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)

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

We studied the effects of cyclosporin A (CYA) on the production of various lymphokines and on the suppressor functions of peripheral blood mononuclear cells (MNC) of ten untreated SLE patients. CYA was found to inhibit the production of IL-2 and of B cell stimulating factor (BSF) by both normal and SLE MNC but it did not alter the LPS-driven production of IL-1 by either of them. However, it did abrogate the spontaneous release of IL-1 by SLE monocytes. CYA strongly inhibited the production of IL-3-like activity by normal T cells, an effect noticed only on cells from 4 SLE patients, three of whom were in remission. Addition of CYA significantly increased suppressor cell function by cells from all SLE patients. T cell clones could be obtained from two of them by using CYA-conditioned medium containing IL-3. These clones were found to have strong suppressor capacity.
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PMID:Presence of an IL-3-producing suppressor T cell resistant to cyclosporin A in the peripheral blood of patients with systemic lupus erythematosus. 297 65

To assess the role of macrophages (MAC) in the pathogenesis of systemic lupus erythematosus, we investigated functional aspects of peritoneal MAC obtained from autoimmune MRL/MpJ-lpr/lpr (MRL-lpr) mice. MRL-lpr and control C3H/HeN MAC were obtained from untreated mice or mice injected i.p. with 1 ml of 10% sterile peptone 3 days before cell harvest. MRL-lpr mice had significantly more peritoneal cells (MAC and lymphocytes) than did control mice. In endotoxin-free conditions, MRL-lpr MAC were similar to C3H/HeN MAC in their baseline, and IFN-gamma and/or LPS enhanced cytolysis of 3T12 fibrosarcoma tumor cells. Compared with C3H/HeN MAC, MRL-lpr MAC had a significant increase in antibody-dependent cellular cytotoxicity activity against sheep erythrocytes. This enhanced activity was not accompanied by a similar increase in adherence and/or phagocytosis of the same targets. Finally, in response to phorbol myristate acetate stimulation, both resident and peptone-induced MAC from MRL-lpr mice produced significantly more hydrogen peroxide than did those from control mice. These results indicate that MAC from MRL-lpr mice display features of selective "activation", and suggest that MAC or their products may play a role in the pathogenesis of inflammatory disorders seen in autoimmune diseases.
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PMID:Functional alterations of macrophages in autoimmune MRL-lpr/lpr mice. 310 99

The precursor frequency for anti-DNA antibody producing cells and the affinity of antibodies secreted by these cells in both immature prereceptor B cell populations and mature B cell populations were compared between 8-week-old C57BL/6 female mice and 9-month-old B/WF1 female mice by producing a large collection of IgM secreting hybridomas from LPS-stimulated B cells. The data indicate that precursor cells for high affinity anti-DNA antibody are eliminated as they mature in C57BL/6 mice, while a sizable number of such clones are present in mature splenic B cells of aged B/WF1 mice. These results suggest that the emergence of precursors for high affinity anti-DNA producing cells in mature B cell population is an important factor in the pathogenesis of SLE.
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PMID:B cell repertoire for anti-DNA antibody in normal and lupus mice: differential expression of precursor cells for high and low affinity anti-DNA antibodies. 325 4

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

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

Several data suggest that the glomerular deposits of DNA and anti-DNA antibodies observed in SLE result from complex formation in situ. The aim of this study was to investigate this hypothesis in normal C57BL/6 mice by using monoclonal anti-DNA antibodies (mAb). Renal localization of intravenously introduced ds DNA was demonstrated in mice injected intraperitoneally with LPS 48 h before. Then, a single IgG2b or a mixture of IgG2a and IgG2b anti-ds DNA mAb were given with the aim of forming DNA: anti-DNA complexes at the glomerular level. No immunoglobulin deposits were observed regardless of the antibody dose used. The mAb used may possess some of the qualitative properties suspected to be nephritogenic. Thus, the limiting factors in the induction of a passive nephritis could be either the absence of glomerular DNA deposits or the inability by using a single antigen-antibody system, to recreate the pathophysiological conditions seen in SLE, where a high number of antigen-antibody systems is implicated in the genesis, of glomerular lesions.
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PMID:Monoclonal anti-DNA antibodies: an approach to studying SLE nephritis. 387 83

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

In vivo, prolonged polyclonal activation of B cells by the nonantigenic but potent mitogenic lipid A portion of lipopolysaccharide (LPS-R595) resulted in acceleration of the late life systemic lupus erythematosus disease of female MRL/n, BXSB, and NZW mice, mimicking the time, form, and histopathological features characteristic of their early life disease counterparts, i.e., MRL/l females, BXSB males, and (NZB X NZW)F1 females. Similar polyclonal B cell activation of "immunologically normal" mice has less effect and led to a limited expression of autoimmune disease. This R595-induced autoimmunity and immune complex-mediated disease seemed to be the direct result of activation of the immune system and not from other effects of endotoxin since C3H/HeJ, a strain lacking lymphocyte receptors for LPS-R595, had neither serological nor histological evidence of autoimmune disease despite identical treatment.
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PMID:Induction of murine autoimmune disease by chronic polyclonal B cell activation. 633 69


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