflects differences in the sensitivity of autoreactive B cells to lymphokine-mediated IgG secretion. Twenty-five percent of normal BALB/c B cells produced IgG1 when stimulated in vitro with IL-4 plus LPS. This was comparable with the effect of IL-4 on small resting B cells from MRL-lpr/lpr and NZB/W mice. In contrast, less than 8% of the resting B cells from NZB mice produced IgG1 under these conditions. LPS plus IFN-gamma induced 5% of BALB/c and NZB/W but only 1% of NZB B cells to secrete IgG2a. Because lymphocytes from both young and old NZB mice showed diminished IgG1 and IgG2a secretion after lymphokine treatment, B cells from this strain appeared to be intrinsically resistant to the effects of IL-4 and IFN-gamma. In contrast, a disproportionately large proportion (22%) of B cells from adult MRL-lpr/lpr mice produced IgG2a when treated with IFN-gamma in vitro. Only B cells from MRL-lpr/lpr mice with active disease responded with such high levels of IgG2a production: cells from animals that had not yet developed clinical disease produced normal levels of IgG2a. Within each strain, B cells producing antibodies against autoantigens such as DNA, bromelain-treated mouse RBC and Sm responded to treatment with IL-4 and IFN-gamma in a manner indistinguishable from B cells producing antibodies against conventional Ag such as TNP and ARS.
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PMID:IgG1 and IgG2a production by autoimmune B cells treated in vitro with IL-4 and IFN-gamma. 210 5

TNF-alpha is a macrophage-derived cytokine with diverse biologic activities, including potent immunomodulatory effects. In vitro studies have implied that TNF-alpha has predominantly proinflammatory and immunostimulatory effects, but paradoxically in vivo studies have demonstrated that administration of TNF-alpha suppresses murine lupus. To assess the effects of TNF-alpha on immune function in normal mice, we treated C57BL/6 mice with recombinant murine TNF-alpha (10 micrograms i.p.) or PBS on alternate days for up to 8 wk. Administration of TNF-alpha decreased the percentage of splenic T and B cells and increased the percentage of splenic macrophages without significantly altering the total number of mononuclear cells. Administration of TNF-alpha also caused progressive inhibition of splenic lymphocyte function, out of proportion to the quantitative reduction in B and T cells. After 8 wk of therapy, the proliferative responses of splenic lymphocytes to Con A, PHA, and LPS were reduced by 100, 90, and 60%, respectively, in treated mice compared with control mice. The reduction in T cell proliferation was due primarily to alteration of accessory cell function rather than direct inhibition of T cell function. Treatment with TNF-alpha markedly inhibited T cell cytotoxicity induced by immunization with allogenic target cells, and it virtually ablated NK cell activity. Inhibition of these in vitro tests of lymphocyte function correlated with inhibition of delayed type hypersensitivity in vivo. In contrast, treatment with TNF-alpha did not impair humoral immunity. These findings imply that TNF-alpha may affect cell-mediated immunity more profoundly than humoral immunity. This observation may be relevant to the mechanism whereby TNF-alpha suppresses murine lupus.
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PMID:Effects of recombinant murine tumor necrosis factor-alpha on immune function. 230 39

