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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analyzed the roles of tumor necrosis factor alpha (TNF-alpha) in human systemic lupus erythematosus (SLE) and murine models of lupus as well as in type 1 diabetes in NOD mice. These studies suggest an important role for TNF-alpha in the pathogenesis of autoimmune disease. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of this cytokine in the genetic predisposition to SLE. The data may imply that the effect of TNF on the immune system may be more relevant to the pathogenesis of the autoimmune disease than direct local effects at some target organs. Based on the data presented, one should be cautious in extrapolating the effects of this cytokine in various in vitro systems to the in vivo situation.
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PMID:Studies on the role of tumor necrosis factor in murine and human autoimmunity. 150 8

The role of TNF-alpha and IFN-gamma in various models of autoimmune disease were analyzed. These include murine models of lupus, type 1 diabetes in NOD mice and the adjuvant arthritis model in rats. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement of these cytokines in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of TNF-alpha in the genetic predisposition to SLE. Based on the data presented, one should be cautious in extrapolating the effects of these cytokines in various in vitro systems to the in vivo situation.
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PMID:Tumor necrosis factor and interferon gamma: relevance for immune regulation and genetic predisposition to autoimmune disease. 162 86

The murine alloantigen, Ly-6C, is found on 45% of bone marrow cells, 25% of splenocytes and 15% of lymph node cells in all inbred strains of mice tested, with the exception of NOD, NZB and ST. In these three strains, Ly-6C expression can be detected on only 5% of bone marrow cells and not at all on cells from spleen or lymph node. NOD and NZB, which are models for the autoimmune diseases, diabetes and lupus, respectively, also exhibit a depressed syngeneic mixed lymphocyte reaction. Southern blot analysis reveals a restriction fragment length polymorphism involving the Ly-6C gene which is unique to these three strains. Cloning of the affected genomic segment from the NOD mouse indicates the presence of an interruption in the flanking region of the Ly-6C gene at a point 475 bp upstream of the transcription initiation site and the consequent separation of distal 5' sequences from the body of the gene by at least 10 kb. Inspection of the recombination borders reveals a set of inverted copies of a mouse repetitive R element. Transfection of the Ly-6C genes from NOD and BALB/c into a murine carcinoma line indicates relative functional impairment of the NOD gene, thus paralleling performance in vivo.
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PMID:A recombination event in the 5' flanking region of the Ly-6C gene correlates with impaired expression in the NOD, NZB and ST strains of mice. 216 72

The NOD mouse is a model of human juvenile type I diabetes mellitus. As in humans and in the BB rat model, the development of diabetes in NOD mice is accompanied by evident manifestations of cell-mediated and humoral autoimmunity. Beside autoantibodies directed at putative islet cell antigens, NOD sera contain antibodies with specificity for lymphocyte cell-surface determinants. Here we demonstrate that these anti-lymphocyte antibodies have the same characteristics of target cell specificity, of isotype, and of temperature reactivity, as do natural thymocytotoxic autoantibodies (NTA) from lupic NZB mice, or from mice undergoing polyclonal B cell activation. We also demonstrate that the thymocytotoxic activity of NOD sera is not due to cross-reactive anti-insulin antibodies. Biochemical characterization of the determinants recognized by these anti-lymphocyte antibodies reveals two membrane-associated proteins of 28 and 33 kD, partially similar to the two peptides recognized by NTA from NZB mice (30 and 33 kD). Altogether, these results suggest that NOD mice develop manifestations of polyclonal B cell activation similar to those observed in lupus-prone mice. The relationship of these anomalies with the organ-specific pancreatic disease remains to be properly evaluated.
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PMID:Natural thymocytotoxic autoantibodies in non-obese diabetic (NOD) mice: characterization and fine specificity. 239 10

Autoimmunity (AI) exemplifies the potent and destructive activity expressed by the immune system when normal constraints against self-reactivity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) from young AI-prone mice [1-3]. There are two points in particular that we believe speak to the importance of this observation: (i) Cytokine dysregulation is distinguished from many of the aberrancies reported in AI-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarkably consistent characteristic of M phi from strains that develop manifestations of systemic AI, including MRL/+, NZB, NZB/W F1, BXSB, and NOD, and distinguishes these strains from mice whose disease is predicated on defects in apoptosis (e.g., the lpr and gld mutations). The multigenic basis for disease and renal pathology in the former strains more closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key mediators of lymphocyte growth and function, a defect in the cytokine network has the potential to disrupt the normal regulation of self-reactivity, leading to the initiation of systemic AI.
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PMID:Cytokine dysregulation and the initiation of systemic autoimmunity. 773 85

