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)

The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.
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PMID:Perforin protects against autoimmunity in lupus-prone mice. 955 99

Massive accumulation of CD4-CD8-TCRalphabeta+ cells in secondary lymphoid organs is characteristic of lupus-prone MRL/lpr mice. However, the role of these double negative T cells (DNT) in human lupus patients receive only limited attention. Herein, we investigate the frequency of DNT in the peripheral blood mononuclear cells of forty seven Chinese patients with systemic lupus erythematosus (SLE) and forty four normal individuals. DNT were measured with dual-fluorescence flow cytometry. The results showed that DNT only constituted a very minor subset of lymphocytes both in patients and normals, it normally did not exceed 2% of the lymphocyte population. Compared with normal subjects, patients with SLE had slightly increased levels of DNT within the total lymphocyte population (0.66+/-0.45% vs 0.51+/-0.33%) or within TCRalphabeta+ population (1.14+/-0.88% vs 0.88+/-0.54%). The difference, however, did not reach statistical significance. The levels of DNT correlated neither with the titers of anti-DNA antibodies in sera nor with the presence of active and severe lupus nephritis in SLE patients. Longitudinal follow-up of six patients at the stages of active and inactive nephritis revealed similar levels of DNT in the same individual. The preliminary results suggest that circulating DNT do not appear to play a critical role in Chinese patients with SLE.
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PMID:Double-negative (CD4-CD8-) TCRalphabeta+ cells in patients with systemic lupus erythematosus. 957 39

A new strategy for the treatment of autoimmune diseases in chimeric resistant MRL/lpr mice is established. The strategy includes injection of cyclophosphamide (CY), fractionated irradiation (5 Gy x 2), bone grafts (to recruit stromal cells), and two transplantations of whole bone marrow cells (WBMCs) from allogeneic normal C57BL/6 mice (CY/2X/Bone/2BMT). MRL/lpr mice, thus treated, survived more than 40 weeks (1 mouse survived for >40 weeks, 7 for >50 weeks, and 4 for >60 weeks after these treatments). Immunohistological studies showed that the mice were completely free from both lymphadenopathy and autoimmune diseases such as systemic lupus erythematosis and rheumatoid arthritis. The levels of autoantibodies (IgM/IgG rheumatoid factors and IgM/IgG anti-ssDNA antibodies [Abs]) in the treated mice decreased to those in the normal mice. In addition, successful cooperation among T cells, B cells, and antigen-presenting cells (APCs) was observed. Abnormal T cells with immunophenotypes of B220+/Thy-1+/CD3+/CD4-/CD8- present in untreated MRL/lpr mice disappeared, and the hematolymphoid cells of the treated mice were of donor origin. However, the mice that had been irradiated with 8.5 Gy and then reconstituted with T-cell-depleted BMCs plus bone grafts died within 2 weeks due to the side effect of irradiation. The depletion of CD8+ cells (not CD4+ cells) from WBMCs resulted in graft failure; 60% of the recipient mice, thus treated, died within 2 weeks, and all recipients died by 15 weeks. Furthermore, limiting dilution assays showed that approximately more than 0.5% of T cells contained in the BMCs are necessary not only for engraftment of BMCs but also for long-term disease-free survival of the recipients. In contrast, recipients that had received CD4-depleted BMCs with CY plus fractionated irradiation (5Gy x 2) survived for more than 40 weeks without showing graft-versus-host reaction (GVHR). This indicates that CD8(+)cells in the BMCs are essential for the successful engraftment of the donor-type hematolymphoid cells.
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PMID:A new strategy for treatment of autoimmune diseases in chimeric resistant MRL/lpr mice. 961 58

It is known that lpr mice develop systemic lymphadenopathy and lupus erythematosus-like autoimmune disease that are associated with the accumulation of CD4- CD8- (double-negative; DN) CD3+ B220+ abnormal T cells as well as normal mature CD4+ or CD8+ single-positive (SP) CD3+ T cells. In order to clarify the role of B cells in the lymphoproliferation and autoimmunity of lpr mice, we created B-cell-deficient C57BL/6 (B6) lpr mice (B6lpr/lpr microMT/microMT) by crossing B6lpr/lpr mice with B6 microMT/microMT mice in which the B-cell development was arrested at pre-B stage owing to a targeted disruption of the immunoglobulin mu heavy-chain gene locus. In the B-cell-deficient B6-lpr mice, both lymphadenopathy and splenomegaly were markedly suppressed. Although the accumulation of both CD3+ B220- SP normal T cells and CD3+ B220+ DN abnormal T cells was inhibited in the B-cell-deficient lpr mice, the decrease in numbers of CD3+ B220- SP normal T cells occurred more strikingly than that of the CD3+ B220+ DN abnormal T cells. Glomerulonephritis did not develop in the B-cell-deficient lpr mice over 40 weeks. The present results indicate that the B cells thus play a crucial role in the extensive proliferation of normal CD3+ B220- mature SP T cells rather than the accumulation of abnormal DN T cells.
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PMID:Proliferation of CD3+ B220- single-positive normal T cells was suppressed in B-cell-deficient lpr mice. 961 74

