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)

Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies. T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus.
Lupus 2001
PMID:Thymus function in drug-induced lupus. 1178 89

BXSB mice develop a lupus-like autoimmune syndrome. We have previously identified several intervals that were linked to disease and, in an attempt to characterise lupus susceptibility genes within these intervals, we have sought to isolate differentially expressed genes. Representational difference analysis was used to compare gene expression between BXSB and C57BL/10 mice using spleen and thymus as a source of mRNA. The majority of differentially expressed sequences identified were immunoglobulin and gp70-related sequences, overexpression of these being characteristic of the disease. Among other isolated sequences were a sialyltransferase gene, a mouse tumour virus superantigen gene (Mtv-3), and the virus-related sequence, hitchhiker. In BXSB the sialyltransferase gene not only overexpressed spliced transcripts, but also produced high levels of unspliced mRNA. Further analysis demonstrated that the copy number of the three linked sequences: sialyltransferase, Mtv-3 and hitchhiker, was amplified in BXSB and that the structural organisation of this locus varies in different mouse strains. This locus consists of three parts, Mtv-3-hitchhiker-sialyltransferase, hitchhiker-sialyltransferase, and sialyltransferase alone. Different combinations of the regions are present in different mouse strains. Linkage analysis demonstrated that this region at the distal end of chromosome 11 is weakly linked to phenotypic markers of disease.
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PMID:Representational difference analysis in a lupus-prone mouse strain results in the identification of an unstable region of the genome on chromosome 11. 1188 38

Introduction of antigens to maturing T cells in the neonatal thymus is an effective means of inducing tolerance; however, it is uncertain whether developing, pathogenic, autoreactive T cells can be selectively modulated during systemic autoimmunity. To address this issue, syngeneic cells, derived from the kidneys of pre-diseased, lupus-prone, MRL-lpr/lpr mice were administered intrathymically to either neonatal or young MRL-lpr/lpr mice. For comparison, littermates were injected with splenocytes, islet cells or saline. Kidney cells administered to neonatal mice resulted in attenuation of nephritis, despite elevated serum autoantibody levels, IgG deposits and lymphadenopathy. This effect was not observed with administration of either the renal cell preparations to older mice or islet cells to younger mice, although splenocytes provided some benefit in younger mice. The results indicate that a subset of autoreactive T cells, distinct from those that augment autoantibody production and lymphadenopathy, are necessary for the expression of severe nephritis in MRL-lpr/lpr mice, and they provide further support for a renal antigen-specific component to the phenotype,
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PMID:Intrathymic kidney cells delay the onset of lupus nephritis in MRL-lpr/lpr mice. 1214 23

Bruton's XLA and DiGeorge syndrome patients show that two basic immune systems are distinct from each other in humans - thymus-dependent cell-mediated immunodeficiencies vs. antibody-based immunodeficiencies. The appendix-sacculus lymphoid organ of rabbits, like the bursa of Fabricius, represents a central lymphoid organ. Chronic granulomatous disease of childhood (CGD) revealed that phagocytosis killing of catalase-positive microorganisms employ oxidative burst. Bone marrow transplantation (BMT) proved life saving in severe combined immunodeficiency (SCID). The first BMT cured XSCID and the second BMT cured a complicating aplastic anemia launching BMT as a treatment of many diseases. Now 75 fatal diseases have been cured by myeloablative BMT. BMT also cured experimental autoimmune diseases. BMT alone did not cure lupus with polyarthritis in MRL/lpr mice or polyarthritis in NZB/KN mice, but BMT plus bone (stromal cell) transplants cured these diseases. Autoimmune diseases and lethal glomerulonephritis were prevented or cured in BXSB mice by mixed allogeneic plus syngeneic BMT. X-linked Hyper IgM syndrome (XHIM) was also cured by BMT from a 2-year-old MHC-matched sibling donor. Nonmyeloablative BMT plus mesenchymal stem cells (stromal cells) was effective treatment for a form of collagen-vascular disease and also a lethal form of hypophosphatasia. Mannan-binding lectin, an opsonin that activates the complement system when mutated and at low levels in blood, opens a door to frequent infections throughout childhood and adult life. This new immunodeficiency is based on genetic mutations that involve a native defense system.
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PMID:Cellular immunology in a historical perspective. 1219 Sep 28

