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)

To assess interactions between T cells and APC in patients with SLE, PBL were stimulated in vitro and IL-2 production measured after stimulation with either a MHC-self-restricted Ag (influenza A virus) or an Ag which can use both MHC-self-restricted or unrestricted T cell activation pathways (HLA-alloantigen). SLE patients (n = 26) and controls (n = 8) were categorized as responder (+) or nonresponder (-) for each stimulus and grouped according to their paired response pattern. All controls responded to both influenza virus (Flu) or alloantigen (Allo) and were categorized as +/+. In contrast, SLE patient response patterns were heterogeneous with no evidence for a single SLE-associated defect. Instead, SLE patient responses fell into one of three different patterns: a) normal responses to both Flu and Allo (+/+), observed in nine (35%) patients; b) defective responses to Flu but intact Allo responses (-/+) observed in 12 (46%) SLE patients; and c) defective responses to both Flu and Allo (-/-), observed in five (19%) SLE patients. There was no statistically significant correlation between immune response pattern and the use of immunosuppressants. Further analysis of -/- SLE patients indicated defects in APC function and in both CD4+ and CD8+ T cell function. In contrast, cell depletion and add-back studies in -/+ SLE patients demonstrated defects in APC function only. Thus, similar to the well recognized clinical heterogeneity among SLE patients, our data support the concept that SLE patients are heterogeneous with respect to in vitro T cell-APC function, exhibiting responses ranging from normal function to defects in APC and in both T cell subsets. Prospective studies are in progress to determine the clinical relevance of these observations.
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PMID:T cell-antigen-presenting cell interactions in human systemic lupus erythematosus. Evidence for heterogeneous expression of multiple defects. 837 10

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.
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PMID:Mechanisms of autoimmunity in type I diabetes. 844 41

We have isolated, from NZB.H-2bm12 mice, several autoreactive cloned T cell lines that provide help for anti-dsDNA IgG antibody production in vitro. The purpose of the work described herein was to examine the requirement for cognate help for the production of anti-DNA antibodies in vitro. Thus, the ability of cloned T cell lines or lymphokines derived from them to provide help for T-depleted spleen cells from both normal B6.H-2bm12 mice and SLE-prone NZB.H-2bm12 mice was examined. Two autoreactive cloned T cell lines were selected for detailed study. 410F T cells respond to APC from both I-Ab and I-Abm12 mice, whereas 410H T cells are restricted to I-Abm12. By using Percoll gradients, B cells from both low density and high density fractions were cultured with autoreactive cloned T cell lines or lymphokines secreted by such cloned T cell lines, and anti-DNA antibody production was determined. Lymphokines elicited IgM anti-ssDNA antibody production from cells in all Percoll fractions from both B6.H-2bm12 and NZB.H-2bm12 mice. Lymphokines did not elicit production of IgG anti-dsDNA antibody production by cells from 2-month-old B6.H-2bm12 mice. In contrast, substantial production of IgG anti-dsDNA antibody was observed for NZB.H-2bm12 cells in response to lymphokines alone. Thus, B cells from NZB.H-2bm12 mice, because of previous activation in vivo, can proceed to IgG anti-dsDNA antibody production in vitro without direct T cell interaction. When we examined direct T cell help for the IgG anti-dsDNA antibody response, we found that we could distinguish the actions of the two cloned T cell lines studied. 410F T cells provided help predominantly for cells from low density Percoll fractions whether the cells were derived from B6.H-2bm12 or NZB.H-2bm12 mice. 410H T cells were capable of providing help for cells from both the low and high density fractions, and this help accounted for more than half of the antibody production in vitro by cells from B6.H-2bm12 mice.
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PMID:Comparison of the requirements for cognate T cell help for IgG anti-double-stranded DNA antibody production in vitro: T helper-derived lymphokines replace T cell cloned lines for B cells from NZB.H-2bm12 but not B6.H-2bm12 mice. 845 Feb 23

