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)

Autoimmune New Zealand white (NZW) mice contribute to (New Zealand black x New Zealand white)F1 mice 1 or more major histocompatibility complex-linked genes that strongly correlate with susceptibility to murine lupus. The NZW class II major histocompatibility complex genes, I-E alpha and I-E beta, were cloned and sequenced and found to differ from normal B10.PL (H-2u) mice by 3 amino acids in the first domain of the I-E beta subunit. Of these differences, the arginine at position 72 of NZW mice could be an important disease determinant since it lies in a predicted antigen-binding cleft.
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PMID:Sequence of I-E genes from autoimmune New Zealand white mice. 210 15

Two models of murine graft-versus-host disease (GVHD) were studied with respect to autoantibody production and development of systemic lupus erythematosus (SLE) like disease. One model was induced by injection of (B10.A(4R) x B10.A(2R]F1 mice with parental (B10.A(4R] spleen and lymph node cells (groups I GVHD), the other by injection of (DBA/2 x C57/B16)F1 mice with DBA/2 cells (group II GVHD). Group I GVHD mice remained in a seemingly healthy condition and did not show any proteinuria, in spite of high titres of anti-nuclear antibodies including antibodies to dsDNA, anti-Sm and anti-ribosomal P protein antibodies. Measured levels of these autoantibodies as well as their isotypes were comparable with those found in MRL/lpr and NZB/W mice. Group II GVHD mice developed SLE-like disease signs, including severe proteinuria. At 4 months after induction of the GVHD, almost 50% of these mice had died. At the time nephritis was present, group II mice also produced anti-dsDNA and anti-nuclear antibodies of other (unknown) specificities, but no anti-Sm or anti-P. Furthermore, the incidence of these antibodies was lower than observed in group I GVHD, MRL/lpr or NZB/W mice. It is concluded that (high avidity) anti-dsDNA as well as anti-Sm and anti-P may be present in the circulation without giving rise to the development of nephritis.
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PMID:Fine specificities of anti-nuclear antibodies in murine models of graft-versus-host disease. 237 20

These experiments examined the effects of genes outside of the H-2 region on disease susceptibility and pathogenesis. Four strains of mice with the susceptible H-2 type, H-2d, but different non-H-2 genes were studied. B10, D2, Balb/c, NZB, and DBA/2J mice were injected with 4 mg of apoferritin i.p. q.d. for 28 days. B10, D2 and Balb/c mice developed proliferative and crescentic glomerulonephritis. NZB mice developed proliferative and crescentic glomerulonephritis with wire loop lesions suggestive of lupus. DBA/2J mice developed only minimal mesangial proliferation without crescents or necrosis. Electron microscopy showed subepithelial and mesangial deposits in B10, D2, moderate subepithelial and mesangial deposits in Balb/c, and marked mesangial, subendothelial and subepithelial deposits in NZB. Immunofluorescence demonstrated the presence of IgG, IgM, C3 and apoferritin in these deposits. The DBA/2J mice had only minimal mesangial deposits by immunofluorescence and electron microscopy. These experiments demonstrate that non-H-2 genes alter the H-2d determined disease susceptibility seen in H-2 congenic mice. NZB genes can alter the disease so that lupus-like lesions develop and DBA/2J genes can substantially ameliorate the disease.
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PMID:Non-H-2 genes alter the H-2 determined susceptibilities in immune complex nephritis. 253 Mar 82

MRL-+, MRL-lpr and B6-lpr have been shown to be useful models in studying systemic lupus erythematosus. MRL-lpr and B6-lpr differ from their congenic counterparts by the presence and expression of the homozygous recessive lymphoproliferation (lpr) gene. One manifestation of this gene is a massive T-cell proliferation that results in a generalized lymphadenopathy in older animals. A paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigate the basis for this hyporesponsiveness in antigen-induced activation of proliferation and antibody synthesis. We have demonstrated that spleen cells from both MRL-+ and MRL-lpr mice gave minimal stimulation in a one-way mixed lymphocyte reaction against allogeneic T cells. These findings were extended to include antigen-specific proliferation involving antigen that must be processed and presented to responder lymphocytes in a H-2 restricted manner. Thus, MRL-+ and MRL-lpr spleen cells pulsed with ferredoxin also failed to stimulate ferredoxin-primed T cells from B10.Br animals in vitro. We then investigated whether any T-cell defect(s) was also contributing to this proliferative hyporesponsiveness. T lymphocytes from the spleen of MRL-+, 2-month-old MRL-lpr, and 6-month-old MRL-lpr were tested in a one-way mixed lymphocyte reaction. It was found that only the MRL-+ T cells gave responses approaching normal, suggesting lpr gene involvement in T-cell non-responsiveness. This was confirmed by the demonstration of an age-onset T-cell proliferative hyporesponsiveness in B6-lpr mice. This lpr gene-linked non-responsiveness was also shown to extend to T-cell helper function in a positive allogeneic effect assay. We can conclude from these studies that antigenic nonresponsiveness in MRL congenic mice can be explained by two defects: the failure of antigen-presenting cells in MRL-+ and MRL-lpr mice to provide the necessary signal(s) to immunocompetent T cells, this defect not being associated with the lpr gene, and the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay systems.
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PMID:Antigen-specific T-cell hyporesponsiveness in MRL congenic mice can be explained by two independent cellular defects. 295 99