The influence of dietary fat on autoimmunity in lupus-prone (NZB x NZW)F1 mice has been demonstrated. In defining further the effects of dietary lipid on the immune system of this strain, female weanling mice were placed on four diets differing in quantity and type of fat. Their immunologic response was then studied by a variety of tests at 4 and 7 mo of age. Few differences were seen among the four groups at 4 mo of age. At 7 mo of age, however, the mice receiving diets high in saturated and unsaturated fats had a reduced mitogenic response to T cell mitogens and an enhanced response to the B cell mitogen LPS. Immunoglobulin levels and delayed hypersensitivity responses did not show any consistent differences among the diet groups. At 7 mo, however, mice receiving diets high in unsaturated fat demonstrated hyperresponsiveness to injected sheep red blood cells as measured by the hemolytic plaque technique. In addition, peritoneal leukocytes from the same diet group exhibited an increased response to bromelain-treated autologous erythrocytes which was decreased after treatment with anti-Thy-1 antiserum and complement. Phagocytosis by peritoneal macrophages was significantly decreased in the animals fed high-fat diets, particular high saturated fat. Similarly, natural killer cell activity was markedly reduced in the mice with a high intake of saturated lipid, a finding which correlated with the in vitro production of interferon. These results indicate that diets high in fat influence immune responses and thus can affect the onset and severity of autoimmune disease. A low-fat diet can reduce the development of disease by maintaining normal immune responses. The data also suggest that unsaturated fat may influence T helper cell activity and therefore antibody production, whereas saturated fats may affect cellular immune responses which are dependent on membrane contact.
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PMID:Dietary fat and immune function. I. Antibody responses, lymphocyte and accessory cell function in (NZB x NZW)F1 mice. 241 89

Systemic lupus erythematosus (SLE) is characterized by multiple defects affecting B and T lymphocyte cell function. In view of the influence that monocytes may have on these functions, we have examined monocyte function in patients with SLE and normals. Monocytes were examined as to number, their ability to modulate IgG synthesis, phagocytose yeast particles, and acid phosphatase activity. Patients had more monocytes and mononuclear cells made more IgG, but these factors appear to be independent of each other. Monocytes from lupus patients are less phagocytic but show similar levels of acid phosphatase activity to normal controls. Normal, but not lupus monocytes, show enhanced phagocytosis following treatment with LPS. The effect of monocyte stimulation on acid phosphatase activity is the same in lupus and normal monocytes. Taken together, these observations suggest that the increased numbers of monocytes in lupus patients and some subtle functional differences in these cells may be important in the progression of this disease.
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PMID:Monocyte function in systemic lupus erythematosus. 250 Feb 77

These studies explore the regulation of immunoglobulin production in autoimmune mice. B cells were transferred from normal or autoimmune mice into H-2 compatible xid recipients. When transferred to autoimmune-prone xid mice, cells from either donor produced significant levels of autoantibody. Cells from the same animals transferred to normal xid recipients produced little autoantibody. An ELISA spot assay was then used to study the development of B cell repertoires in autoimmune animals. Young lupus-prone mice developed repertoires in which B cells reactive with both conventional antigens and autoantigens were simulated to a similar degree, a finding consistent with the influence of polyclonal B cell activation. To examine the effect of exogenously administered immune activators on the development of B cell repertoires, normal DBA/2 mice were stimulated with LPS or goat anti-mouse IgD. This led to a quantitative increase in the number of Ig-secreting cells and expression of a repertoire similar to that present in autoimmune mice. Immunization with a specific antigen induced a repertoire skewed toward reactivity against that antigen which did not resemble that present in autoimmune mice. These findings are consistent with the view that polyclonal activation contributes to the production of autoantibodies in early murine lupus.
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PMID:Regulation of B cell activation in autoimmune mice. 279 46

Spleen cells from MRL-lpr/lpr, CBA and BALB/c mice were cultured in vitro and assayed for production of anti-nuclear antibodies. Spleen cells from all species produced IgM antibodies to a nRNP (U1-RNP)-specific antigen and to double-stranded DNA (dsDNA) after stimulation with LPS. The specificity of the anti-nRNP antibodies was shown, by immunoblotting, to be directed against the 33,000 MW polypeptide of nRNP/Sm. CBA mice produced more IgM autoantibody in vitro than MRL/lpr or BALB/c mice. In contrast, IgG anti-nRNP and anti-dsDNA antibody were not produced by any of the strains. Our data show that anti-nRNP and anti-dsDNA precursor B cells are part of the normal murine immune repertoire and are not confined to the MRL/lpr strain. This suggests that the spontaneous development of anti-nRNP and anti-dsDNA antibodies associated with systemic lupus erythematosis (SLE) is dependent on clonal stimulation and removal of suppressive influences.
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PMID:Anti-nRNP anti-nuclear antibody-secreting cells are represented in the B-lymphocyte repertoire of normal and MRL/MP-lpr/lpr lupus mice. 325 71

