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)

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

In order to analyze relation of immunological abnormalities to the development of lupus glomerulonephritis (LGN) at an early stage, various immunological parameters were examined in BXSB and MRL/lpr mice at 8 and 13 weeks of age. The following results were obtained. (a) Male BXSB mice showed slight LGN already at 8 weeks of age and the disease became obvious at 13 weeks of age. On the other hand, glomerular change of MRL/lpr mice became apparent at 13 weeks. (b) Immunofluorescent studies to semiquantify degree of the deposition of immune complexes (IC) at glomeruli revealed that there were no difference in fluorescence intensities among BXSB mice at 8 and 13 weeks and 13-week-old MRL/lpr mice. (c) MRL/lpr mice had much higher level of serum IC than male BXSB mice at 13 weeks as assessed by fluid- and solid-phase C1q-binding assays. Both strains showed almost the same level of Raji cell-binding IC which might be related to glomerular depositing ones. (d) Spleen of 13-week-old MRL/lpr mice contained extraordinary number of IgG-producing cells in spleen as compared with 8-week-old mice or male BXSB mice at 8 or 13 weeks. There were no differences in IgM-producing cell numbers among the strains and ages of mice. These results indicate that MRL/lpr and male BXSB mice have different immunological backgrounds for the development of LGN. It was noticeable that male BXSB mice showed some degree of LGN already at 8 weeks of age, without apparent polyclonal B cell activation and enhanced serum level of IC, as compared with MRL/lpr mice of the same age.
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PMID:Studies on the mechanisms of the development of lupus nephritis in BXSB mice. II. Comparative studies between male BXSB and MRL/lpr mice at the onset period. 325 31

T cell growth is principally regulated by the lymphokine interleukin 2 (IL 2). Following induction of IL 2 receptors, immunologically normal cells proliferate and will continue to do so until the level of IL2 becomes limiting. Spleen cells from autoimmune-prone mice and peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE), however, are severely deficient in their capacity to both produce and respond to IL 2 following a challenge with mitogenic lectins. These observations have suggested the possibility that IL 2 may not function as a T cell growth factor in the autoimmune milieu. In order to determine the requirements for T lymphocyte proliferation in autoimmunity, MRL-lpr/lpr mice were studied. Spleen cells from this murine model of lupus exhibit profound defects in IL 2 activity in vitro. Yet, paradoxically, massive expansion of the T cell pool occurs in vivo. While spleen cells from such mice were, indeed, unable to produce IL 2 or to proliferate when stimulated with concanavalin A (Con A), the combination of Con A plus the comitogen phorbol myristate acetate (PMA) engendered substantial IL 2 production and normal cellular proliferation. Since numerous lymphokines are produced when cells are cultured with Con A + PMA, it remained to be shown that IL 2 was, in fact, the responsible growth factor. We found that culturing lpr spleen cells with an anti-IL 2 receptor antibody abrogated the mitogenicity of Con A + PMA; that on stimulation with Con A + PMA, MRL-lpr/lpr T cells expressed IL 2 receptors, and that addition of recombinant IL 2 to the receptor positive population resulted in marked proliferation. Furthermore, by two-color flow cytometric analysis it was demonstrated that T cells which bear the phenotype of those which undergo clonal expansion in the lpr were capable of expressing IL 2 receptors. Thus, IL 2 can be utilized as a growth factor, in vitro, by autoimmune as well as normal T cells. The etiology of the Con A unresponsiveness of MRL-lpr/lpr cells remained to be clarified. We observed that, in contrast to the refractoriness of fresh cells, lymph node cells which had been cultured for several days in the absence of antigenic stimulation were capable of expressing IL 2 receptors and of proliferating on exposure to Con A. Using flow cytometry it was found that selective expansion of a subset of phenotypically "normal" lymphocytes had not occurred.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Signals required for activation and growth of autoimmune T lymphocytes. 608 44

systemic lupus erythematosus (SLE) and related rheumatic and connective-tissue diseases are often associated with the production of antibodies directed against a variety of specific cellular components. Recent evidence indicates that two such autoantigens, the Sm and RNP antigens recognized by SLE sera, exist in small ribonucleoprotein complexes found in the nuclei of higher eukaryotes. Studies of the structure and function of these autoantigenic particles with human sera used as probes have been limited because of the multiplicity of autoantibodies often found in an individual serum. Through this communication, we report that MRL/Mp-+/+ (MRL/n) mice, which spontaneously develop a disease exhibiting many of the characteristics of human SLE, possess anti-RNP antibodies in addition to anti-Sm and anti-DNA as previously reported. Spleen cells from one such autoimmune mouse were used to produce a stable hybridoma secreting antibodies that react simultaneously with a protein of Mr 40,000 and a doublet of approximately 70,000, a pattern of reactivity identical to and characteristic of human SLE anti-RNP autoantibodies.
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PMID:Anti-RNP monoclonal antibodies derived from a mouse strain with lupus-like autoimmunity. 617 24