In an effort to characterize further the role of T cells in the autoimmune disease of MRL/Mp-lpr/lpr (lpr) mice, continuous cell lines were established from spleen and lymph nodes using EL-4 lymphoma supernatants as a source of T-cell growth factor(s). Five lines were derived from lpr spleen and lymph nodes, and an equal number from MRL/Mp- +/+ (+/+). All of the lines lost their alloreactivity after a short time in culture. Surprisingly, every line manifested marked proliferation in response to autologous irradiated spleen cells. This response was restricted to I-Ak, as it was blocked with monoclonal anti-I-Ak antibodies, and as B10.A(4R) accessory cells were stimulatory while B10.A(3R) were not. There was no difference in the degree of stimulation from lpr accessory cells compared to that in those from +/+ or other H-2k mice. The T-cell lines bore Thy-1, Ly-1, L3T4, and 7D4 (interleukin 2 (IL-2) receptor), but lacked Ly-2 and surface Ig. They proliferated in response to both conventional and recombinant DNA-derived IL-2. When cocultured with Ia-identical B cells, the T-cell lines provoked B-cell division and antibody production. The cells also caused intense proliferation when cultured with freshly isolated lpr (but not +/+) lymph node cells. The results indicate that lpr lymphoid tissue contains functional T cells reactive to autologous Ia molecules and capable of inducing both B-cell activation and the proliferation of lpr lymphocytes. Such cells may be of importance in inducing hypergammaglobulinemia, autoantibody production, and lymphoproliferation in these SLE mice.
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PMID:Characterization of functional T-cell lines derived from MRL mice. 308 56

Systemic lupus erythematosus is an immunologically mediated autoimmune disease which has been reported to be aggravated by certain environmental agents such as ultraviolet irradiation (UV). To further investigate this interaction, we examined the consequences of UV exposure on the autoimmune process of several strains of autoimmune mice. Strains of age- and sex-matched, 3- to 4-month old, autoimmune (MRL-lpr/lpr, (NZB X NZW)F1, BXSB) and nonautoimmune (BALB/c, B10.A) mice were shaved and exposed to an acute (2 h daily X 7 days) and a chronic (3 h/weekly X 4 weeks) dose of UV (FS40 lamps, 2 mJ/cm2/s). UV-induced changes in survival, autoantibody production, splenic B-cell activity, and target organ pathology were examined. After an acute UV exposure there were (10/15) deaths in the UV BXSB males and (4/15) in the UV BXSB females, compared to (1/15) in the non-UV BXSB male group and (0/15) in the non-UV BXSB females. No deaths occurred in the other UV autoimmune or nonautoimmune groups. Likewise, chronic UV resulted in increased UV BXSB male mortality (13/15) compared to UV BXSB females (2/15) and non-UV BXSB males and females. No deaths occurred in the other autoimmune (MRL-lpr/lpr, (NZB X NZW)F1) or nonautoimmune (BALB/c, B10.A) strains, after chronic UV exposure. Equivalent doses of Mylar-filtered FS40 UV (UVB deleted) resulted in no deaths in the UV BXSB male group. Acute and chronic UV also resulted in a significant increase in serum single-stranded DNA antibody production, splenic polyclonal B-cell activity, and renal glomerular inflammatory changes in the UV BXSB male mice. Thus, UV resulted in premature death and accelerated autoimmunity in UV BXSB males and may serve as a useful model for phototoxicity in autoimmunity.
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PMID:Effects of UV radiation on autoimmune strains of mice: increased mortality and accelerated autoimmunity in BXSB male mice. 389 90

Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. In the present paper we analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. First, nonirradiated F1 mice were used as the recipients. We found that unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients; these cells were capable, however, of inducing a vigorous formation of SLE-like autoantibodies and the formation of severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. In another experiment, the sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and by comparing donor-cell inocula that contained similar numbers of T lymphocytes. In addition, donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients, too, unseparated donor T cells were superior to T cell subsets in inducing LGVHD; Lyt-1-2+ donor cells were completely and Lyt-1+2- donor cells were almost incapable of doing so. In contrast, Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.
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PMID:Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes. 622 82