Individual MRL-lpr mice vary in their capacity to generate anti-Sm autoantibodies spontaneously. We have compared the frequency of B-cell precursors for this autoantibody in serologically negative and serologically positive MRL-lpr mice, and in normals. Anti-Sm precursors were present in a frequency of approximately 1 per 10-30,000 in spleen cell cultures from anti-Sm positive mice, but were undetectable when spleen cells from serologically negative MRL-lpr mice or from normal mice were examined. Despite LPS stimulation, neither IgM nor IgG precursors could be detected. In parallel cultures, in contrast, anti-DNA autoantibody precursors were readily detected. The results thus indicate that, for the lupus-specific autoantibodies, the absence of antibody in autoimmune mice reflects a deficit in precursor B lymphocytes rather than an active regulatory mechanism. It is suggested that the generation of anti-Sm may reflect a low-probability random event in the generation of B-cell diversity.
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PMID:Anti-Sm autoantibodies in MRL mice: analysis of precursor frequency. 387 7

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

The onset of clinical disease in autoimmune MRL-lpr/lpr mice is preceded by a switch from predominantly IgM production to IgG production. Previous studies have shown that IgG autoantibodies play a central role in the development of life-threatening glomerulonephritis in this strain. Delaying or preventing the switch from IgM to IgG production might therefore be of therapeutic benefit. We previously documented similarities in the B cell repertoire expressed by young MRL-lpr/lpr mice and normal mice treated with the polyclonal activator LPS. Recent in vivo studies indicate that cross-linking membrane IgM or IgD can suppress LPS-dependent IgG production in normal animals. These observations led us to examine whether membrane cross-linking could also lower serum IgG levels in MRL-lpr/lpr mice. Lupus-prone animals were treated with multivalent anti-IgD conjugated to high m.w. dextran. This anti-IgD dextran conjugate was previously shown to reduce IgG production in LPS-stimulated normal animals. Treatment of young lupus-prone MRL-lpr/lpr mice resulted in a significant reduction in the total number of B cells secreting IgG and lower serum titers of IgG anti-DNA and IgG anti-histone autoantibodies. Anti-IgD dextran treatment also delayed the development of glomerulonephritis and improved survival. Thus, anti-IgD dextran interfered with autoantibody-dependent disease progression, perhaps by inhibiting the switch from IgM to IgG autoantibody production.
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PMID:Treatment with dextran-conjugated anti-IgD delays the development of autoimmunity in MRL-lpr/lpr mice. 751 19

Acebutolol induces transient polyclonal B cell activation in C57B1/6 mice but down-modulates the spontaneous polyclonal activation of NZBxNZW lupus mice. The immunomodulatory effects of this beta-blocker were studied in C57l/6 mice injected with LPS or immunized with sheep red blood cells. The effect of acebutolol on the polyclonal activation of lymphocytes induced by LPS was also investigated in heterozygous and nu/nu C57BL/6 mice. Finally, the direct effect of acebutolol on spleen cells was studied in vitro. Acebutolol treatment for 15 days (50mg/kg/day) inhibited the polyclonal activation of lymphocytes induced by LPS in C57BL/6 and in C57BI/6 nu/nu mice, but increased the humoral response to sheep red blood cells in C57Bl/6 mice. Moreover, spleen cells from C57Bl/6 mice treated for 15 days with acebutolol showed an increased number of CD5+ and CD4+ lymphocytes, as well as an increased reactivity to concanavalin A but not to LPS. In vitro, acebutolol at 10(-5)-10(-7) M induced an increased reactivity of spleen cells from naive mice to concanavalin A, whereas it did not affect the B cell responsiveness to LPS. These results indicate that acebutolol modulates both T-cells and non T-cells in the immune system.
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PMID:Evidence for a dual effect of acebutolol, a beta blocker, on the mouse humoral immune response. 857 44


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