The number of peripheral blood CD8 T cells declines in advanced stages of human immunodeficiency virus (HIV) infection coinciding with the transition from a clinically asymptomatic state of infection to AIDS. Although blood monocytes/macrophages exhibit cytotoxicity for CD4 T cells soon after HIV infection, cytotoxicity against CD8 T cells occurs at the time when HIV infection advances. The cytotoxic reaction is mediated by immunoglobulins that bind to T cells and which can be eluted from them. The immunoglobulins enable macrophages from noninfected persons to destroy healthy T cells in tissue culture. Lymphocyte-reactive autoantibodies (LRAs) occur physiologically as a result of chronic allo- or self-antigen stimulation. Lymphopenic, autoimmune lupus erythematosus patients exhibit LRAs that facilitate the deletion of T cells by macrophages. It is proposed that LRAs represent an immunoregulatory cytotoxic mechanism that is activated after chronic immune stimulation and is engaged by HIV to deplete host lymphocytes.
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PMID:Lymphocyte-reactive autoantibodies in human immunodeficiency virus type 1-infected persons facilitate the deletion of CD8 T cells by macrophages. 969 20

CD44 variant isoforms are frequently expressed on tissue-infiltrating lymphocytes. By the high incidence of autoimmune reactions of the skin and aiming at new strategies of therapeutic intervention, we became interested in evaluating the CD44 isoform expression profile in autoimmune reactions of the skin. Expression of CD44s, CD44v3, v5, v6, v7, v7-v8, and v10 was evaluated in 55 biopsies of lupus erythematosus, bullous pemphigoid, vasculitis, morphea, and pemphigus vulgaris. Biopsies did not contain CD44v5-, CD44v6-, CD44v7-, or CD44v7-v8-positive leukocytes. Staining with anti-CD44v10 was seen in vasculitis and occasionally in lupus erythematosus, morphea, and bullous pemphigoid. All biopsies contained CD44v3(+) leukocytes, the percentage of CD44v3(+) leukocytes being increased in autoimmune infiltrates with the exception of pemphigus vulgaris. CD44v3 was expressed by CD4(+) cells as well as by part of CD8(+) cells, Langerhans cells, and monocytes. Vascular endothelium also contained CD44v3(+) cells. Only monocytes expressed CD44v10. We assume that CD44v3 and CD44v10 may be targeting leukocytes toward the skin or allow for their retention and expansion via binding of cytokines and chemokines harbored by activated, skin-associated endothelium or provided by cells surrounding the infiltrate. The absence of CD44v6, frequently associated with lymphocyte activation, appears to be a peculiarity of skin-infiltrating leukocytes.
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PMID:CD44 variant isoform expression in a variety of skin-associated autoimmune diseases. 975 27

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.
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PMID:Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2 alpha. 982 Apr 86

Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age-dependent accumulation of activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3-bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.
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PMID:Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. 1035 64

Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4(+) T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.
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PMID:Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. 1037 75

MRL-lpr/lpr is a strain of mice that develops spontaneous signs of the autoimmune disease, systemic lupus erythematosus (SLE or lupus). The lpr (lymphoproliferation) defect has been identified as an insertion of an early transposon (ETn) derived sequence into the fas apoptosis gene. We studied the in vivo effects of difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), on the expression of fas in MRL-lpr/lpr mice as well as in congenic MRL- + / + and autoimmune NZB/W strains. Using Northern blot hybridization and reverse transcription polymerase chain reaction (RT-PCR), we found that DFMO treatment resulted in an increase in the expression of fas mRNA in the thymus of MRL-lpr/lpr mice. Using RT-PCR, we further found that the increased expression of fas was associated with the suppression of chimeric ETn/fas mRNA. With fractionated CD4 + and CD8 + T cells, we found a cell-specific effect of DFMO on chimeric ETn/fas expression in CD8 + cells. ETn/fas expression was detected in CD8+ T cells from untreated mice, but it was eliminated after DFMO treatment. HPLC analysis of polyamines showed depletion of putrescine and partial reduction of spermidine (35%) in DFMO-treated mice compared to controls. These results indicate that DFMO-mediated polyamine depletion is linked to the regulation of fas and chimeric ETn/fas in MRL-lpr/lpr mice. Elevated levels of polyamines in this strain, as found in earlier studies, may be associated with the progression of the autoimmune disease by altering the expression of fas gene or by facilitating the expression of chimeric ETn/fas. Our data also provide new mechanistic insights into the beneficial effects of DFMO on these mice.
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PMID:Polyamine-fas interactions: inhibition of polyamine biosynthesis in MRL-lpr/lpr mice is associated with the up-regulation of fas mRNA in thymocytes. 1043 86


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