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)

A structural analysis of cells that contained the interferon-alpha-induced lupus inclusions (LI) was performed using a high-voltage electron microscope to determine the exact cellular location of LI and their association with normal cell organelles. LI were induced in the human B lymphoblastoid cell line, Daudi, by culturing with the pure recombinant human leukocyte interferon, IFLrA. Just prior to harvesting, a portion of the cells was treated with monensin to selectively swell the Golgi apparatus, and thereby simplify their identification using the electron microscope. Organellar associations between LI and the outer nuclear envelope and Golgi apparatus were identified in stereopairs of 1-micron sections prepared from both cells that were not treated with monensin and those that were treated with monensin. Serial 0.25-micron sections of the monensin-treated cells were prepared, and seven arbitrarily chosen cells were examined. Each of these cells contained a single LI, and it formed throughout an endoplasmic-reticulum region that made contact with both the outer nuclear envelope and the Golgi vesicles. Reconstruction of a cell by computer from the digitized negatives of serial sections clearly illustrated these relationships. This study reports the first determination of the association between LI and the Golgi apparatus. It also identifies the presence of only one LI in every cell, and the routine association of the LI with both the outer nuclear envelope and the Golgi apparatus. The unique cell location of LI formation suggests their functioning in membrane biogenesis, the trafficking of proteins to the plasma membrane or to cytoplasmic vesicles, or the processing of proteins for secretion.
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PMID:Localization of interferon-induced lupus inclusions demonstrated by computer image reconstruction of monensin-treated Daudi cells. 137 90

Mononuclear cells purified from umbilical cord blood activated oligoadenylate synthetase and formed human lupus-type inclusions (LI) when cultured with the purified recombinant human leukocyte interferon, IFLrA. LI frequencies increased from 0% to a low of 0.75% and a high of 6.25% in 4-day cultures with IFLrA (100 units/ml). These interferon-induced responses in the mononuclear cells of neonates indicate that LI are solely an intrinsic product of normal cells, and not an exogenous virus or some other environmental agent.
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PMID:Human lupus-type inclusions in umbilical cord blood mononuclear cells. 216 48

Quantitative electron microscope autoradiography has been used to define the macromolecular composition of the interferon-induced human lupus-type inclusions (LI) in the human B lymphoblastoid cell line, Daudi. LI were first apparent in Daudi cell cultures 12 h after the addition of 100 units/ml of the purified recombinant human leukocyte interferon, IFLrA. Radiolabels were added at this time and allowed to incorporate over the following 12 h during which an estimated greater than 99% of the LI material present at 24 h was formed. The LI-incorporated radiolabels were present only during this discrete 12-h period after the interferon activation of LI cell pathways in order to detect LIs de novo synthesized macromolecular components. The estimate relative specific activities of the LI-incorporated radiolabels were: choline at 4.042, mannose at 2.631, uridine at 0.664, glucosamine at 0.578, and amino acids at 0.477. With thymidine the estimated LI specific activity was 0.000. LI isolated from whole cells retained the tubular elements and the interwoven membrane network. These results provide direct evidence that the interferon-induced Daudi cell LI are de novo synthesized complexes of ribonucleoprotein and membrane.
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PMID:Evidence that the interferon-induced Daudi cell human lupus inclusions are de novo synthesized complexes of ribonucleoprotein and membrane. 278 94

A sensitive in vitro bioassay for the alpha-interferon induction of lupus-type inclusions (LI) has been established with the human B lymphoblastoid cell line, Daudi. Sera from 11 patients with systemic lupus erythematosus (SLE) were evaluated with this assay. LI induction by these sera increased in proportion to their antiviral activity on Madin-Darby bovine kidney (MDBK) cells. Two of these sera did not induce LI; they showed no antiviral activity on the MDBK cell assay. Clinically and serologically, their donors were in remission. Two sera induced the formation of LI that exceeded the maximum frequencies obtained with 3 alpha-interferon preparations. These sera had the greatest antiviral activities, and their donors had the greatest disease activities. Antisera to alpha-interferons prevented the induction of LI with the pure and homogeneous recombinant human leukocyte interferon, IFLrA, and SLE sera. Together, these results provide evidence that the alpha-interferon endogenous to SLE patients has a great ability to induce LI, and the SLE serum induction of LI corresponds well to the patient's disease activity.
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PMID:Induction of lupus inclusions by sera from patients with systemic lupus erythematosus. 348 63

