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)

Fifty-four patients with cutaneous tuberculosis, consisting of 23 with lupus vulgaris, 22 with scrofuloderma, and nine with verrucosa cutis, were investigated for cell-mediated immunity, through estimation of peripheral total T lymphocytes (CD3+), CD4+ (helper/inducer), and CD8+ (cytotoxic/suppressor) lymphocytes, by immunohistochemical staining of peripheral blood smears, using specific monoclonal antibodies and the alkaline phosphatase-antialkaline phosphatase (APAAP) method. Absolute values of total T lymphocytes (CD3+), and CD4+ and CD8+ subsets, were found to be significantly raised in scrofuloderma, but the percentage values and the CD4+/CD8+ ratio remained unaltered. In tuberculosis verrucosa cutis, only the percentage of the CD8+ subset of T lymphocytes was found to be significantly lowered, and this altered the CD4+/CD8+ ratio. No significant change was observed in the peripheral blood T cells and their subpopulations in patients suffering from lupus vulgaris.
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PMID:Peripheral T lymphocytes and their subsets in cutaneous tuberculosis. 155 33

Purified RNA polymerase I was phosphorylated by the endogenous protein kinase or dephosphorylated by alkaline phosphatase and used as antigen in a radioimmunoassay with sera from systemic lupus erythematosus patients or serum from an immunized rabbit. Enzyme incubated in the absence of ATP or phosphatase served as control. Three to seven times more of the autoantibodies in the patients' sera reacted with phosphorylated RNA polymerase I than with control enzyme. The reactivity of the dephosphorylated enzyme with lupus autoantibodies was only 50-60% of that observed with control enzyme. Neither phosphorylation nor dephosphorylation of the enzyme had an effect on its reaction with the rabbit antibodies. The effect of phosphorylation on the reaction of each RNA polymerase I subunit (S1-S8; Mr = 190,000-17,000) with the patients' antibodies was determined by an immunoblot procedure following resolution of the subunits on polyacrylamide gels. Prior phosphorylation of the enzyme resulted in a dramatic increase in binding of each patient's antibodies to all polymerase subunits with the exception of S4. Anti-S4 antibody was not detected with either phosphorylated or control enzyme. Strikingly, antibodies in each patients' sera reacted with S6 only after its phosphorylation. Similarly, anti-S5 antibodies in the serum of one patient were only detected with phosphorylated RNA polymerase I. The present data suggest that at least a significant fraction of the anti-RNA polymerase I autoantibodies in the sera of systemic lupus erythematosus patients might be directed against phosphorylated sites on the enzyme and that phosphorylation may have a role in the production of this and other autoimmunogenic nuclear components which are hallmarks of this disease.
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PMID:Phosphorylation of RNA polymerase I augments its interaction with autoantibodies of systemic lupus erythematosus patients. 650 Dec 73

Motheaten mice homozygous for the recessive mev mutation develop a fatal immunodeficiency syndrome associated with hypergammaglobulinemia, thymic aplasia, production of autoantibodies and development of a severe lupus like systemic autoimmune disease. Most B lymphocytes in this mutant strain belong to B-1 subset. We have addressed the question if differences existed in the V-gene repertoire of autoimmune mev/mev mice as compared to phenotypically normal mev/+ and C57BL/6 background strain by examining the VH and V kappa gene family expression as well as the association of VH and V kappa gene families among B lymphocyte clones. The data outlined here demonstrate that both the expression of VH and V kappa gene families and their association is skewed in mev/mev mice, suffering from systemic autoimmune disease, and differs significantly from phenotypically normal mev/+ litter mates as well as the C57BL/6 background strain. In addition, VH+V kappa gene family pairs in phenotypically normal mev/+ differed from normal C57BL/6 mice suggesting that motheaten mutation, whether homozygous or heterozygous, alters the development of the B lymphocyte repertoire. These observations suggest positive selection of B-1 lymphocytes in autoimmune motheaten mice either as a result of selective processes, via receptor-ligand interactions, operating on the development of the primary antibody repertoire or defective B lymphocyte haematopoiesis due to the deficiency of haematopoietic cell phosphatase involved in determining the threshold by which B cells respond to self antigen(s).
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PMID:Skewed VH and V kappa gene family expression and pairing occurs among B lymphocytes in autoimmune motheaten mice. 882 76

