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)

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not "spread" to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti-H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.
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PMID:Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. 950 78

We tested 154 peptides spanning the entire length of core histones of nucleosomes for the ability to stimulate an anti-DNA autoantibody-inducing T helper (Th) clone, as well as CD4(+) T-cell lines and T cells, in fresh PBMCs from 23 patients with lupus erythematosus. In contrast to normal T cells, lupus T cells responded strongly to certain histone peptides, irrespective of the patient's disease status. Nucleosomal peptides in histone regions H2B(10-33), H4(16-39) (and overlapping H4(14-28)), H4(71-94), and H3(91-105) (and overlapping H3(100-114)) were recurrently recognized by CD4 T cells from the patients with lupus. Remarkably, these same peptides overlap with major epitopes for the Th cells that induce anti-DNA autoantibodies and nephritis in lupus-prone mice. We localized 2 other recurrent epitopes for human lupus T cells in H2A(34-48) and H4(49-63). All the T-cell autoepitopes have multiple HLA-DR binding motifs, and the epitopes are located in histone regions recognized by lupus autoantibodies, suggesting a basis for their immunodominance. Native nucleosomes and their peptides H4(16-39), H4(71-94), and H3(91-105) induced a stronger IFN-gamma response, whereas others, particularly, H2A(34-48), favored an IL-10- and/or IL-4-positive T-cell response. The major autoepitopes may reveal the mechanism of autoimmune T-cell expansion and lead to antigen-specific therapy of human lupus.
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PMID:Major peptide autoepitopes for nucleosome-specific T cells of human lupus. 1043 Jun 16

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.
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PMID:Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives. 1116 8

Blood mononuclear cells from 20 lupus patients were cultured in the presence of nucleosomal antigens to determine whether they induce lymphocyte proliferation. The predominant effect seen, however, was one of inhibition of the background proliferation. Such inhibition was rare with cells from female or male controls. Nucleohistone (NH), crude histone and enriched preparations of histones H2A/H4, H2B and H3 showed this effect in approximately one-third of patients, but H1 and single-stranded (ss) DNA had no such activity. Double-stranded (ds) DNA may show this inhibitory action, but further tests are required. ssDNA was the only antigen that showed evidence (two patients) of disease-related stimulation of proliferation. Histones and NH induced proliferation in many subjects but the strongest responders were controls. Patients responded poorly to tuberculin PPD but gave an exceptionally strong proliferative response to pokeweed mitogen. It is suggested that the inhibition of background proliferation in patients is a consequence of the interaction of nucleosomal antigens with sensitised T cells. If T cell sensitisation to histones is an important factor in the development of lupus, the disease may be preventable in those at risk by inducing tolerance to the appropriate peptides.
Lupus 2001
PMID:Counter-proliferative effects of nucleosomal antigens in cultures from lupus patients. 1140 63

To be positively selected, immature thymocytes must receive signaling through their T-cell receptor (TCR), and engagement of relatively low-affinity self-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cells acquire a higher threshold for activation during thymopoiesis. We wondered whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into the thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for several months. The murine antichromatin antibodies reacted with the (H2A-H2B)-DNA subnucleosome complex, the predominant specificity in patients with procainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-present antigen, but acted on CD4+ CD8+ immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at position 99 (lys-->ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regulators that accumulate in response to partial signaling through the TCR. These results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in autoreactive T cells and systemic autoimmunity.
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PMID:A nondeletional mechanism for central T-cell tolerance. 1164 11

The clinical symptoms of drug-induced lupus (DIL) are similar to those of idiopathic systemic lupus erythematosus. The literature indicates that in patients with DIL, sera generally contain antinuclear antibodies (ANAs); however, ANA-negative DIL has been reported. The list of medications implicated as etiologic agents in DIL continues to grow. This list includes two different types of angiotensin-converting enzyme inhibitors--captopril and enalapril. We report the first case of DIL caused by lisinopril. Our patient had negative results on ANA testing and had histone antibodies (IgG anti-[H2A-H2B]-DNA) mirroring the disease course. Antibodies to the (H2A-H2B)-DNA complex are seen in more than 90% of patients with active DIL, excluding those with DIL due to hydralazine. Thus, it is important to recognize the clinical significance of IgG anti-(H2A-H2B)-DNA antibodies and that negative ANA test results do not preclude the diagnosis of DIL.
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PMID:Antinuclear antibody-negative, drug-induced lupus caused by lisinopril. 1178 Jun 82

