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)

Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cell (DC) precursors, represent the key effectors in antiviral innate immunity and triggers for adaptive immune responses. IPCs play important roles in the pathogenesis of systemic lupus erythematosus (SLE) and in modulating immune responses after hematopoietic stem cell transplantation. Understanding IPC development from hematopoietic progenitor cells (HPCs) may provide critical information in controlling viral infection, autoimmune SLE, and graft-versus-host disease. FLT3-ligand (FLT3-L) represents a key IPC differentiation factor from HPCs. Although hematopoietic cytokines such as interleukin-3 (IL-3), IL-7, stem cell factor (SCF), macrophage-colony-stimulating factor (M-CSF), and granulocyte M-CSF (GM-CSF) promote the expansion of CD34+ HPCs in FLT3-L culture, they strongly inhibit HPC differentiation into IPCs. Here we show that thrombopoietin (TPO) cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers and to generate more than 6 x 10(6) IPCs per 10(6) CD34+ HPCs within 30 days in culture. IPCs derived from HPCs in FLT3-L/TPO cultures display blood IPC phenotype and have the capacity to produce large amounts of interferon-alpha (IFN-alpha) and to differentiate into mature DCs. This culture system, combined with the use of adult peripheral blood CD34+ HPCs purified from G-CSF-mobilized donors, permits the generation of more than 10(9) IPCs from a single blood donor.
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PMID:Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. 1467 Sep 16

Recent advances in the study of global patterns of gene expression with the use of microarray technology, coupled with data analysis using sophisticated statistical algorithms, have provided new insights into pathogenic mechanisms of disease. Complementary and reproducible data from multiple laboratories have documented the feasibility of analysis of heterogeneous populations of peripheral blood mononuclear cells from patients with rheumatic diseases through use of this powerful technology. Although some patterns of gene expression, including increased expression of immune system cell surface activation molecules, confirm previous data obtained with other techniques, some novel genes that are differentially expressed have been identified. Most interesting is the dominant pattern of interferon-induced gene expression detected among blood mononuclear cells from patients with systemic lupus erythematosus and juvenile dermatomyositis. These data are consistent with longstanding observations indicating increased circulating interferon-alpha in the blood of patients with active lupus, but draw attention to the dominance of the interferon pathway in the hierarchy of gene expression pathways implicated in systemic autoimmunity.
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PMID:Microarray analysis of gene expression in lupus. 1468 May 3

Altered regulation of interferon-alpha (IFNalpha) in systemic lupus erythematosus (SLE) was first demonstrated nearly 25 years ago. However, only recently has due attention been directed towards the central role of this cytokine family in SLE. Several laboratories have used large-scale microarray technology to study global gene expression patterns in heterogeneous populations of peripheral blood cells from lupus patients and control subjects. The results of these studies demonstrate that IFN-regulated genes are among the most significantly overexpressed in SLE mononuclear cells. In view of the protean effects of IFNs on immune system function, increased activity of IFNs may account for many of the immune system alterations that characterize SLE and contribute to autoimmunity. Definition of the nature of the major IFNs, or other factors, that drive the IFN-regulated gene expression signature noted in SLE is an important area for investigation that may lead to new approaches to targeted therapy of SLE.
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PMID:Microarray analysis of interferon-regulated genes in SLE. 1498 25

Systemic vasculitis represents a broad range of diseases characterized by the presence of blood vessel inflammation. Immunosuppressive therapy forms the foundation of treatment for almost all forms of systemic vasculitis. Newer agents such as mycophenolate mofetil, rituximab and tumour necrosis factor-alpha inhibitors are finding new indications in the therapy of conditions such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura, skin vasculitis, cytoplasmic antineutrophil antibodies-positive vasculitis, sarcoidosis, ocular inflammation, nephritis, inflammatory bowel disease and Takayasu's arteritis. However, older agents such as methotrexate, cyclophosphamide and interferon-alpha are still being explored for newer, more effective and less toxic indications in conditions such as giant cell arteritis and cutaneous polyarteritis nodosa.
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PMID:Pharmacological therapy of vasculitis: an update. 1506 63

System lupus erythematosus (SLE) is an autoimmune disease with multicellular pathogeneic components. Recent studies suggest an important role for interferon-alpha (IFN) in the immunopathogenesis of SLE. Data demonstrating a correlation between IFN-alpha and SLE disease severity range from elevated IFN-alpha levels in patients' serum and induction of IFN-regulated genes in peripheral blood mononuclear cells, to drug induced lupus disease in hepatitis C or cancer patients treated with recombinant IFN-alpha. In addition, mouse models of lupus in which the IFNR is deleted fail to develop disease manifestations. Thus, targeting IFN-alpha promises to be therapeutically efficacious for SLE.
Lupus 2004
PMID:Targeting interferon-alpha: a promising approach for systemic lupus erythematosus therapy. 1523 Feb 91

