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)

After administration to normal mice, a subset of monoclonal (m) anti-DNA antibodies (Ab) derived from MRL-lpr/lpr mice was identified that enter cells, in vivo. In the kidneys, this was associated with glomerular hypercellularity and proteinuria. In cultured cells, the same mAb bound to myosin 1 on the cell surface, prior to internalization, nuclear localization and inhibition of apoptosis. The present study focuses on the mechanisms underlying the observed functional effects. Subcellular localization studies revealed that following internalization, a prototypic, nuclear localizing, m antibody (Ab; termed H7) co-localized with myosin 1, shortly after internalization, within caveolae, near the cell membrane. Cell fractionation studies confirmed the presence of both H7 and myosin within the caveolar fraction. Since variations in caveolin protein expression have been associated with apoptotic events in cancer cells, through p53 dependent and independent pathways, modulation of caveolin by intracellular H7 was evaluated. Cellular entry of the anti-DNA Ab resulted in an increase in caveolin protein expression. Furthermore, after exposure of cells to dexamethasone to induce apoptosis, the usual increase in p53 was inhibited in the presence of intracellular H7. Taken together, the results suggest that upregulation of caveolin and inhibition of p53 induction are involved in H7-induced, inhibition of apoptosis. Furthermore, they suggest that this inhibition contributes to the glomerular hypercellularity observed in normal mice with intranuclear H7. The results also raise the possibility that inhibition of apoptotic pathways during inflammation or/and autoimmunity could influence subsequent disease events. The novel mechanism of cellular perturbation is indirect and dependent on apoptotic stimuli, and it may account for the presence of intranuclear antibodies in inflammatory and normal tissues of individuals with lupus.
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PMID:Nuclear localizing anti-DNA antibodies enter cells via caveoli and modulate expression of caveolin and p53. 1582 7

Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lupus-like disease. However, these effects are only observed at high doses of Hg that are above the levels to which humans would be exposed through contaminated fish consumption. While there is presently no evidence to suggest that Hg induces frank autoimmune disease in humans, a recent epidemiological study has demonstrated a link between occupational Hg exposure and lupus. In our studies, we have tested the hypothesis that Hg does not cause autoimmune disease directly, but rather that it may interact with triggering events, such as genetic predisposition, exposure to antigens, or infection, to exacerbate disease. Treatment of mice that are not susceptible to Hg-induced autoimmune disease with very low doses and short term exposures of inorganic Hg (20-200 microg/kg) exacerbates disease and accelerates mortality in the graft versus host disease model of chronic lupus in C57Bl/6 x DBA/2 mice. Furthermore, low dose Hg exposure increases the severity and prevalence of experimental autoimmune myocarditis (induced by immunization with cardiac myosin peptide in adjuvant) in A/J mice. To test our hypothesis further, we examined sera from Amazonian populations exposed to Hg through small-scale gold mining, with and without current or past malaria infection. We found significantly increased prevalence of antinuclear and antinucleolar antibodies and a positive interaction between Hg and malaria. These results suggest a new model for Hg immunotoxicity, as a co-factor in autoimmune disease, increasing the risks and severity of clinical disease in the presence of other triggering events, either genetic or acquired.
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PMID:Mercury and autoimmunity: implications for occupational and environmental health. 1602 90

