Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0024141 (systemic lupus erythematosus)
44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autosomal recessive mutant gene, lpr, has been shown to accelerate the progression of lupus-like autoimmune disease, which is associated with a massive expansion of a unique CD4-CD8- double-negative T cell subset, in MRL/MpJ mice. Here we report a substrain of MRL/MpJ-lpr/lpr (MRL-lpr) mice which live almost twice as long with delayed development of glomerulonephritis, compared with conventional MRL-lpr mice. This substrain, termed MRL-lpr.II (II for long-lived), develops generalized lymphadenopathy characteristically seen in MRL-lpr mice. However, the expansion of a double negative lpr T cell subset is markedly limited with a mean value of 15% in their lymph nodes compared to about 70% in conventional MRL-lpr mice. Overall production of autoantibodies, such as anti-DNA and rheumatoid factors, does not significantly differ between the two MRL-lpr mice. However, serum levels of cryoglobulins, whose major component is IgG3, are markedly diminished in MRL-lpr.II mice with a parallel decrease in IgG3. Since MRL-lpr.II mice still carry the lpr mutation, as documented by the presence of defects in the Fas antigen, a possible new mutation in this substrain may play a significant role in the pathogenesis of lupus-like autoimmune syndrome.
...
PMID:An MRL/MpJ-lpr/lpr substrain with a limited expansion of lpr double-negative T cells and a reduced autoimmune syndrome. 831 55

The murine autosomal recessive gene, lpr, induces a progressive lymphadenopathy and lupus-like autoimmune syndrome characterized by the accumulation of immature, dull Thy 1.2+, TCR+, L3T4-/Lyt 2- (double-negative, DN) T cells in peripheral lymphoid organs. Previous studies demonstrated that the thymic microenvironment is required for the generation of the abnormal, peripheral DN T cells, while a more recent report linked the lpr gene defect with a failure of thymocytes to express a functional form of the Fas antigen, which mediates apoptosis. Thus, the lpr gene defect apparently prevents lpr thymocytes from responding to the ordered sequence of differentiation and proliferation signals involved in normal thymocyte maturation and selection. We compared the responses of thymocytes from C57BL/6 +/+ (normal) and congenic C57BL/6 lpr/lpr (lpr) mice to a thymic stromal cell product which down-regulates DNA synthesis in vitro. The results indicate that (a) thymic stromal cells from lpr mice produce a factor that can down-regulate DNA synthesis as efficiently as that from normal mice, even at an age when massive lymphadenopathy is present, (b) mitogen-stimulated thymocytes of normal, but not lpr, mice are sensitive to the inhibitory factor, (c) normal DN thymocytes are the cellular target of the inhibitory factor, which acts at some postmembrane receptor-ligand binding event during mitogen-stimulated proliferation, and (d) IL-4-dependent DN thymocyte proliferation seems to be the main target of the inhibitory factor.
...
PMID:Double-negative (L3T4-, Lyt2-) thymocytes of autoimmune lpr/lpr mice are resistant to down-regulation of DNA synthesis by a thymic stromal cell product. 837 81

The BXSB Y chromosome-linked mutant gene, Yaa, promotes autoimmune responses in mice predisposed to a lupus-like autoimmune disease. We have previously shown that a cognate interaction of T cells with B cells expressing the Yaa gene appears to be responsible for the accelerated production of autoantibodies. To investigate whether T cells that provide help for autoantibody production by Yaa+ B cells need to express the Yaa gene, we have made radiation bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene and differing by the Thy-1 and Igh allotypes. We then determined autoantibody production following the selective elimination of T cells of Yaa+ origin by treating mice with allele-specific anti-Thy-1 monoclonal antibody. Our results demonstrated that the selective production of autoantibodies by Yaa+ B cells in Yaa(+)-Yaa- double bone marrow chimeras can be mediated as efficiently by T cells from non-autoimmune mice lacking the Yaa gene as by T cells from autoimmune mice bearing the Yaa gene. This indicates that T cells from non-autoimmune Yaa- mice are capable of providing help for autoimmune responses by collaborating with Yaa+ B cells. These data thus strongly suggest that the Yaa gene defect is not functionally expressed in T cells, but only in B cells, and contrast with parallel experiments in the lpr model, in which defects of the Fas antigen in both T and B cells are crucial for the lpr gene-mediated promotion of autoantibody production.
...
PMID:The Yaa gene-mediated acceleration of murine lupus: Yaa- T cells from non-autoimmune mice collaborate with Yaa+ B cells to produce lupus autoantibodies in vivo. 856 31

The autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mouse is characterized by the lpr mutation, which is a defect in the Fas antigen. Since Fas mediates apoptosis, this defect results in CD4-CD8- double negative T-cell proliferation, lupus nephritis, and macroscopic lupus erythematosus-like skin lesions. The control counterpart of MRL/lpr mouse is the MRL/Mp-+/+ (MRL/n) mouse, which lacks the lpr mutation and is almost normal during the first 6 mo of life. The lpr mutation, however, accelerates autoimmune phenomena in MRL/lpr mice. Thus, it is important to investigate autoimmune diseases like systemic lupus erythematosis in relation to the autoimmune disease-prone genetic background of MRL/n mice. We found that skin lesions in aged MRL/n mice had unique characteristics. The first characteristic is spontaneous occurrence, and the second is epidermal cell nuclear immunostaining with IgGs by direct immunofluorescence. The skin lesions in aged MRL/n mice showed milder inflammation than in MRL/lpr mice. A homogeneous pattern of epidermal cell nuclear staining was always associated with nuclear staining in kidney cells and also correlated with the in vitro binding of sera to keratinocytes cultured from newborn MRL/n mice. These results suggest that the skin lesions of aged MRL/n mice are a good model for certain types of cutaneous lupus erythematosus and also can provide new insights into the long-standing controversy whether epidermal cell nuclear staining occurs in vivo.
...
PMID:Spontaneous autoimmune skin lesions of MRL/n mice: autoimmune disease-prone genetic background in relation to Fas-defect MRL/1pr mice. 875 29

The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/ lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1 alpha, II-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+2 and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+2 or normal nonautoimmune control mice. Furthermore, a modest increase in the expression of both IL-1 beta and IFN-gamma message was observed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice compared with MRL/+2 and C57BL/6 controls, respectively. Increased IL-1 beta gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1 beta gene expression, in concert with a more limited up-regulation of both TNF-alpha and IFN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.
...
PMID:Cytokine gene expression in the MRL/lpr model of lupus nephritis. 880 76

We reported previously that CD4+ T cells and B cells in mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) caused by LP-BM5 murine leukemia virus (MuLV) mixtures increased the expression of Fas antigen (Fas) during progression of the disease. However, the contribution of the Fas/Fas ligand (Fas L) system to the pathogenesis of MAIDS remained unknown. Here, we examined the susceptibility of C57BL/6 (B6) lpr/lpr mice, which has been reported to be defective for the expression of Fas, to MAIDS. We found that the Thy1.2- CD4T cells and Ig kappa dull B220+ cells, which are characteristic of MAIDS, increased after the inoculation of LP-BM5 MuLV in B6 lpr/lpr mice. B220+ TCR alpha beta T cells, unique to lupus prone mice, also increased in the B6 lpr/lpr mice after infection. CD4+ B220+ TCR alpha beta T cells increased profoundly among the B220+ TCR alpha beta T cells from LP-BM5 MuLV-infected B6 lpr/lpr mice, while the B220+ TCR alpha beta T cells observed in non-infected B6 lpr/lpr mice were largely of the CD4-CD8- phenotype. A DNA PCR analysis of the LP-BM5 MuLV-infected B6 lpr/lpr mice revealed the genome integration of defective LP-BM5 virus, further confirming that MAIDS is inducible to B6 lpr/lpr mice. LP-BM5 MuLV-infected lpr/lpr mice died within 3 months, while MAIDS-infected B6 +/+ mice usually died within 5 to 6 months, and B6 lpr/lpr mice not infected with LP-BM5 MuLV lived more than 6 months. Taken together, these results suggest that MAIDS is inducible independently with functional Fas expression and the possibility of accelerated progression of murine AIDS and lpr-associated autoimmune disease in B6 lpr/lpr mice infected with LP-BM5 MuLV.
...
PMID:Accelerated progression of a murine retrovirus-induced immunodeficiency syndrome in Fas mutant C57BL/6 lpr/lpr mice. 913 Feb 34