Groups of nonirradiated BDF1 mice were injected with unseparated spleen cells from B10, B10.D2, or DBA/2 donors. The diverse clinical and pathologic symptoms that developed during the course of the ensuing graft-vs-host reaction (GVHR) were related to the functional subsets of donor-T cells activated in the host. The activation of F1-specific donor T suppressor (TS) cells was confined to those GVH F1 mice that developed acute GVH disease (GVHD) (donor B10 or B10.D2). Moreover, activation in these GVH F1 mice of the Lyt-1-2+ donor TS cells sharply preceded the onset of and coincided with (week 2 to 6) the suppressive pathologic symptoms characteristic of acute GVHD, such as pancytopenia and suppression of splenic IgG production. The activation of these alloreactive TS effector cells was briefly preceded by the activation of F1-specific Lyt-1+-2- donor T helper (TH) cells and stimulation of the host's lymphoid tissue. Thus, in acute GVHD, a sequential alloactivation first of donor TH and then of TS cells was found. Those F1 mice that recovered from acute GVHD and developed stimulatory pathologic symptoms showed a concomitant loss of donor TS cell activity. An initial activation of F1-specific Lyt-1 +2- donor TH cells was also found in that parent----F1 combination (donor DBA/2), which failed to develop acute GVHD. Significantly in that combination, the alloactivation of donor TH cells was not followed by activation of significant numbers of donor TS cells. Instead, the DBA/2-injected BDF1 mice directly developed a persistent increase in splenic Ig formation and lupus-like GVHD.
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PMID:Allosuppressor- and allohelper-T cells in acute and chronic graft-vs-host disease. IV. Activation of donor allosuppressor cells is confined to acute GVHD. 623 Mar 90

Lupus-prone (NZB X NZW)F1 (B X W) mice and MRL-lpr and BXSB mice were examined for the prevalence of hypertension and levels of plasma renin activity (PRA). Hypertension (greater than 145 mmHg) was observed only in female and male B X W mice with severe nephritis; in female MRL-lpr and male BXSB mice severe nephritis developed without blood pressure elevation (80-135 mmHg). The B X W parental strains, NZB and NZW, and the MRL-lpr congenic partners, MRL- +, did not become hypertensive as they aged. Other strains of mice, aged 3-32 months (A/HeN, BALB/cJ, BALB/cByJ, B10.S/Sg, B10.D2/ oSn , CBA/J, C3H/HeJ, SJL/J and [SJL X NZW]F1), also had normal blood pressure (98-122 mmHg). All mice with lupus nephritis had low PRA, even those with hypertension; furthermore, the MRL-lpr strain had low or undetectable PRA (2 +/- 1 ng/ml/hr), even when kidneys were normal. NZB, NZW, and MRL- + mice had normal PRA (10-16 ng/ml/hr). Thus, B X W mice frequently developed low renin hypertension during the last phase of their renal disease; whereas MRL-lpr and BXSB mice died from renal disease without observable increases in blood pressure.
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PMID:Differences in the occurrence of hypertension among (NZB X NZW)F1, MRL-lpr, and BXSB mice with lupus nephritis. 637 6

By induction of a suitable graft-vs-host reaction (GVHR) in H-2-different F1 mice, one can induce the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). The purpose of the present study was to define the intra-H-2 differences in the F1 recipients that are capable of triggering this process. A GVHR was induced in [B10.A(2R) x B10.A(4R)]F1 mice by injecting 10(8) lymphocytes from either parental strain. Whereas the donor B10.A(4R) induced a massive formation of autoantibodies to thymocytes, erythrocytes, nuclear antigens, and double-stranded DNA, the donor B10.A(2R) failed to do so. The intra-H-2 genetics of these two parent leads to F1 combinations are such that the observed autoantibody formation after the injection of B10.A(4R) T cells must have been triggered exclusively by the incompatible I-Ek subregion of the [B10.A(2R) x B10.A(4R)]F1 recipients. Because I-E appears to be the murine analogue of HLA-D/DR, this finding is of interest with respect to the increased frequency of certain HLA-DR alleles in SLE patients, as discussed.
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PMID:Diseases caused by reactions of T lymphocytes towards incompatible structures of the major histocompatibility complex. VI. Autoantibodies characteristic of systemic lupus erythematosus induced by abnormal T-B cell cooperation across I-E. 697 76


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