The effect of interferon inducers of viral and nonviral nature as well as of exogenous leukocyte interferon on interferon response of leukocytes (IRL) was studied in patients with different rheumatic diseases, mostly in patients with systemic lupus erythematosus (SLE). Studies in vitro showed that synthetic polyribonucleotide poly(1) X poly(C) induced in SLE patients on the average 3 times as high IRL indices as the viral interferon inducer Newcastle disease virus. A two-week course of treatment of some SLE patients with exogenous leukocyte interferon in various dosages (10(6), 3 X 10(5), and 10(4) units) resulted in a 2--16-fold increase of IRL values in the majority of the patients.
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PMID:[alpha-Interferon indices in systemic lupus erythematosus and the effect of interferon therapy]. 667 Feb 58

Some immunologic parameters in homosexual patients with Kaposi's sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-alpha) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.
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PMID:Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy. 711 75

Autoantibodies against interferon (IFN) can be found in patients with systemic lupus erythematosus (SLE). However, detailed information about the occurrence of type-specific antihuman IFN antibodies is not available. In this study, we investigated the incidence of autoantibodies specifically recognizing various type I IFNs (alpha1, alpha2, beta, omega) and type II IFN (gamma). Sera from 100 SLE patients were screened for the presence of IFN-binding antibodies by ELISA, using various types of recombinant IFNs as antigen. On the whole, autoantibodies against type I or type II or both IFNs were detected in 45% (45 of 100) of the serum samples investigated. More than half (56%) of the positive samples (25 of 45) contained antibodies specific only for type I IFNs, and 36% of positive sera (16 of 45) had autoantibodies only against type II IFN. Antibodies against both type I and type II IFNs were detected in 8% (4 of 45) of the positive samples. Among autoantibodies to type I IFNs, the most abundant were those against the type IFN-omega (15%) and the subtype IFN-alpha2 (11%). Autoantibodies binding subtype IFN-alpha1 and type IFN-beta were detected at a relatively lower incidence of about 3%-4%. The highest occurrence (20%) showed autoantibodies to the proinflammatory cytokine, IFN-gamma. We did not find any correlation between the production of autoantibodies against particular IFN species and an antibody response to other IFN species. We further observed that 84% (38 of 45) of the positive sera bound only one IFN species, and 13% (6 of 45) of positive samples contained antibodies against two IFN species of five different combinations (alpha1/beta, alpha1/omega, alpha2/omega, alpha2/gamma, omega/gamma). One sample uniquely showed reactivity with three IFN species (alpha2/omega/gamma). Our findings suggest that formation of autoantibodies could reflect humoral immune responses to increased spontaneous production of the respective IFN species in SLE patients.
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PMID:Incidence of autoantibodies against type I and type II interferons in a cohort of systemic lupus erythematosus patients in Slovakia. 1271 86

Type I interferons (IFNs) are multifunctional cytokines that activate cellular responses by binding a common receptor consisting of two subunits, IFNAR-1 and IFNAR-2. Although the binding of IFNs to IFNAR-2 is well characterized, the binding to the lower affinity IFNAR-1 remains less well understood. Previous reports identified a region of human IFN-alpha2 on the B and C helices ("site 1A": N65, L80, Y85, Y89) that plays a key role in binding IFNAR-1 and contributes strongly to differential activation by various type I IFNs. The current studies demonstrate that residues on the D helix are also involved in IFNAR-1 binding. In particular, residue 120 (Arg in IFN-alpha2; Lys in IFN-alpha2/alpha1) appears to be a "hot-spot" residue: substitution by alanine significantly decreased biological activity, and the charge-reversal mutation of residue 120 to Glu caused drastic loss of antiviral and antiproliferative activity for both IFN-alpha2 and IFN-alpha2/alpha1. Mutations in residues of helix D maintained their affinity for IFNAR-2 but had decreased affinity for IFNAR-1. Single-site or multiple-site mutants in the IFNAR-1 binding site that had little or no detectable in vitro biological activity were capable of blocking in vitro antiviral and antiproliferative activity of native IFN-alpha2; i.e., they are type I IFN antagonists. These prototype IFN antagonists can be developed further for possible therapeutic use in systemic lupus erythematosus, and analogous molecules can be designed for use in animal models.
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PMID:Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. 1893 99