We studied neurite regeneration in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus, using a culture system to investigate the influences of immunological abnormalities on neurons. The regeneration of cultured dorsal root ganglion (DRG) neurons from MRL-lpr/lpr mice was delayed compared with control MRL-+/+ mice. This modification of regeneration was age-dependent. MRL-lpr/lpr mice older than 16 weeks of age exhibited less neurite regeneration than controls but those younger than 6 weeks of age showed equal regeneration. Regeneration was improved by adding nerve growth factor (NGF) to culture medium. Following immunocytochemical staining, we counted the low affinity NGF receptor p75-positive DRG neurons in MRL mice. The percentage of p75-positive neurons in MRL-lpr/lpr mice older than 16 weeks of age was higher than that in MRL-+/+ mice. These neuronal abnormalities were thought not to be directly dependent on the genetic defect of Fas antigen, which is related to apoptosis in MRL-lpr/lpr mice, but to be the result of immunological abnormalities. The present study is the first to demonstrate a modification of neurite regeneration by immunological dysfunction in autoimmune mice.
...
PMID:Delayed neurite regeneration and its improvement by nerve growth factor (NGF) in dorsal root ganglia from MRL-lpr/lpr mice in vitro. 916 60

Fas ligand (FasL) is a type II membrane protein which belongs to the tumor necrosis factor family. Ligation of its receptor (Fas/APO-1/CD95) by FasL induces apoptosis of Fas-expressing cells. However, the in vivo function of these molecules in cutaneous immunity is presently unknown. In the present study, we investigated the involvement of Fas and FasL in the pathogenesis of cutaneous lupus by immunohistochemical methods. In normal skin, expression of Fas was observed on keratinocytes in the basal to granular layers. Unexpectedly, FasL was constitutively expressed on histiocytes in the dermis. In specimens of cutaneous lupus, Fas was expressed on infiltrating lymphocytes, as well as on keratinocytes as observed in normal skin. FasL was expressed on a portion of infiltrating CD4+ T cells and on histiocytes more frequently than those in normal skin. Double staining indicated that these FasL-expressing histiocytes were CD68 positive macrophages. Especially, FasL-expressing macrophages were distributed around appendages such as hair follicles. These results suggest the Fas/FasL interaction may be involved in the destruction of hair follicles which is a characteristic feature of cutaneous lupus.
...
PMID:Expression of Fas ligand and its receptor in cutaneous lupus: implication in tissue injury. 917 10

Studies reported during the past year have added new knowledge to our understanding of the pathogenesis of systemic lupus erythematosus. A study of sibpairs with lupus revealed a strong linkage of a region located at chromosome 1q41-42 that crossed ethnic barriers. B-cell receptor-initiated signaling events, such as tyrosine protein phosphorylation and intracellular calcium concentrations, were found to be increased in patients with lupus in a disease- and clinical activity-independent manner. T cells from patients with lupus express increased amounts of the CD40 ligand, which is functional because it helps B cells to produce anti-DNA antibodies and express more CD80 (B7-1) on their surface. Only occasionally do lupus patients display structural defects of either Fas antigen or ligand molecules, and although spontaneous apoptosis is increased in lupus cells (as well as in other systemic autoimmune disorders), the activation-induced T-cell death is defective.
...
PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 930 92

The Fas ligand induces apoptosis upon binding to Fas/APO-1 (CD95) bearing target cells. Activation induced cell death (AICD) in T cells is mediated by upregulation of Fas ligand on the cell surface membrane upon crosslinking of the TCR. AICD is considered to be essential for the elimination of autoreactive T cells in the peripheral blood. To elucidate possible abnormalities in the process of AICD in human SLE, we studied the expression and function of Fas ligand in polyclonal T cell lines from patients with SLE, patients with other rheumatic diseases and normal controls. SLE T cells expressed on their surface significantly higher amounts of Fas ligand compared to the two control groups. Stimulation of the cells with anti-CD3 mAb lead to further increase in surface membrane Fas ligand expression in all three groups with SLE expressing the highest amounts. The percentage of increase was though lower in SLE T cells than in normal T cells or disease control cells. The T cells were examined for Fas ligand-mediated cytotoxicity in a 51Cr release assay using Fas-expressing normal T cells as target cells. There was no difference in SLE and control T cells with regard to specific 51Cr lysis, indicating that the Fas ligand expressed by the SLE T cells is functional. Our data show that activated T cells from patients with SLE express high amounts of functional Fas ligand with intact TCR-mediated upregulation. This could account for the high apoptotic rates that have been observed in lymphocytes from patients with SLE.
...
PMID:Increased expression of functional Fas-ligand in activated T cells from patients with systemic lupus erythematosus. 934 29


<< Previous 1 2 3 Next >>

---