Nephrophilic autoantibodies dominate the seroprofile in lupus, but their fine specificities remain ill defined. We constructed a multiplexed proteome microarray bearing about 30 antigens known to be expressed in the glomerular milieu and used it to study serum autoantibodies in lupus. Compared with normal serum, serum from B6.Sle1.lpr lupus mice (C57BL/6 mice homozygous for the NZM2410/NZW allele of Sle1 as well as the FAS defect) exhibited high levels of IgG and IgM antiglomerular as well as anti-double-stranded DNA/chromatin Abs and variable levels of Abs to alpha-actinin, aggrecan, collagen, entactin, fibrinogen, hemocyanin, heparan sulphate, laminin, myosin, proteoglycans, and histones. The use of these glomerular proteome arrays also revealed 5 distinct clusters of IgG autoreactivity in the sera of lupus patients. Whereas 2 of these IgG reactivity clusters (DNA/chromatin/glomeruli and laminin/myosin/Matrigel/vimentin/heparan sulphate) showed association with disease activity, the other 3 reactivity clusters (histones, vitronectin/collagen/chondroitin sulphate, and entactin/fibrinogen/hyaluronic acid) did not. Human lupus sera also displayed 2 distinct IgM autoantibody clusters, one reactive to DNA and the other apparently polyreactive. Interestingly, the presence of IgM polyreactivity in patient sera was associated with reduced disease severity. Hence, the glomerular proteome array promises to be a powerful analytical tool for uncovering novel autoantibody disease associations and for distinguishing patients at high risk for end-organ disease.
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PMID:Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. 1632 90

Complement receptor type 2 (CR2) is a receptor that serves as an important interface between the complement system and adaptive immunity. Recent studies have shown that CR2 is also centrally involved in innate immunity, and one key area is the development of potentially pathogenic natural antibodies that target neo-epitopes revealed in ischemic tissue undergoing reperfusion. Mice lacking either total immunoglobulins or CR2 alone are protected from the development of ischemia-reperfusion injury, and this effect can be reversed by introducing CR2-sufficient B-1 cells or by transferring polyclonal natural IgM antibody from wild type mice as well as monoclonal antibodies that recognize phospholipids, DNA or non-muscle myosin. We will report at the XXI ICW an additional membrane-associated protein to which pathogenic IgM antibodies are directed. Whether B cells producing these natural antibodies are differentially selected in CR2-deficient mice is as yet not well understood, and the complement-related mechanism(s) whereby this differential repertoire selection process could occur have yet to be explored in any detail. In addition to this important role in innate immunity, CR2 can also act as a receptor for other components or activators of innate immunity. One such component is interferon-alpha, an anti-viral cytokine that binds CR2 and induces a component of its mRNA signature in B cells through this receptor. Other potential CR2 ligands are DNA and DNA-containing complexes such as chromatin. The biologic role of these CR2 interactions with interferon-alpha and DNA-containing complexes is not well understood, but may be important in the development of the autoimmune disease systemic lupus erythematosus that is characterized by enhanced interferon-alpha levels and loss of self tolerance to DNA-containing self antigens.
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PMID:Complement receptor 2, natural antibodies and innate immunity: Inter-relationships in B cell selection and activation. 1687 64

Idiosyncratic drug reactions (IDRs) represent a major clinical problem, and at present, the mechanisms involved are still poorly understood. One animal model that we have used for mechanistic studies of IDRs is penicillamine-induced autoimmunity in Brown Norway (BN) rats. Previous work in our lab found that macrophage activation preceded the clinical autoimmune syndrome. It is thought that one of the interactions between T cells and macrophages involves reversible Schiff base formation between an amine on T cells and an aldehyde on macrophages, but the identity of the molecules involved is unknown. It is also known that penicillamine reacts with aldehyde groups to form a thiazolidine ring, which unlike a Schiff base, is essentially irreversible. Such binding could lead to macrophage activation. Generalized macrophage activation could lead to the observed autoimmune reaction. Hydralazine and isoniazid also react with aldehydes to form stable hydrazones, and they also cause an autoimmune lupus-like syndrome. In this study, isolated spleen cells from male BN rats were incubated with biotin-aldehyde-reactive probe (ARP, a hydroxylamine), biotin-hydrazide, or D-penicillamine. At all concentrations, ARP, hydrazide, and penicillamine preferentially "stained" macrophages relative to other spleen cells. In addition, preincubation of cells with penicillamine or hydralazine decreased ARP staining of macrophages, which further indicates that most of the ARP binding to macrophages involves binding to aldehyde groups. This provides support for the hypothesis that the interaction between aldehyde-containing signaling molecules on macrophages and penicillamine could be the initial event of penicillamine-induced autoimmunity. Several of the proteins to which ARP binds were identified, and some such as myosin are attractive candidates to mediate macrophage activation.
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PMID:Covalent binding of penicillamine to macrophages: implications for penicillamine-induced autoimmunity. 1946 40

