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)

Autoantibody production and leukocytopenia may be linked in patients with lupus erythematosus (LE). Unclear is the ability of different autoantibody species to induce apoptosis and cell loss. Laboratory routine analyses (white blood cell counts, autoantibody detection), and flow cytometry (annexin V, CD3, CD4, CD8) have been performed in 126 consecutive LE-patients. Nuclei of PBMC were investigated flow cytometrically for the presence of the 85 kDa poly-(ADP-ribose)-polymerase (PARP) fragment. Peripheral total white blood cells (WBC), lymphocytes, T-cells, CD3+ CD4+, and CD3+ CD8+ cells were significantly decreased in patients with LE (P from 1.2 x 10(-14) to P < .0008). In the presence of either antinuclear (P from 1.2 x 10(-14) to P < .0008) or anti-dsDNA antibodies (P from 2.9 x 10(-12) to P < .007) were significantly diminished. Differences in cell numbers in LE patients with versus without anti-Ro/SSA were less pronounced: significant differences could be only obtained in lymphocytes and T-cells (P < .02). Anti-La/SSB antibodies were accompanied by significant increased leukocytes (P < .02). PARP cleavage (85 kDa) in nuclei was preferentially observed in cases with nuclear targeting autoantibodies. These results indicate that nuclear targeting autoantibodies are associated to lower peripheral blood cells counts than Ro/SSA, and La/SSB cytoplasmic targeting autoantibodies. This provides an explanation for the pathogenesis of cytopenias associated with SLE.
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PMID:Nuclear-targeting autoantibodies induced nuclear PARP cleavage accompanied by more pronounced decrease of peripheral white blood cells than Ro/SSA and La/SSB antigen-targeting autoantibodies. 1582 86

Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A, and CD40, and their elevated production of various cytokines, including IL-12 and IL-1beta, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.
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PMID:T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. 1595 39

Increased expression of TRAIL in membrane-bound and soluble form in patients with systemic lupus erythematosus (SLE) has been previously reported. In this study, we characterized the upregulation of T-cell-associated and soluble TRAIL (sTRAIL) in vivo and the modulation of TRAIL expression and soluble protein release in vitro following T cell activation and IFNalpha exposure. The expression of membrane-bound TRAIL as determined by flow cytometry was higher on CD4(+) and CD8(+) T cells from lupus patients compared to controls, particularly on activated CD69(+)CD8(+) T cells. Similarly, sTRAIL levels determined by ELISA were significantly elevated in serum from patients with active SLE and correlated with levels of IFNalpha. In vitro, both T-cell-associated and sTRAIL were maximally induced by T cell activation plus IFNalpha in patients and controls. By Western blot analysis, sTRAIL was detected in sera in both the monomeric and multimeric, functional form. Both forms of TRAIL were functional in vitro as determined by Annexin V staining and (51)Cr release assay but the apoptotic activity of membrane TRAIL was 2.5-fold higher compared to that of sTRAIL. These results indicate that IFNalpha-induced enhancement of TRAIL expression and of TRAIL-mediated apoptosis may amplify the abnormal apoptotic process in SLE.
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PMID:Increased expression and release of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by T cells from lupus patients with active disease. 1596 46

Sle1 on chromosome 1 and Sle3/5 on chromosome 7 are two of the most critical lupus susceptibility loci of the New Zealand Black/White-derived NZM2410 mouse strain. In contrast to C57BL/6 mice congenic for either Sle1 (B6.Sle1) or Sle3/5 (B6.Sle3/5), strains that express only a modest lupus-related phenotype, the bicongenic B6.Sle1.Sle3/5 strain has a robust phenotype, suggesting a critical role for epistatic interactions in lupus pathogenesis. Mixed chimera experiments indicated that the two loci are functionally expressed by different cell populations and predicted that phenotypic expression of the phenotypic features of the B6.Sle1.Sle3/5 strain could be fully reproduced with a combination of B6.Sle1 and B6.Sle3/5 bone marrow. Contrary to our expectations, there was only a partial functional complementation in these mixed chimeras. Spleen enlargement, CD4:CD8 ratio elevation, and epitope spreading of autoantibodies were fully developed in B6+B6.Sle1.Sle3/5 but not in B6.Sle1+B6.Sle3/5 mixed chimeras. This study is the first to present evidence that the pathways mediated by two critical lupus susceptibility loci derived from the New Zealand White strain must be integrated intracellularly for epistatic interactions to occur. Our mixed chimera approach continues to provide novel insights into the functional genetic pathways underlying this important murine model of systemic autoimmunity.
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PMID:Genetic dissection of systemic lupus erythematosus pathogenesis: partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular coexpression for full phenotypic expression of lupus. 1600 39