Systemic lupus erythematosus (SLE) predominantly affects women (9:1 compared to men) of childbearing age and often decreases its intensity in postmenopausal women, suggesting that sex hormones play a role in its pathogenesis. Comparison of steady-state levels of calcineurin mRNA using RNase protection assays revealed increased calcineurin expression in response to estradiol in cultured T cells from nine female lupus patients. Calcineurin mRNA levels did not increase significantly in T cells from eight age-matched normal control female volunteers. Estrogen-dependent calcineurin mRNA increased in a dose-dependent fashion, while progesterone and dexamethasone did not increase calcineurin mRNA in patient cells. Lupus T cell calcineurin mRNA increased in response to estradiol at 6 h but not at 3 h. Calcineurin phosphatase activity increased in lupus T cell extracts after incubation of cells with estradiol, while phosphatase activity in normal T cells was unaffected by estrogen. Calcineurin expression in T cells from patients with vasculitis and rheumatoid arthritis taking medications similar to those taken by the lupus patients was unaffected by estradiol. This study provides the first evidence for a molecular marker of estrogen action in lupus patients and suggests that estrogen-dependent changes in lupus T cell calcineurin could alter proinflammatory cytokine gene regulation and T-B cell interactions.
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PMID:Gender differences in autoimmune diseases: estrogen increases calcineurin expression in systemic lupus erythematosus. 983 88

Previous experiments in our laboratory indicated that calcineurin expression and PP2B phosphatase activity increased when estrogen was cultured with SLE T cells but not with T cells from normal women. In this report we extended our findings to show that estrogen receptor (ER) antagonism by ICI 182,780 inhibited the estrogen-dependent increase in calcineurin mRNA and phosphatase PP2B activity indicating that estrogen action was mediated through the ER. Inhibition of de novo protein synthesis with cycloheximide suggested that the estrogen-dependent increase in T cell calcineurin mRNA was a direct effect of the ER and new protein synthesis was not required. Estrogen increased calcineurin mRNA in systemic lupus erythematosus (SLE) T cells at 6 h after the start of culture correlating with increased phosphatase activity at this same time. Phosphatase activity increased significantly (P < 0.02) in lupus T cells cultured for 8 h in estradiol-containing medium. Reverse transcription and polymerase chain amplification revealed that ER-beta and ER-alpha were expressed in female and male T cells from SLE patients and normal controls. However, calcineurin steady-state mRNA levels were unaffected by estradiol in cultured T cells from male SLE patients and normal male and female controls. These data indicate that estrogen, bound to the ER, evokes a direct increase in calcineurin expression in T cells from female lupus patients. This gender-specific response suggests that ER function is altered in women with the female predominant autoimmune disease, SLE.
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PMID:Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells. 1077 6

Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women (9:1 compared to men). Estrogen is a female sex hormone that acts on target cells through specific receptor proteins and alters the rate of transcription of target genes. Experiments in our laboratory have shown that calcineurin steady-state mRNA levels and phosphatase activity increase when estrogen is cultured with SLE T cells. This estrogen-dependent increase is dose-dependent, hormone-specific and temporally regulated. Estrogen receptor antagonism by ICI 182,780 inhibits the increase in calcineurin mRNA and phosphatase activity, while cycloheximide has no effect suggesting that new protein synthesis is not required. Reverse transcription and polymerase chain amplification indicate that estrogen receptor-alpha and estrogen-beta are expressed in human T cells. However, calcineurin does not respond to estrogen stimulation in T cells from normal females, males and lupus males. Taken together, these results indicate a differential function of the estrogen receptor in women with lupus. A model is proposed that suggests estrogen, acting through the estrogen receptor, enhances T cell activation in women with lupus resulting in amplified T-B cells interactions, B cell activation and autoantibody production.
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PMID:Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. 1140 98