On the non-autoimmune C57BL/6 (B6) background, the chromosome 7-derived lupus susceptibility loci Sle3 and Sle5 have been shown to mediate an elevated CD4:CD8 ratio with an increase in activated CD4(+) T cells, decreased susceptibility to apoptosis, and a break in humoral tolerance. Development of subcongenic strains has subsequently shown that the elevated CD4:CD8 ratio is due to Sle3 but that both loci contribute to the development of autoantibodies. To elucidate the functional expression patterns of these loci, adoptive transfer experiments were conducted. All possible combinations of bone marrow reconstitution, including syngenic, were conducted between the congenic B6 and B6.Sle3/5 strains. It was found that the Sle3/5 locus was functionally expressed by bone marrow-derived cells, but not by host cells, and that the elevated CD4:CD8 phenotype could be reconstituted in radiation chimeras. Using Ly5-marked congenic strains and B6 host mice, additional experiments surprisingly demonstrated that the elevated CD4:CD8 ratio was neither an intrinsic property of the T cells nor of single positive thymocytes. Allotype-marked chimeras indicated that autoantibody production by B cells was also an extrinsic property, as shown by the fact that B cells without the Sle3/5 interval contributed to autoantibody production. These experiments strongly suggest that a gene within the B6.Sle3/5 interval was expressed by a bone marrow-derived, nonlymphocyte population in the thymus and periphery and was affecting T cell selection and/or survival.
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PMID:Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells. 1224 5

In vitro treatment of thymocytes and splenocytes with rabbit complement (C') alone induced significant reductions in the proportion of NK-T cells in murine system. The reduction appeared to be prominent in the thymic NK-T cells compared to that in splenic NK-T cells. No reductions were detected in other populations, such as T, B and NK cells. Thus, NK-T cells lineage-specifically showed the enhanced C' sensitivity. However, NK-T cells in T cell receptor (TCR) transgenic mice of RAG-/- background that lack B cells and antibodies exhibited no C' sensitivity. On the other hand those from the same TCR transgenic mice of RAG intact background that have a normal population of B cells and antibodies showed the C' sensitivity similar to that in normal mice. These findings suggest that the enhanced C' sensitivity observed in the NK-T cell population is associated with the NK-T specific autoantibodies. Indeed, we found that a subset of NK-T cells in the thymus bound mouse immunoglobulins. Similar observations were obtained with several strains of lupus model mice, some of which show a decrease of NK-T cells with aging. Possible roles of the enhanced C' sensitivity of NK-T cells in pathophysiological conditions in various mouse strains including lupus models are discussed.
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PMID:Enhanced complement sensitivity of NK-T cells in murine thymus and spleen associated with presence of serum immunoglobulin. 1243 69

Thymic nurse cells (TNCs) represent a unique microenvironment in the thymus for MHC restriction and T cell repertoire selection composed of a cortical epithelial cell surrounding 20-200 immature thymocytes. TNCs have been isolated from many classes of animals from fish to humans. Studies performed using TNC lines showed that TNCs bind viable alphabetaTCRlow CD4(+)CD8(+)CD69(-) thymocytes. A subset of the bound cells is internalized, proliferates within the TNC, and matures to the alphabetaTCRhigh CD4(+)CD8(+)CD69(+) stage, indicative of positive selection. A subset of the internalized population is released while cells that remain internalized undergo apoptosis and are degraded by lysosomes within the TNC. A TNC-specific monoclonal antibody added to fetal thymic organ cultures resulted in an 80% reduction in the number of thymocytes recovered, with a block at the double positive stage of development. Together these data suggest a critical role for TNC internalization in thymocyte selection as well as the removal and degradation of negatively selected thymocytes. Recent studies have shown that in addition to thymocytes, peripheral circulating macrophages are also found within the TNC complex and can present antigens to the developing thymocytes. These circulating macrophages could provide a source of self-antigens used to ensure a self-tolerant mature T cell repertoire. A reduction in TNC numbers is associated with a variety of autoimmune diseases including thyroiditis and systemic lupus erythematosis.
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PMID:Thymic nurse cells: a microenvironment for thymocyte development and selection. 1264 Dec 9