B6.Sle1 mice, congenic for the NZM2410-derived lupus susceptibility locus, Sle1 on chromosome 1 exhibit many of the features seen in human lupus including activated lymphocytes and high titers of antinuclear autoantibodies. Among the different surface molecules that were aberrantly expressed on the B6.Sle1 lymphocytes was Ly-6A/E. Splenic B- and T-lymphocytes but not myeloid cells from B6.Sle1 mice exhibited enhanced levels of Ly-6A/E compared to B6 controls. In particular, MZ B cells, GC B cells and B-cell blasts expressed the highest levels of Ly-6A/E in both strains, with the levels being even higher on B6.Sle1 derived cells. Following stimulation with LPS or anti-IgM, there was a profound up-regulation in Ly-6A/E, particularly on MZ B cells and B-cell blasts. CD4 and CD8 T cells also up-regulated Ly-6A/E after stimulation with anti-CD3 and anti-CD28. These studies were extended to additional autoimmune strains including B6.Sle3, B6.Sle1.lpr and BXSB. Importantly, Ly-6A/E levels on lymphocytes were commensurate with the degree of disease exhibited by these lupus strains. Finally, it appears that increased interferon levels, in addition to antigen receptor stimulation, may also be a factor accounting for elevated Ly-6A/E in lupus. Given these observations it is important to elucidate the functional role of Ly-6A/E in lupus in future studies.
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PMID:Enhanced expression of stem cell antigen-1 (Ly-6A/E) in lymphocytes from lupus prone mice correlates with disease severity. 1624 22

To test the value of decreased peripheral leuko-/lymphocytes as screening test for the diagnosis lupus erythematosus (LE). Laboratory routine analyses, and flow cytometry (CD3, CD4, CD8) have been performed in 124 LE-patients. Other subjects included 57 healthy controls, 130 patients with non-autoimmune inflammatory diseases (dermatitis, psoriasis), and 17 patients with another autoimmune disease (progressive systemic sclerosis [PSS]). Numbers of peripheral blood leukocytes (P<0.0005), lymphocytes (P<0.00002), CD3+, and CD3+ CD4+ cells from LE-patients were significantly lower than from controls, patients either with dermatitis, psoriasis or PSS. CD3+ CD8+ cells were significantly diminished in patients with LE and PSS. Decreased numbers of white blood cells, lymphocytes and some of their subsets seem to indicate LE. Patients with PSS only had decreased T-cytotoxic cells. Inflammatory dermatoses lacking the autoimmunity as background have normal cell counts. For screening purpose absolute values of the mentioned blood cell subsets seem to be useful to distinguish both autoimmunity from non-autoimmune inflammatory diseases, and LE from PSS.
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PMID:Quantification of absolute peripheral white blood cells and their subsets in patients with lupus erythematosus: comparison with other inflammatory diseases with and without autoimmune background. 1625 1

The antibiotic-induced eruption of infectious mononucleosis is a well-known clinical phenomenon. Latent viral infection with herpesviridae (eg, human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV)) is suspected to play a role in the drug hypersensitivity syndrome. The cutaneous pathologic findings have not been reported in the former, and are infrequently reported in the latter entity. Herein, we describe the biopsy findings of a cefprozil-induced rash in infectious mononucleosis and a minocycline-associated drug hypersensitivity syndrome. Biopsy of these exanthematous eruptions revealed an acute vacuolar interface superficial and deep perivascular and interstitial lymphocytic dermatitis. CD8(+) lymphocytes predominated and were associated with non-neutrophilic nuclear (karyorrhectic) debris and numerous small CD68(+) and CD123(+) monocytes. These aforementioned features have been described in cutaneous lesions of Kikuchi-Fujimoto disease, an entity whose clinicopathologic findings overlap with both infectious mononucleosis and lupus erythematosus. Serologic evidence of active and chronic active EBV infection was found in both patients, respectively. No evidence of EBV or HHV6 was found in the cutaneous lesions. Plasmacytoid monocytes (CD68(+)/CD123(+) cells), which produce type I interferon, are believed to play a role in viral immunity by protecting other cells from viral infections and promoting survival of antigen-activated T cells. Their presence in these two putative examples of viral-drug immune dysregulation could be a clue to pathogenesis and represent a common cellular component of some adverse cutaneous drug eruptions.
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PMID:Adverse antibiotic-induced eruptions associated with epstein barr virus infection and showing Kikuchi-Fujimoto disease-like histology. 1645 26