There is now increasing evidence that the hormonal form of vitamin D, 1,25(OH)2D3, is involved in the regulation of the immune system. Local production of the hormone in various infectious diseases can benefit the immune environment. 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptor. These receptors are present in monocytes and activated lymphocytes. The hormone inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion. It also blocks the accumulation of the mRNAs for IL-2, IFN-gamma and GM-CSF. It interferes with T helper cell (Th) function, reducing Th-induction of immunoglobulin production by B-cells and inhibits the passive transfer of cellular immunity by Th in vivo. The steroid hormone promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. The expression of Class II antigen by lymphocytes and monocytes is also affected. In vivo, 1,25(OH)2D3 is particularly effective in preventing auto-immune diseases such as experimental auto-immune encephalomyelitis, murine lupus, and diabetes in NOD mice. Synthetic analogues of vitamin D3 that bind to receptors but have no hypercalcemic effect in vivo have recently been developed for therapeutic use.
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PMID:[Vitamin D and the immune system]. 809 May 62

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/BxN animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/6 x NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/BxN serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/BxN model will bear fruit.
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PMID:Genetic influences on the end-stage effector phase of arthritis. 1148 51

The use of the NOD/SCID mouse as a transplant recipient for human cord blood B cell progenitors as a tool for investigations into the development of human B cells has become an exciting reality. The characteristics of the immunoglobulin repertoire in such a model is important to investigate, as it is possible that normal or skewed representations could be produced. Here we review our current work in which we describe a normal VH4 repertoire produced in this chimeric mouse model and describe the differences in combinatorial diversity between the human cells that were isolated from the bone marrow and spleen. The implications of this model for studies of systemic lupus erythematosus are also discussed.
Lupus 2003
PMID:The NOD/SCID chimeric mouse model of human B cell development: studies on the VH4 family immunoglobulin repertoire and implications for SLE. 1270 73

Previously we have successfully delayed the onset of vasculitis and death in MRL Lpr/Lpr mice that are considered to have an autoimmune disease similar to human lupus erythematosus. Likewise, with the use of megadose human umbilical cord blood mononuclear cells, we were able to delay the onset of symptoms and death in SOD1 mice that carry a transgene for amyotrophic lateral sclerosis, considered by some to be an autoimune disease. A similar approach was utilized with NOD/LtJ type 1 diabetic mice. By administering megadoses of human umbilical cord blood mononuclear cells we were able to ameliorate the disease and improved the life span. This occurred to a greater extent than with bone marrow obtained from congenic mice. No immunosuppression was utilized in this study. This study raises the possibility of utilizing human cord blood mononuclear cells in conjunction with pancreatic islet transplantation.
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PMID:NOD/LtJ type I diabetes in mice and the effect of stem cells (Berashis) derived from human umbilical cord blood. 1293 17

Rheumatoid arthritis and Crohn's disease are costly diseases that result in significant long-term patient disability. They are chronic inflammatory diseases that are associated with increased production of Tumor Necrosis Factor (TNF). Blockage of this cytokine with bio-engineered compounds has significantly changed therapy of these diseases and has ushered in the era of biological therapy. The pro-inflammatory role of TNF is mediated by its essential respiratory burst function that is effectively inhibited by anti-TNF therapy. Anti-TNF therapy is effective in approximately two-thirds of patients to whom it is administered, but the effect is temporary. Lack of response to anti-TNF therapy stems from interplay of host-factors including: host cytokine response, disease phenotype, and antibody response to the anti-TNF agents. NOD 2, a defect present in approximately 50% of Crohn's disease patients, bears no relationship to non-response. Additionally, TNF promoter gene polymorphisms and TNF receptor gene heterogeneity play a significant role in non-response and disease course/severity. Adverse effects of anti-TNF therapy include early and delayed hypersensitivity reactions, cell-mediated infections, lupus-like syndrome, demyelinating diseases, and exacerbation of CHF.
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PMID:The biology of TNF blockade. 1455 Aug 76


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