Seventy-eight women with a history of thromboembolism were studied for cardiolipin antibodies (CLa), lupus anticoagulant activity (LA) and resistance to activated protein C (APC-resistance). Elevated CLa were found in 15 (19%) and LA in 15 women (19%), respectively. Twenty-six patients (33%) were APC-resistant, 17 of them had LA and/or CLa. No correlation was observed between the LA coefficient, CLa level and the extent of APC-resistance. The study shows the difference in the nature of phospholipid antibodies (PLa) and APC-resistance: cause-dependent for APC-resistance and time-dependent for the LA activity. APC-resistance was commoner in thrombosis triggered by endogenous (pregnancy, delivery) than by exogenous (oral contraceptives, surgery) factors (P < 0.05). The incidence of PLa was not connected to the cause of thrombosis. Time-dependent changes in the PLa spectrum manifested by a reduction of isolated LA frequency five years after thrombosis (P < 0.05). The response of APC seemed to show no variation with time passed after thrombosis. The co-existence of PLa and APC-resistance in 22% of thrombophilic women may stress the role of phospholipids in the blood coagulation process.
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PMID:Phospholipid antibodies and resistance to activated protein C in women with thrombophilia. 858 7

Kidney tubule cells (KTC) are targets of T lymphocyte injury during allograft rejection and interstitial nephritis. KTC process and present self- and foreign Ags for immune recognition by CD4+ T cells in vivo and in vitro. However, it is not known whether KTC can provide the costimulatory signal required to fully activate CD4+ T cells. Using the MRL/MpJ fas<lpr> model of lupus interstitial nephritis, we found that KTC did not express the costimulators B7-1 or B7-2. Nevertheless, KTC from both normal and systemically infected mice provided non-B7 costimulation to splenic CD4+ T cells. T cell proliferation was blocked by mAbs binding intercellular adhesion molecule-1 (ICAM-1) but not by mAb or fusion proteins binding B7-1, B7-2, heat-stable Ag, or vascular cell adhesion molecule-1. Importantly, ICAM-1 expression was necessary but not sufficient to provide costimulation. The transformed KTC line D3.B7- expressed high levels of ICAM-1 but did not provide costimulation. Interestingly, KTC provided costimulation to splenic T cells but not to a Th1 clone. These results show that freshly isolated KTC can provide non-B7 costimulation to splenic T cells via an unidentified costimulator and ICAM-1. Furthermore, these experiments demonstrate the complex nature of T cell activation and show that at least for splenic T cells, three or more signals may be required for full activation on live APC.
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PMID:Intercellular adhesion molecule-1 is necessary but not sufficient to activate CD4+ T cells. Discovery of a novel costimulator on kidney tubule cells. 862 99

In this review we will discuss the possible interference of antiphospholipid antibodies with the protein C system. Antiphospholipid antibodies can interfere with the protein C system in different ways: (i) via inhibiting the formation of thrombin; (ii) via interference with the activation of protein C by the thrombomodulin-thrombin complex; (iii) via inhibition of the assembly of the protein C complex; (iv) via inhibition of the activity of protein C, directly or via its cofactor protein S, and (v) via antibodies directed against the substrates of APC, factors Va and VIIIa, thereby protecting them for inactivation. The experimental and theoretical indications that one of these mechanisms will explain the pathogenesis of the antiphospholipid syndrome is critically examined.
Lupus 1996 Oct
PMID:Protein C and other cofactors involved in the binding of antiphospholipid antibodies: relation to the pathogenesis of thrombosis. 890 88

To evaluate if the presence of anti-beta 2GPI antibodies (a beta 2GPI) is associated with activated protein C resistance (APC-R) phenotype, we performed the APC-R APTT-based assay in 74 plasma samples from patients with antiphospholipid antibodies (aPL). Samples were diluted 1:5 in factor V-deficient plasma. Lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and a beta 2GPI (IgG and IgM) were also performed. A control group of 22 healthy volunteers was used. The prevalence of reduced APC-R ratio in patients with aPL was significantly higher than in normal controls (31.1 vs 4.5%, P < 0.05) and the mean APC-R ratio was lower (mean +/- SD; 2.32 +/- 0.40 vs 2.55 +/- 0.21, P < 0.02). There were no differences in the prevalence of APC-R and the ratio values between LA(+) and LA(-). Among the LA(+), the aCL(+) had a higher prevalence of APC-R than the aCL(-) (P < 0.01) and lower APC-R ratios (P < 0.01). The latter group was no different to normal controls. Anti-beta 2GPI antibodies were associated with a higher prevalence of APC-R (50.0 vs 19.6%, P < 0.001), and lower APC-R ratios (2.15 +/- 0.41 vs 2.42 +/- 0.35, P < 0.005), compared with a beta 2GPI(-). In conclusion, the acquired APC-R in patients with aPL seems to be associated with aCL and a beta 2GPI rather than an in vitro interference by LA.
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PMID:Activated protein C resistance in patients with anti-beta 2 glycoprotein I antibodies. 895 93