An estimated incidence of drug-induced lupus erythematosus caused by all drugs is 15,000 to 20,000 cases a year, and represents approximately 5 to 10% of the total number of patients with systemic lupus erythematosus. Approximately 22% of the patients treated with isoniazid for a mean of 6 months develop antinuclear antibodies. Isoniazid-induced lupus erythematosus affects either sex equally and the most common presenting feature is arthralgia or arthritis with anemia. Fever and pleuritis occur in approximately half of the cases, and pericarditis in approximately 30% of cases. IgG antibody to the (H2A-H2B)-DNA complex appears specific for the isoniazid-induced lupus erythematosus. The drug-induced lupus presenting with cardiac tamponade is a recognized feature of many drugs such as hydralazine, procainamide, and sulfasalazine. Reported here is a case of isoniazid-induced lupus erythematosus presenting with cardiac tamponade. A 73-year-old man was treated with isoniazid for 8 months at a dose of 300 mg a day. The patient responded to the withdrawal of the isoniazid therapy and placement of a pericardial window. The existing literature on the subject is reviewed.
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PMID:Isoniazid-induced lupus erythematosus presenting with cardiac tamponade. 1189 31

This study was designed to find out the incidence of various autoantibodies in patients receiving iron chelators. Two groups were studied for comparison. One group consisted of thalassemia major cases on deferiprone (L1) and the second group were those receiving desferrioxamine therapy. Various autoantibodies such as antihistone antibodies and its subfractions H1, H2A-H4B, H2B, H3, ANF, anti-dsDNA, anti-nRNP, anti-Sm, ANCA and rheumatoid factor were tested. Out of 180 patients 50 patients (27.8%) were on desferrioxamine therapy, and 60 patients (33.3%) were taking deferiprone, whereas 70 patients (38.9%) were untreated. Antihistone antibodies were found in 30% of patients receiving deferiprone and 48% in the desferrioxamine group, respectively, as compared to control thalassemics (14.3%). Also, the levels of antihistone antibody were significantly elevated in the chelator groups as compared to controls. When antibodies to subfractions of the histone molecule were studied, it was observed that antibodies to H1 were most commonly seen and IgG was the major immunoglobulin subclass. Anti-dsDNA and anti-Sm antibodies, which are the diagnostic markers of idiopathic SLE, were absent in these patients. beta-Thalassemia major patients on iron chelators such as desferrioxamine and deferiprone show changes in their autoimmune profile suggestive of some humoral immune alterations.
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PMID:Antihistone and other autoantibodies in beta-thalassemia major patients receiving iron chelators. 1466 75

Anti-chromatin autoantibodies were one of the first autoantibodies ever detected since they make up the majority of antibodies causing LE Cell formation. Anti-chromatin autoantibodies have had many names over the last few decades: LE cell factor; anti-nucleosome; anti-deoxyribonucleoprotein (DNP); and anti-(H2A-H2B-DNA). These autoantibodies are found in approximately 75% of people with systemic lupus erythematosus and up to 100% of people with drug-induced lupus. They are also found in 20-50% of patients with autoimmune hepatitis type I (lupoid hepatitis). Anti-chromatin are not generally found in any other disease, thus showing very good sensitivity and specificity for patients with lupus, drug-induced lupus and lupoid hepatitis. A number of studies have shown that in patients with lupus, anti-chromatin often correlates better with kidney disease than anti-DNA. Recent genetic analyses of murine models of lupus have identified at least three loci that work together to cause anti-chromatin antibodies and glomerulonephritis in mice. It will be an important breakthrough when the functions of the genes at these loci are identified.
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PMID:Anti-chromatin (anti-nucleosome) autoantibodies. 1284 87

A spontaneous, autoreactive autoantibody called SN5-18 (IgG2b, kappa) binds to a complex of H2A/H2B/dsDNA in chromatin, but erroneously appears to bind dsDNA when the Ab is used in a form that is not highly purified. Because of this finding, we evaluated the antigenic specificity of a prototypic anti-dsDNA Ab, 3H9/Vkappa4, now used widely in transgenic studies of tolerance and autoimmunity. We found that the purified mAb 3H9/Vkappa4 binds chromatin and specifically a complex of H2A/H2B/dsDNA, but not dsDNA in solid phase or in solution. When used in the form of culture supernatant or as a standard protein G preparation, mAb 3H9/Vkappa4 appears to bind dsDNA, apparently due to nuclear proteins in the preparation that assemble on target DNA. Because of the reported role of V(H)CDR3 Arg residues in dsDNA binding and the near identity of the SN5-18 sequence to other dsDNA-specific Ab, we tested the contributions of two V(H)CDR3 Arg residues in SN5-18 to chromatin specificity. We found that both these Arg residues at positions 104 and 106 were required for detectable chromatin binding. These results indicate a role for V(H)CDR3 Arg residues in chromatin specificity of lupus-derived autoantibodies. Further, they provide an explanation for a possible discrepancy in the form of tolerance observed in different anti-DNA Ig transgene models.
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PMID:Chromatin specificity of anti-double-stranded DNA antibodies and a role for Arg residues in the third complementarity-determining region of the heavy chain. 1500 32


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