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

Anti-histone antibodies have been demonstrated in the sera of patients with both idiopathic and drug-induced lupus. We measured anti-histone antibodies in female NZB/NZW (F1) mice, which are considered to be a model of human SLE. Using a sensitive and quantitative enzyme-linked immunosorbent assay (ELISA), we detected minimal serum antibody activity in NZB/NZW mice younger than 4 mo of age and in nonautoimmune mice at all ages tested. Serum anti-histone antibodies progressively increased in NZB/NZW mice from 4 to 8 mo of age and showed an age-related maturation from IgM to IgG. The predominant antibody activity in the older mice was to the individual histones H2B and H3, and the pattern of reactivity to the histone proteins was similar to that seen in human SLE. We also studied the spontaneous in vitro production of anti-histone antibodies using spleen cells from NZB/NZW mice of different ages. Culture supernatants were analyzed for antibody activity by an ELISA with total histones as the antigen. Spleen cells from older NZB/NZW mice, with elevated serum levels, produced 10-fold higher levels of antibody activity compared to age-matched nonautoimmune mice. Antibody production was maximal at 4 days of culture and was inhibited by the addition of puromycin to the culture. Surprisingly, spleen cells from 1 to 3-mo-old NZB/NZW mice, with normal serum levels, also demonstrated significantly elevated production. The antibodies produced by these young mice were mostly IgM, whereas spleen cells from older mice produced mostly IgG anti-histone antibodies. The present results provide the basis for using the anti-histone antibody system to study further the immune abnormalities that allow for autoantibody production.
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PMID:In vivo and in vitro production of anti-histone antibodies in NZB/NZW mice. 686 18

IL 2 production was studied in autoimmune mice to assess the role of this lymphokine in the pathogenesis of murine lupus. Spleen and lymph node cells from autoimmune-susceptible mice show an age-dependent loss in the ability to produce functional IL 2. This defect correlates with disease expression and is most severe in MLR/Mp-Ipr/Ipr mice. MLR/Mp-Ipr/Ipr thymocytes gradually lose responsiveness to IL 2 with age. These results suggest that the immunoregulatory abnormalities of autoimmune mice may be due in part to IL 2 deficiency.
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PMID:Interleukin 2 deficiency is a common feature of autoimmune mice. 697 25

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

Previous studies (Y. Borel and M.C. Young, Proc. Natl. Acad. Sci. USA 1980 77: 1593) have shown that one can raise nucleic acid-specific suppressor T cells which diminish either the T-dependent immune response in vivo or the T-independent immune response in vitro. The results presented here confirm and extend these observations in several different strains of mice. Administration of nucleoside-modified spleen cells diminishes antibody-forming cells to nucleoside in mice immunized with nucleoside linked to keyhole limpet hemocyanin (KLH), Immune suppression was obtained in all strains except SJL and NZW, which are known to be high responders to denatured DNA. Both the primary and secondary immune responses were suppressed in C57BL/6 mice. Autologous cells exhibit a different ability to function as carriers. Spleen cells are the most effective, and to a certain extent, thymus cells. In contrast, bone marrow cells and red cells fail to induce immune suppression. A strain difference was found between NZB and NZW mice in their susceptibility to immunosuppression by nucleoside-modified spleen cells. Whereas NZB mice are high responders to nucleoside-KLH, they were easily suppressed by nucleoside coupled to spleen cells. In contrast, NZW mice, although relatively low responders to nucleoside-KLH, were not suppressed by administration of nucleoside coupled to spleen cells. Both male and female (NZB X NZW) F1 mice appeared to behave like the NZW parental strain and were resistant to immunosuppression by nucleoside-modified spleen cells. The significance of this observation for the pathogenesis of murine systemic lupus erythematosus is discussed.
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PMID:Immune suppression to nucleosides: differences between NZB and NZW mice. 702 Nov 67

Disturbances in suppressor cell function have been considered important in the pathogenesis of systemic lupus erythematosus (SLE), a conclusion supported by studies with New Zealand mice. To determine whether other SLE mice display similar immunoregulatory defects, we investigated the susceptibility of autoimmune MRL mice to unresponsiveness induced by hapten-modified self (HMS). The response of splenocytes from MRL-lpr/lpr mice (lpr) was compared with those of sex- and age-matched, congenic MRL-+/+ mice (+/+), and H-2-identical (H-2k) CBA/J mice. Spleen cells (NSC) were cultured in vitro with hapten-modified syngeneic splenocytes (TNP-SC) and tested for responsiveness to TNP-LPS (for tolerance) or their ability to suppress the response of fresh cells. There was no difference in the susceptibility of lpr splenocytes from 3- and 10-mo-old mice to the induction of tolerance or suppression when compared with those from age-matched +/+ or CBA mice. To evaluate any quantitative defects in the responsiveness of lpr splenocytes to HMS, we modified the conditions under which suppressor activity was generated. Varying the ratio of NSC to TNP-SC from 10:1 to 2000:1, or changing the concentration of TNBS for haptenation from 10 mM to 0.5 mM per 10(8) spleen cells revealed no differences in the dose-response curves of lpr splenocytes for both tolerance and suppression when compared with those of the CBA. These results indicate that clinically affected MRL mice have intact suppressor cell activity in response to antigen-modified self and suggest a possible therapeutic role of this modality in inducing tolerance to self-antigens.
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PMID:The induction of tolerance and suppression in autoimmune MRL mice using hapten-modified self. 725 56


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