Long-lived humoral immune responses are a hallmark of thymus-dependent immunity. The cellular basis for enduring antibody-mediated immunity is long-lived memory B cells and plasma cells (PCs). Both of these cell populations acquire longevity as a result of antigen-specific, CD40-dependent, cognate interactions with helper T cells within germinal centers (GCs). At the molecular level, defined functional domains of CD40 control the post-GC fate of B cells. PC precursors that emerge from these GC reactions are highly proliferative and terminally differentiate to end-stage cells within the bone marrow (BM). The striking phenotypic similarities between the PC precursors and the putative malignant cell in multiple myeloma (MM) suggests that MM may result from the transformation of PC precursors. Within the domain of autoimmune disease, recent studies have shown that dysregulated migration of PCs to the BM may impact immune homeostasis and the development of lupus. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of differentiated B-cell disorders.
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PMID:The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease. 1284 8

The objective was to determine the sensitivity and specificity of an automated multiparameter line immunoassay system compared with other techniques for the identification of autoantibodies in rheumatic diseases. We studied sera from 90 patients. Anti-U1RNP, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Jo 1 and anti-Scl 70 antibodies were identified by counterimmunoelectrophoresis (CIE) techniques, enzyme-linked immunosorbent assay (ELISA), immunoblotting (IB) using extracts of rabbit thymus and human placenta, and an automated multiparameter line immunoassay system (INNO-LIA ANA UPDATE K-1090) that detects nine different antibodies simultaneously (anti-U1RNP, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Scl 70, anti-Jo 1, anticentromere, antihistone, and antiribosomal P protein). The line immunoassay system equaled or surpassed the other techniques in the identification of anti-Sm, anti-La/SS-B, anti-Jo 1 and anti-Scl 70 antibodies (sensitivity 100%, specificity 94-100%) and was similarly effective in the case of anti-U1RNP (sensitivity 87.5%, specificity 93.9%) and anti-Ro/SS-A (sensitivity 91.4%, specificity 87.2%) antibodies. In addition, this technique detected more 52 and 60 kD anti-Ro/SS-A sera than IB. Nine antibodies can be detected with this method at a cost of 25.38 Euros per serum sample. In five hours, 19 sera can be studied. The approximate cost of detecting these nine antibodies with an automated ELISA system would be 28.93 Euros, which allows 10 sera to be studied in four hours. In conclusion, the automated multiparameter line immunoassay system is a valid method for the detection of autoantibodies in rheumatic diseases. Its most notable advantages are automated simultaneous detection of several autoantibodies in the same serum and its lower cost compared with ELISA techniques.
Lupus 2003
PMID:Simultaneous identification of various antinuclear antibodies using an automated multiparameter line immunoassay system. 1294 22

The role of the nitric oxide (NO) radical in systemic lupus erythematosus (SLE) pathogenesis has been investigated in the present study. The binding characteristics of SLE autoantibodies with native calf thymus DNA, native and NO-modified plasmid DNA were assessed. Binding characteristics and specificity of antibodies were analysed by direct binding and inhibition ELISA, gel retardation assay and quantitative precipitin titration. The data shows preferential binding of SLE autoantibodies to NO-modified plasmid DNA (NO-DNA) in comparison with native plasmid DNA. Inhibition ELISA reiterates the direct binding results. Gel retardation assay further substantiated the enhanced recognition of NO-DNA by anti-DNA autoantibodies. The binding affinity of modified and native plasmid DNA with one of the SLE IgGs was calculated, using the Langmuir plot. The apparent association constant for NO-plasmid DNA was found to be highest, followed by native calf thymus DNA and native plasmid DNA. The results suggest that the NO radical modification of plasmid DNA causes perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen. The DNA modified with the NO radical may be one of the factors for the induction of circulating SLE anti-DNA autoantibodies.
Lupus 2004
PMID:Role of nitric oxide modified DNA in the etiopathogenesis of systemic lupus erythematosus. 1499 1


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