We present the case of a 53-year-old woman who developed systemic lupus erythematosus (SLE) after being treated with interferon-alpha (IFN-alpha) for cryoglobulinemic vasculitis associated with hepatitis C virus (HCV) infection. Her cryoglobulinemic vasculitis resolved rapidly with IFN-alpha treatment. However, after 10 months of IFN-alpha therapy, she developed a photosensitive malar rash, oral ulcers, arthralgias, lymphopenia, and anti-SSA autoantibodies. She was diagnosed with SLE induced by IFN-alpha therapy. IFN-alpha was discontinued, she was treated with a short course of prednisone and hydroxychloroquine, and she improved rapidly. This is the first report of IFN-alpha-induced SLE complicating treatment of cryoglobulinemic vasculitis associated with HCV infection. The development of SLE during therapy with IFN-alpha could be due to direct immunomodulation by IFN-alpha, and review of experimental data and prior case reports suggests a pathogenic role for IFN-alpha in SLE.
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PMID:Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C. 1556 95

Lymphocytes from aged autoimmune MRL/lpr mice overexpress Fas ligand (FasL), and are cytotoxic against Fas+ target cells. This cytotoxic potential is only partly due to FasL, as wild-type MRL+/+ lymphocytes are not able to kill Fas+ targets after induction of FasL. In addition, serum levels of interferon-alpha (IFN-alpha) increase in parallel with the Fas-dependent cytotoxic potential of lymphocytes from MRL/lpr mice as they age. To understand the mechanisms underlying these observations, combined suppression subtractive hybridization (SSH) and RT-PCR were used to study differential gene expression in splenocytes from MRL/lpr mice compared with splenocytes from MRL+/+ mice. Twenty-two genes were upregulated transcriptionally in MRL/lpr splenocytes compared with their MRL+/+ counterparts. Furthermore, 9 of these genes were also upregulated after treatment of MRL/lpr splenocytes with IFN-alpha, and 4 were strongly downregulated. MRL/lpr lymphocytes were also found to be hyperresponsive to IFN-alpha. Thus, MRL/lpr lymphocytes overexpressed mRNA for the IFN-alpha receptor (IFNAR-1 and IFNAR-2) chains of the IFN-alpha/beta receptor and exhibited high endogenous levels of both Stat1 and phosphorylated Stat1 proteins. Lymphocytes from young MRL/lpr mice, with low Fas-dependent cytotoxic activity, were found to become highly cytotoxic against Fas+ targets after treatment with IFN-alpha. These data suggest that IFN-alpha plays an important role in the physiopathology of the systemic lupus erythematosus (SLE)-like syndrome that occurs in MRL/lpr mice.
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PMID:An essential role for IFN-alpha in the overexpression of Fas ligand on MRL/lpr lymphocytes and on their spontaneous Fas-mediated cytotoxic potential. 1568 39

Cerebral thrombotic microangiopathy was found at autopsy in one of two sisters with Aicardi-Goutieres syndrome, whereas the other revealed increased serum levels of anticardiolipin IgG antibodies (measured only in the living sister); both typical features of systemic lupus erythematosus. These findings add support to the suggestion that Aicardi-Goutieres syndrome and systemic lupus erythematosus are closely related disorders in which dysregulated production of interferon-alpha might play a crucial role.
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PMID:Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutieres syndrome--report of two sisters. 1642 82

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.
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PMID:Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. 1585 1

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of antinuclear autoantibodies and clinical involvement in multiple organ systems. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Abnormal expression of key signaling molecules, defective signal transduction pathways, and permanent mitochondrial dysfunction--associated with a significantly increased mitochondrial mass--appear to be the axis of T-lymphocyte dysfunction. Lupus T cells exhibit persistent mitochondrial hyperpolarization (MHP), cytoplasmic alkalinization, increased ROI production, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and may account for increased interferon-alpha production, inflammation, and antinuclear antibody production. Recent data indicate that B cells are not merely the passive producers of autoantibodies, but also play a central role in autoimmunity via nonconventional mechanisms, including autoantigen presentation and modulation of other immune cells. This article reviews recent advancements in the understanding of the molecular mechanisms involved in the pathogenesis of lupus autoimmunity and highlights the development of novel therapies in SLE.
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PMID:T- and B-cell abnormalities in systemic lupus erythematosus. 1595 33


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