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)

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
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PMID:Costimulation requirements of induced murine systemic autoimmune disease. 1549 42

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by a wide range of immunological abnormalities that underlie the loss of tolerance. In this study we show that administration of atorvastatin to lupus-prone NZB/W F(1) mice resulted in a significant reduction in serum IgG anti-dsDNA Abs and decreased proteinuria. Histologically, the treatment was associated with reduced glomerular Ig deposition and less glomerular injury. Disease improvement was paralleled by decreased expression of MHC class II on monocytes and B lymphocytes and reduced expression of CD80 and CD86 on B lymphocytes. Consequent upon this inhibition of Ag presentation, T cell proliferation was strongly impaired by atorvastatin in vitro and in vivo. A significant decrease in MHC class II expression was also observed in the target organ of lupus disease (i.e., the glomerulus). Serum cholesterol in atorvastatin-treated lupus mice fell to the level found in young NZB/W mice before disease onset. This is the first demonstration that atorvastatin can delay the progression of a spontaneous autoimmune disease and may specifically benefit patients with systemic lupus erythematosus.
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PMID:Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. 1558 92

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

The use of mAbs to abrogate costimulatory interactions has attracted much attention with regard to prevention and modulation of adverse (auto)immune-like reactions. However, the role of costimulatory molecules and possible therapeutic use of Ab-treatment in drug-induced immunostimulation is poorly elucidated. In the present studies, we show that CD28/CTLA-4-CD80/CD86 costimulatory interactions differently regulate drug-induced type 1 and type 2 responses to an identical bystander Ag, TNP-OVA, in BALB/c mice using the reporter Ag popliteal lymph node assay. The antirheumatic drug D-Penicillamine, which may induce lupus-like side-effects, stimulated type 2 responses against TNP-OVA, characterized by the production of IL-4 and TNP-specific IgG1 and IgE. These responses were abrogated in CD80/CD86-deficient mice and in wild-type mice that were treated with anti-CD80 and anti-CD86, or CTLA-4-Ig. Anti-CTLA-4 intensively enhanced the D-Penicillamine-induced effects. In contrast, the type 1 response (IFN-gamma, TNF-alpha, IgG2a) to TNP-OVA induced by the diabetogen streptozotocin still developed in the absence of CD80/CD86 costimulatory signaling. In addition, it was demonstrated that coadministration of anti-CD80 and anti-CD86 mAbs slightly enhanced streptozotocin-induced type 1 responses, whereas the CTLA-4-Ig fusion protein completely abrogated this response. In conclusion, different drugs may stimulate distinct types of immune responses against an identical bystander Ag, which are completely dependent on (type 2) or independent of (type 1) the CD28/CTLA-4-CD80/CD86 pathway. Importantly, the effects of treatment with anti-CD80/CD86 mAbs and CTLA-4-Ig may be considerably different in responses induced by distinct drugs.
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PMID:Differential requirement for CD28/CTLA-4-CD80/CD86 interactions in drug-induced type 1 and type 2 immune responses to trinitrophenyl-ovalbumin. 1614 16

We analyzed the activation and function of dendritic cells (DCs) in the spleens of diseased, lupus-prone NZM2410 and NZB-W/F1 mice and age-matched BALB/c and C57BL/6 control mice. Lupus DCs showed an altered ex vivo costimulatory profile, with a significant increase in the expression of CD40, decreased expression of CD80 and CD54, and normal expression of CD86. DCs from young lupus-prone NZM2410 mice, before the development of the disease, expressed normal levels of CD80 and CD86 but already overexpressed CD40. The increase in CD40-positive cells was specific for DCs and involved the subset of myeloid and CD8alpha+ DCs before disease onset, with a small involvement of plasmacytoid DCs in diseased mice. In vitro data from bone marrow-derived DCs and splenic myeloid DCs suggest that the overexpression of CD40 is not due to a primary alteration of CD40 regulation in DCs but rather to an extrinsic stimulus. Our analyses suggest that the defect of CD80 in NZM2410 and NZB-W/F1 mice, which closely resembles the costimulatory defect found in DCs from humans with systemic lupus erythematosus, is linked to the autoimmune disease. The increase in CD40 may instead participate in disease pathogenesis, being present months before any sign of autoimmunity, and its downregulation should be explored as an alternative to treatment with anti-CD40 ligand in lupus.
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PMID:Abnormal costimulatory phenotype and function of dendritic cells before and after the onset of severe murine lupus. 1650 74