Activated protein C resistance (APCR) has proved to be a frequent finding in association with thrombosis. The majority of patients with APCR have been found to be homozygous or heterozygous for the polymorphic variant factor V Q506 (factor V Leiden; FVQ506). However a small number of patients have APCR as assessed by functional tests but do not possess the FVQ506 polymorphism. Some of these cases are due to the presence of a lupus type anticoagulant but in this report we demonstrate that the remainder are almost entirely (nine out of ten) associated with an elevated level of FVIIIc. Spiking experiments in normal patient plasma and venous occlusion tests demonstrated that elevation of the FVIIIc results in a reduced APCR ratio and shortening of the APTT. Variation in FVIIIc, in conjunction with other factors, may therefore explain the variable phenotype associated with FVQ506 and the phenomenon of thrombosis associated APCR in the absence of FVQ506. We conclude that FVIIIc as well as FVQ506 should be taken into account when assessing thrombotic risk. APCR, elevated FVIIIc and shortened APTT have all been previously identified with an increased risk of thrombosis. It follows that resistance to APC may arise from a number of factors and is in itself a risk factor for thrombosis. The net effect of these factors is assessed in the functional test for APCR and it may be premature therefore to replace functional tests for APCR with DNA analysis alone.
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PMID:The influence of factor VIII on measurement of activated protein C resistance. 903 55

The activated protein C resistance (APC-R) ratios in 50 patients with steady state homozygous sickle cell (SS) disease and 59 healthy AA controls was measured. There was a significant reduction in median APC-R ratio in sickle cell disease compared to controls. This reduction in APC-R ratio was not explained by (1) the presence of the factor V Leiden, found in only one of 165 patients with SS disease including those tested for APC-R, or (2) the presence of lupus anticoagulants. However, the raised levels of factor VIIIC in SS patients in this study may be contributing to increased resistance to APC, which in turn may contribute to the vaso-occlusive complications of SS disease.
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PMID:Activated protein C resistance in homozygous sickle cell disease. 907 31

Inherited resistance to activated protein C (APC resistance) is an important risk factor of venous thrombosis. It is caused by a point mutation in the gene coding for coagulation factor V, called FV:Q506. Arterio-venous thrombosis is a common and serious medical problem in patients with systemic lupus erythematosus (SLE). We studied the prevalence of the factor V mutation associated with APC resistance and IgG anticardiolipin antibodies (aCLs) in an epidemiological cohort of 78 Swedish SLE patients, to determine their roles as risk factors for thrombosis. In addition, a detailed evaluation of the clinical manifestations in these patients was performed. Totally, 19 (24%) of the 78 SLE patients had thrombosis, 11 (14%) had venous thrombosis and 8 (10%) had a cerebral infarction caused by occlusion of cerebral vessels. Twenty-six (33%) SLE patients were aCL positive and 8 (10%) were heterozygous for the factor V mutation. Only one of the patients with venous thrombosis and one of the patients with cerebral thrombosis had the FV:Q506 mutation, whereas 3 patients with venous thrombosis and 5 patients with cerebral infarction were aCL positive. Eleven of 19 patients with heart valve disease were aCL positive, a statistically significant association (P = 0.01). In conclusion, we found no statistically significant association between venous thrombosis and FV:Q506 mutation or venous thrombosis and aCL positivity. There was, however, an association between heart valve disease and aCL positivity.
Lupus 1996 Dec
PMID:Factor V:Q506 mutation and anticardiolipin antibodies in systemic lupus erythematosus. 911 3


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