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)

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

Plasma from 126 patients with various autoimmune diseases and 118 healthy subjects were examined to determine the presence of autoantibodies to FKBP12, one of immunophilins. The frequency of IgG and/or IgM anti-FKBP12 autoantibodies detected by ELISA was as follows; SLE (15/39), SSc (11/27), CREST (4/7), RA (2/8), MCTD (0/5), Graves' disease (4/12), IDDM (2/6), PM/DM (0/3), MG (1/4), AIH (2/6), PBC (4/9), and healthy subjects (5/118). The specificity of the autoantibodies was demonstrated by absorption of the plasma samples with r-FKBP12 and other recombinant proteins. In immunoblotting, IgM anti-FKBP12 autoantibodies reacted with two bands of 12 and 24 kD, the latter representing the dimer. Anti-FKBP12 autoantibodies in some patients reacted more strongly with the dimer than the monomer, suggesting that FKBP12 may also exist as the dimer in vivo. The majority of anti-FKBP12 autoantibodies bound to two synthetic peptides corresponding to amino acid residues of FKBP12, Pro16 approximate to Tyr26 and Thr27 approximate to Phe46. These epitopes are phylogenetically well conserved and responsible for the binding to calcineurin and FK506. The autoantibodies inhibited pentamerization of FKBP12 with FK506, calcineurin, calmodulin, and Ca2+ in vitro. These data define the frequent occurrence of a novel set of autoantibodies to a cytosolic protein involved in the regulation of the immune response.
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PMID:Autoantibodies to FK506 binding protein 12 (FKBP12) in autoimmune diseases. 1043 96

The disease systemic lupus erythematosus (SLE) is a complex one. One major clinical manifestation that relates to both cause and pathogenesis of all autoimmune diseases but specifically SLE is the sexual predilection for females. A consideration of mechanisms for this manifestation is the subject of this paper. The cytokine network is a major aspect of immune regulation and directly affected by sex steroids. The sexual dimorphism of the immune system relates to both organ-specific and general synthesis of sex steroids that are affected by and in turn affect cytokine profiles of T helper cells. There are also specific responses in cells from diseased patients that support the molecular activities of sex hormones on cells. Among these is the rise of calcineurin mRNA in SLE T cells in response to estrogen. Clinical research provides support for a more estrogenic environment in patients with SLE of both sexes. A preferential hydroxylation of estrone and increased oxidation of testosterone in patients with SLE maximizes the effects of estrogens on T cell functions. The effects of gonadotrophins like prolactin are discussed as stimulants of immune functions when elevated in SLE. Last, while the roles of exogenous estrogens on immune functions are known, the effects of such steroids alone or in combination with progestogens on SLE are not known. Investigation of both hormone replacement therapy and premenopausal hormone use are in progress.
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PMID:The role of sex hormones in systemic lupus erythematosus. 1050 54

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

To identify intrinsic defects in lupus, we studied short-term, CD4(+) T cell lines that were established from 16 lupus patients (active or inactive) and 15 normal subjects by stimulating once with anti-CD3, anti-CD28, and IL-2. After resting, the pure CD4(+) T cells were exposed to anergy-inducing stimulation with plate-bound anti-CD3 mAb in the absence of APC. Lupus T cells showed prolonged high level expression of CD40 ligand (CD40L, CD154) even in the face of anergy protocol, which shut down CD40L expression in normal T cells. The sustained CD40L expression in lupus T cells did not correlate with memory status or Th deviation, and was relatively independent of IL-2 or other autocrine or paracrine signals via CD28 or CTLA-4. Cyclosporin A could block CD40L expression by lupus T cells when added early during the anti-CD3 stimulation period, but only partially when added later, indicating that another mechanism regulates the prolonged hyperexpression of CD40L besides the Ca(2+) --> calcineurin-dependent NF-AT pathway. When exposed to the anergy protocol, lupus T cells, in marked contrast to normal T cells, did not phosphorylate Cbl/Cbl-b but continued to express strongly phosphorylated extracellular signal-regulated kinase (ERK); U0126, a specific inhibitor of mitogen-activated protein kinase kinase --> ERK, could block both the early and the prolonged hyperexpression of CD40L. Thus, pathways regulating the activities of Cbl and one particular mitogen-activated protein kinase, ERK, are involved in the prolonged hyperexpression of CD40L in lupus T cells.
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PMID:Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. 1108 8

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

To explore the regulatory defects underlying the overexpression of CD40 ligand (CD40L, CD154) in human lupus we studied the effects of cyclosporin-A (CsA), which blocks Ca2+/calcineurin-dependent CD40L gene expression, on peripheral blood-derived T cells and monocytes. In contrast to control subjects, CsA failed to inhibit the prolonged CD40L expression observed in vitro on anti-CD3-activated lupus T cells. Resistance to CsA was not restricted to CD4+ or CD8+ T cell subsets and was disease activity-independent. Experiments assessing the effects of dexamethasone on CD40L expression, as well as of CsA on the early activation marker CD69 expression and on surface CD40L cleavage, confirmed the unique regulation of CD40L in lupus T cells. On the other hand, co-culture with anti-CD3-activated T cells caused surface CD40L expression on monocytes, which was not an Fc receptor-mediated event. Lupus monocytes clearly overexpressed CD40L comparing to healthy and disease-control monocytes, and, similarly to lupus T cells, displayed a prominent resistance to CsA inhibitory effects. These findings indicate that, besides Ca2+/calcineurin-dependent mechanisms, other pathways are involved in the dysregulation of CD40L in SLE immune cells, dissection of which may have important therapeutic implications.
Lupus 2002
PMID:CD40L overexpression on T cells and monocytes from patients with systemic lupus erythematosus is resistant to calcineurin inhibition. 1213 75