Systemic lupus erythematosus (SLE) is characterized by a systemic autoimmune response with profound and diverse T cell changes. Dendritic cells (DCs) are important orchestrators of immune responses and have an important role in the regulation of T cell function. The objective of this study was to determine whether myeloid DCs from individuals with SLE display abnormalities in phenotype and promote abnormal T cell function. Monocyte-derived DCs and freshly isolated peripheral blood myeloid DCs from lupus patients displayed an abnormal phenotype characterized by accelerated differentiation, maturation, and secretion of proinflammatory cytokines. These abnormalities were characterized by higher expression of the DC differentiation marker CD1a, the maturation markers CD86, CD80, and HLA-DR, and the proinflammatory cytokine IL-8. In addition, SLE patients displayed selective down-regulation of the maturation marker CD83 and had abnormal responses to maturation stimuli. These abnormalities have functional relevance, as SLE DCs were able to significantly increase proliferation and activation of allogeneic T cells when compared with control DCs. We conclude that myeloid DCs from SLE patients display significant changes in phenotype which promote aberrant T cell function and could contribute to the pathogenesis of SLE and organ damage.
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PMID:Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus. 1705 12

The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4(+) T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.
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PMID:IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. 1718 64

Polyclonal B cell activation is a well-described feature of systemic lupus erythematosus (SLE), but the immune mechanisms leading to this activation are unclear. To gain insight into these processes, we extensively characterized the activated peripheral blood B cell populations in SLE. PBMC from lupus patients and healthy controls were stained with various combinations of conjugated Ab to identify distinct peripheral B cell subsets, and activation was assessed by measurement of forward scatter and CD80 or CD86 expression using flow cytometry. SLE patients had altered proportions of several B cell subsets, many of which demonstrated increased activation as assessed by forward scatter. This activation occurred at an early developmental stage, as B cells in the transitional (T2) stage were already significantly larger than those seen in controls. Increased proportions of CD80- or CD86-expressing cells were also seen in multiple B cell subsets, with the most striking differences observed in the naive CD27-CD23+ population. Within the CD23+ subset, increased costimulatory molecule expression was most pronounced in an IgD+IgMlow population, suggesting that activation follows Ag engagement. Although controls also had IgD+IgMlowCD23+ cells, they were reduced in number and not activated. Thus, there is an altered response to Ig receptor engagement with self-Ags in lupus.
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PMID:Expanded population of activated antigen-engaged cells within the naive B cell compartment of patients with systemic lupus erythematosus. 1817 68

Recent studies show that a CD8+CD28- phenotype of T-cell population inhibits the reactivity of T-helper cells either by a contact-dependent mechanism or with secreting suppressive cytokines. In this study, we have explored the peripheral blood CD8+CD28- T-cell population in 53 patients with systemic lupus erythematosus (SLE) in comparison to healthy and diseased control groups. The distribution of CD28- cells within CD8+ population has been found significantly lower in patients with SLE than in healthy individuals. While there were no significant differences in the expression of costimulatory molecules CD80 and CD86, the CD40 expression on monocytes was found significantly lower and there was a slight decrease of expression of Interleukin-10 (IL-10) in CD8+CD28- population in patients with SLE. The Transforming growth factor-beta (TGF-beta) mRNA expression was found higher in CD8+CD28- T cells. Neither activation induced nor time-dependent change in the frequency of CD8+CD28- cells has been observed following stimulation at various time-points indicating that the control of CD28 expression was not dependent on the presence of sustained stimulations. Decrease in CD8+CD28- T cells which normally produce TGF-beta and their low-level IL-10 content may reflect impaired T-cell suppression and accordingly, increased T cell help to autoreactive B cells in patients with SLE.
Lupus 2008 Jul
PMID:CD8+CD28-, suppressive T cells in systemic lupus erythematosus. 1862 35

Systemic lupus erythematosus (SLE) is characterized in its early stages by the expansion of autoreactive T cells that trigger B-cell activation with subsequent multi-organ injury. Dendritic cells (DCs) in lupus were found to display an aberrant phenotype with higher expression of the maturation markers major histocompatibility complex (MHC) class II, CD80 and CD86, as well as higher production of proinflammatory cytokines including interleukin-12 (IL-12), resulting in an increased ability to activate T cells. A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorated SLE in both induced and spontaneous lupus models by downregulating T-cell functions. Our objectives were to determine whether DCs play a role in promoting the beneficial effects of hCDR1. We showed here that treatment with hCDR1 lowered the expression levels of MHC class II, CD80 and CD86 on DCs. The latter effect was associated with downregulation of messenger RNA expression and secretion of IL-12, a cytokine that upregulated T-cell proliferation and interferon-gamma (IFN-gamma) secretion. Moreover, DCs derived from hCDR1-treated mice downregulated proliferation and IFN-gamma secretion by T cells from untreated mice. Upregulation of transforming growth factor-beta (TGF-beta) secretion by T cells, following treatment with hCDR1, resulted in downregulation of IFN-gamma production and contributed to the phenotypic changes and magnitude of IL-12 secretion by DCs. The ameliorating effects of hCDR1 are therefore mediated at least partially by the upregulated secretion of TGF-beta by T cells that contribute to the induction of DCs with immature phenotype and suppressed functions. The resulting DCs further downregulate autoreactive T-cell functions.
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PMID:The role of dendritic cells in the mechanism of action of a peptide that ameliorates lupus in murine models. 1904 Apr 26


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