Regulation of lymphocyte survival is essential for the maintenance of lymphoid homeostasis preventing the development of autoimmune diseases. Recently, we described a systemic lupus erythematosus associated with an IgA nephropathy in autoimmune-prone (NZW x C57BL/6)F(1) overexpressing human Bcl-2 (hBcl-2) in B cells (transgenic (Tg) 1). In the present study, we analyze in detail a second line of hBcl-2 Tg mice overexpressing the transgene in all B cells and in a fraction of CD4(+) and CD8(+) T cells (Tg2). We demonstrate here that the overexpression of hBcl-2 in T cells observed in Tg2 mice is associated with a resistance to the development of lupus disease and collagen type II-induced arthritis in both (NZW x C57BL/6)F(1) and (DBA/1 x C57BL/6)F(1) Tg2 mice, respectively. The disease-protective effect observed in autoimmune-prone Tg2 mice is accompanied by an increase of peripheral CD4(+)CD25(+) hBcl-2(+) regulatory T cells (T(regs)), expressing glucocorticoid-induced TNFR, CTLA-4, and FoxP3. Furthermore, the in vivo depletion of CD4(+)CD25(+) T(regs) in (DBA/1 x C57BL/6)F(1) Tg2 mice promotes the development of a severe collagen type II-induced arthritis. Taken together, our results indicate that the overexpression of hBcl-2 in CD4(+) T cells alters the homeostatic mechanisms controlling the number of CD4(+)CD25(+) T(regs) resulting in the inhibition of autoimmune diseases.
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PMID:CD4+CD25+ T cell-dependent inhibition of autoimmunity in transgenic mice overexpressing human Bcl-2 in T lymphocytes. 1731 21

T cells play an essential role in driving humoral autoimmunity in lupus. Molecules such as TRAIL exhibit strong T cell modulatory effects and are up-regulated in lupus, raising the possibility that they may influence disease severity. To address this possibility, we examined the role of TRAIL expression on pathogenic T cells in an induced model of murine lupus, the parent-into-F(1) (P-->F(1)) model of chronic graft-vs-host disease (GVHD), using wild-type or TRAIL-deficient donor T cells. Results were compared with mice undergoing suppressive acute GVHD. Although chronic GVHD mice exhibited less donor T cell TRAIL up-regulation and IFN-alpha-inducible gene expression than acute GVHD mice, donor CD4(+) T cell TRAIL expression in chronic GVHD was essential for sustaining effector CD4(+) Th cell numbers, for sustaining help to B cells, and for more severe lupus-like renal disease development. Conversely, TRAIL expression on donor CD8(+) T cells had a milder, but significant down-regulatory effect on CTL effector function, affecting the perforin/granzyme pathway and not the Fas ligand pathway. These results indicate that, in this model, T cell-expressed TRAIL exacerbates lupus by the following: 1) positively regulating CD4(+) Th cell numbers, thereby sustaining T cell help for B cells, and 2) to a lesser degree by negatively regulating perforin-mediated CD8(+) CTL killing that could potentially eliminate activated autoreactive B cells.
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PMID:T cell TRAIL promotes murine lupus by sustaining effector CD4 Th cell numbers and by inhibiting CD8 CTL activity. 1733 97

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. In this study we investigated the beneficial effects on murine lupus accomplished by a peptide based on the sequence of the complementarity-determining region 1 of an anti-DNA autoantibody (hCDR1) when given alone or in combination with cyclophosphamide (CYC), and determined the mechanisms underlying those effects. SLE-afflicted (NZB x NZW) F(1) mice were treated for 12 weeks with injections of hCDR1, CYC or a combination of both drugs. We found that hCDR1 and CYC ameliorated serological and renal manifestations of the diseased mice, down-regulated interferon-gamma and interleukin-10, and up-regulated transforming growth factor-beta. These effects were associated with an increment of naive CD4(+) cells at the expense of the number of CD4(+) cells with the memory/activated phenotype. Further, the number of CD8(+) cells in the diseased mice was increased by the two drugs, resulting in a significant decrease in the CD4 : CD8 ratio. However, whereas the frequency and activity of CD4(+) CD25(+) CD45RB(low) regulatory T cells and the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4(+) cells were up-regulated by hCDR1 treatment, they were minimally affected following treatment with CYC. CTLA-4 played an important role in the activity of the hCDR1-induced CD4(+) CD25(+) cells as manifested by down-regulation of CD28 expression, decrease of activation-induced apoptosis, and modulation of the cytokine profile in CD4(+) CD25(-) cells derived from SLE-afflicted mice. Thus, although the two drugs have similar ameliorative effects, hCDR1 but not CYC elicits regulatory pathways that are of importance for tolerance induction in SLE.
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PMID:Clinical amelioration of murine lupus by a peptide based on the complementarity determining region-1 of an autoantibody and by cyclophosphamide: similarities and differences in the mechanisms of action. 1734 82


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