Within the immune system, multiple isoforms of the human prolactin receptor (PRLr) serve to mediate the effects of its ligand (PRL). Now numbering four, these isoforms are structurally and functionally distinct, demonstrating significant differences in ligand affinities, kinetics of transduction and the transduction proteins activated. The proximal transduction pathways activated during PRLr-associated signaling include the tyrosine kinases Jak2, Fyn and Tec, the phosphatase SHP-2, the guanine nucleotide exchange factor Vav, and the signaling suppressor SOCS. Differential activation of these pathways may contribute to the pleiotropism of PRL action in tissues of the immune system.
Lupus 2001
PMID:Prolactin receptor signal transduction. 1172 97

NZB mice demonstrate common and consistent abnormalities in B-cell activation and signalling. One of the hallmark characteristics of lupus disease is the prevalent hypergammaglobulinaemia, composed primarily of anti-nuclear antibodies. In addition to the hyperproliferation seen in mice exhibiting disease, the B cells also demonstrate a marked degree of hyperactivity in response to B-cell receptor occupancy. This points to an intrinsic defect in the signalling pathways regulating the response to an activation event. Correspondingly, B cells of NZB mice exhibit a significant lack of phosphatase activity, both at baseline and in response to stimulation. This is directly reflected by a higher level of phosphorylation of tyrosine residues. Individually, SAPK and SHIP-1, both players in the B-cell receptor signalling cascade, are also found to be abnormally phosphorylated in the NZB mouse.
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PMID:Phosphorylation abnormalities: NZB mice exhibit a B-cell signalling defect. 1241 80

A male patient receiving azathioprine treatment for discoid lupus erythematodes developed severe cholestatic hepatitis between 14 and 21 days after initiation of the treatment with peak bilirubin levels of 62.4 mg/dL. Other causes of hepatic dysfunction including viral hepatitis were clinically and serologically excluded. Liver biopsy revealed cholestatic hepatocellular damage. At 14 days after discontinuation of azathioprine the liver function (transaminases and bilirubin) began to improve. Only alcaline phosphatase and gamma-glutamyl transferase remained elevated even after 4 months. This case argues for an idiosyncratic cholestatic hepatocellular damage caused by azathioprine.
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PMID:Severe cholestatic hepatitis caused by azathioprine. 1580 61

Signaling of the C3a anaphylatoxin through its G protein-coupled receptor, C3aR, is relevant in a variety of inflammatory diseases, but its role in lupus nephritis is undefined. In this study, we show that expression of C3aR was significantly increased in prediseased and diseased kidneys of MRL/lpr lupus mice compared with MRL/+ controls. To investigate the role of C3aR in experimental lupus, a small molecule antagonist of C3aR (C3aRa) was administered continuously to MRL/lpr mice from 13 to 19 wk of age. All 13 C3aRa-treated mice survived during the 6-wk treatment compared with 9 of 14 (64.3%) control animals given vehicle (p = 0.019). Relative to controls, C3aRa-treated animals were protected from renal disease as measured by albuminuria (p = 0.040) and blood urea nitrogen (p = 0.021). In addition, there were fewer neutrophils, monocytes, and apoptotic cells in the kidneys of C3aRa-treated mice. C3aRa treatment also led to reduced renal IL-1beta and RANTES mRNA and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 protein, whereas the mass of phosphorylated protein kinase B/Akt was increased by C3aRa. Thus, C3aR antagonism significantly reduces renal disease in MRL/lpr mice, which further translates into prolonged survival. These data illustrate that C3aR is relevant in experimental lupus nephritis and may be a target for therapeutic intervention in the human disease.
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PMID:Signaling through up-regulated C3a receptor is key to the development of experimental lupus nephritis. 1603 39


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