Rheumatic heart disease (RHD) or acute rheumatic fever (ARF) develops as a consequence of an exaggerated immune response to Group A beta haemolytic streptococci causing pharyngitis. The molecular mimicry appears between human cardiac myosin and M protein of group A streptococcal membranes. The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to several autoimmune diseases such as SLE and RA. The objective of this study was to investigate whether PTPN22 R620W polymorphism confers susceptibility to RHD in Turkish population. PTPN 22 R620W (rs2476601, A/G) polymorphism was genotyped by PCR-RFLP in 121 patients with RHD who fulfilling the revised classification criteria of Jones, and 160 healthy control (HC), and also 137 SLE as a diseased-control. The frequency of GG and AG genotypes were found to be 94% (114), 6% (7) in RHD, respectively and 96% (153) and 4% (7) in HC, respectively. The homozygous AA genotype was not present in RHD and HC. There was no statistically significant difference between RHD and HC according to the frequency of AG heterozygote genotype (P = 0.831; OR = 1.13; 95% CI 0.37-3.46). The frequency of the rare allele A was also very similar in RHD patients and HC (3, 2% respectively). A similar result was also found between SLE and HC. Our results demonstrated that the PTPN22 R620W polymorphism is not associated with RHD nor with SLE in Turkish population.
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PMID:No association of PTPN22 R620W gene polymorphism with rheumatic heart disease and systemic lupus erythematosus. 2138 70

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by the production of anti-nuclear autoantibodies that lead to subsequent end organ damage. Previous array-based studies in patients with SLE have shown that high immunoglobulin (Ig)G anti-nuclear autoantibody reactivity was associated with severe renal lupus, whereas IgM polyreactivity was associated with less severe disease. To ascertain how different murine lupus strains recapitulate these different autoantibody profiles seen in patients, serum from New Zealand black (NZB)/NZ white (W) F(1), Murphy Roths large (MRL)/lpr, NZ mixed (M)2410 and BXSB strains were compared using a comprehensive array-based screen. The array results were verified using enzyme-linked immunosorbent assays (ELISAs). Serum from MRL/lpr mice exhibited high levels of IgG anti-nuclear antibodies as well as anti-glomerular antibodies and variable levels of antibodies to myosin, Matrigel and thyroglobulin. Elevated anti-nuclear IgG antibodies were associated with severe nephritis in this strain. In contrast, NZM2410 mice exhibited lower IgG autoantibody levels with less severe nephritis but a significantly higher polyreactive IgM autoantibody profile. ELISA analysis confirmed these results. The NZB/NZW F(1) and BXSB strains exhibited an intermediate serological profile. Hence, just as in patients with SLE, whereas strong IgG reactivity to nuclear antigens is associated with severe renal disease, a polyreactive IgM seroprofile is also less ominous in murine lupus.
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PMID:Murine lupus strains differentially model unique facets of human lupus serology. 2247 Dec 78

Specific antibodies produced against a protein of interest are invaluable tools for monitoring the protein structure, intracellular location and biological activity. Inoculation of murine lymphoma cells into the peritoneal cavity of immunized mice provides generation of ascitic fluid containing a significant amount of antibody with desired antigen specificity. Here we demonstrated that the intraperitoneal administration of murine lymphoma NK/Ly cells in mice immunized with 48 kDa isoform of human blood serum unconventional myosin 1c leads to generation of ascitic fluid that contained specific IgG-antibodies. These antibodies were capable of binding of the unconventional myosin 1c isolated from blood serum of patients with multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosis, and could be used for diagnostics of several autoimmune diseases, the multiple sclerosis in particular.
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PMID:The characteristics of antibodies of mice immunized by human unconventional myosin 1c. 2923 66


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