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA-induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell-independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.
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PMID:Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. 1274 May 74

The NTPR maintains an ongoing database to study the outcomes of pregnancies in female transplant recipients as well as those pregnancies fathered by male transplant recipients. Recipients are entered into the database by completing. a single page questionnaire. There is steady follow-up of recipients and their offspring. While the majority of pregnancy outcomes have occurred in kidney recipients, data continue to accrue in the other types of organ recipients. KIDNEY: A small percentage of pregnancies in female kidney recipients are complicated by rejection with poorer outcomes with respect to both maternal graft function and their newborn. Other analyses this year focused on outcomes of recipients with systemic lupus erythematosus and those with multiple gestations. It was observed that recipients with systemic lupus erythematosus were able to maintain a pregnancy with outcomes that appear to be similar to other diagnoses. In an analysis of multiple gestations in female kidney recipients maintained on calcineurin inhibitors, no multiple gestations higher than triplets have been reported to the NTPR. Successful outcomes have been noted among these recipients. This does require continued surveillance, as there has been an increase in the number of multiple gestations in the general population with the use of adjunctive technologies. OTHER ORGANS: In analyzing outcomes in female liver recipients, no specific graft or newborn outcome differences have been noted when a comparison has been made between different caicineurin inhibitor regimens. Pregnancies in female pancreas-kidney recipients appear to be tolerated with respect to pancreas graft function with no diagnoses of gestational diabetes reported to the NTPR. Data continue to accrue among thoracic recipients. Poorer maternal survival postpartum in lung recipients may be related to higher risks inherent in this population and requires further experience and investigation. OTHER ISSUES: With the recent proliferation of newer immunosuppressive agents, a question that is raised is whether a regimen can be specifically designed with recipients of childbearing age in mind. Extensive data published on azathioprine and cyclosporine treated recipients suggests that while there is a pattern of prematurity among the newborn there has not been an increase in the incidence or pattern of specific malformations noted among the newborn. Less assurance can be given with newer agents such as sirolimus and MMF. Calcineurin inhibitor minimization or steroid withdrawal would require that other agents with less reproductive information be implemented. The unknown risk of teratogenicity must be balanced against the potential risk of rejection or graft dysfunction when deciding which agent to use during pregnancy. Through each of the organ recipient groups, there are sporadic cases of rejection, graft dysfunction, and graft deterioration. Birth defect patterns have not appeared to be specific to any specific regimen as yet. Two newborns with malformations have been noted among a limited series with MMF exposure, but other factors may also be at play. The use of MMF during pregnancy continues to be an unresolved issue in the transplant community. As yet, no one regimen has been identified as superior to another for use during pregnancy. Continued surveillance with the newer agents is necessary. Investigators have taken differing views regarding the safety of breastfeeding in the transplant recipient population, especially with regard to drug exposure to the infant. This issue remains unresolved and some transplant recipient mothers have chosen to breastfeed. Other factors for consideration are the potential long-term effects on offspring of transplant recipients. While there may not be specific structural defects noted at birth, more subtle effects on either immunologic or reproductive function may not manifest until later in life. Scott and his group in Utah have raised this issue with a case report and have initiated a study to focus on the next generation. The safety of pregnancy for parent and child remain the goals of the NTPR. Continued entries to the registry, especially in light of newer combinations of immunosuppressive agents, should assist in developing guidelines needed for management in this era of expanding immunosuppressive agents. All centers are encouraged to participate.
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PMID:Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. 1297 41

Recurrence of the initial renal disease after kidney transplantation is a major cause of graft dysfunction and failure. Glomerulopathies are reported to account for 80% of such cases, but this figure should be interpreted with care, as extensive investigations (immunofluorescence or electron microscopy studies of the explanted kidney) are needed to prove that the initial disease has indeed recurred and to determine prevalence rates. In the following order of frequency, focal segmental glomerulosclerosis, membranous glomerulonephritis, mesangiocapillary glomerulonephritis and IgA nephropathy have a tendency to recur, while, surprisingly, anti-glomerular basement membrane nephritis and systemic lupus erythematosus are less likely to relapse on the donor kidney. There is no evidence that anti-calcineurin therapy has any impact on the risk of recurrence. Options for the prevention and treatment of these recurrences are very limited, calling for very cautious use of living familial donors.
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PMID:[Recurrent kidney disease and its prevention after renal transplantation. Review of the literature]. 1565 30


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