Nucleosomes are the dominant autoantigens in patients with systemic lupus erythematosus (SLE), and immune complexes involving nucleosomes are the major cause of tissue damage. The activity of DNase I, the enzyme responsible for nucleosome degradation, has been found to be decreased in patients with SLE. However, it is not known whether DNase activity is a clinically useful parameter. The aim of our study was to assess DNase activity in a prospective study of 113 patients with SLE in relation to disease activity and organ involvement. We included two control groups: 9 patients with undifferentiated connective tissue disease (UCTD) and 14 healthy individuals. DNase activity was found to be lower in patients with SLE (63.75% ؎ 12.1%) than in the controls (81.3% ؎ 9.25%) (P < 0.001). DNase activity in patients with UCTD (64.9% ؎ 18.2%; P ؍ 0.854) did not differ from that in patients with SLE. Patients with SLE had higher antinucleosome antibody titers (356.3 ؎ 851) than the controls (1.44 ؎ 2.77; P < 0.01) or UCTD patients (39.9 ؎ 57.7; P < 0.01). In addition, samples positive for antinucleosome antibodies displayed low levels of DNase activity. Within the SLE group, the presence of renal disease had no impact on DNase activity or antinucleosome antibody titers. Also, the SLE disease activity index showed no correlation with DNase activity. In a longitudinal study of six SLE patients, DNase activity did not follow disease activity or autoantibody titers. Our results confirm that serum DNase activity is decreased in patients with SLE, but we conclude that it is not a clinically useful parameter for the prediction of flare-ups of disease or renal involvement.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of a wide range of pathological autoantibodies. Those directed against chromatin components, e.g., double-stranded DNA (dsDNA), histones, and the nucleosome, are of paramount pathological importance (6,8,20).Recent studies of patients with SLE suggest the increasing diagnostic importance of antinucleosome antibodies, in addition to antibodies directed against dsDNA (1, 17). These circulating antibodies may form immune complexes with their target antigens, the glomerular deposition of which will lead to the development of renal damage (12,14).The incidence of immune complex-mediated glomerulonephritis (GN) among SLE patients varies from 30 to 60%. Several studies have confirmed that autoantibodies are produced through an antigen-driven T-cell-dependent mechanism (13,23,27). According to this model, the defective clearance of apoptotic cell debris predisposes individuals to SLE through the accumulation of the chromatin components arising from the dying cells (5, 28).DNase I (pancreatic DNase) and DNase II (spleen acid DNase) cleave nucleosomal DNA, which promotes the disposal of circulating nuclear material. DNase I, a glycoprotein with a molecular mass of 30,400 Da, is a cation-binding secretory endonuclease that digests dsDNA in a sequence-dependent manner (24). DNase II,...
Summary. Background: We studied 24 Hungarian patients from 23 unrelated families to identify the genetic background of the entire type 3 von Willebrand disease (VWD) population in this country. The current report focuses on the molecular characterization of a novel large deletion. Results: A large partial deletion (delExon1–3) of the 5′‐region of the von Willebrand factor gene (VWF) was detected in 12/48 alleles (25% of all type 3 alleles). The 5′‐deletion breakpoint is located in the untranslated region between VWF and CD9, whereas the 3′ breakpoint is in intron 3 of VWF. Analysis of the breakpoints showed Alu Y and Alu SP repetitive sequences at the ends of the deletion, suggesting that a recombination event caused the subsequent loss of the 35‐kb fragment. DelExon1–3 was not found in any of the other screened populations. Conclusion: We report a large novel deletion including exons 1, 2 and 3 of VWF commonly causing type 3 VWD in the Hungarian population. This mutation, probably caused by an Alu‐mediated recombination event, and subsequently distributed in Hungary by a founder effect, seems to be unique to Hungarian patients with a high allele frequency. Together, delExon1–3 and 2435delC make up 37.5% of the genetic defects in Hungarian patients with VWD type 3. This offers a rational approach to molecular testing of relevant families in Hungary.
In SLE patients, the presence of aPL is a more significant risk factor for the development of thrombosis than the known inherited deficiencies. Based on these data, routine screening for additional hereditary risk factors seems to be unwarranted.
Receptors specific for the Fc part of IgG (Fc + R) are expressed by several cell types and play diverse roles in immune responses. Impaired function of the activating and inhibitory Fc + R may result in autoimmunity. Thus, the modulation of IgG-Fc + R interaction can be a target for the development of treatments for some autoimmune and inflammatory diseases. This study addresses the localization and functional characterization of linear sequences in human IgG1 which bind to Fc + RII. Peptides with overlapping sequences derived from the CH2 domain of human IgG1 between P 234 and S 298 were synthesized and used in binding and functional experiments. Binding of the peptides to Fc + R was assayed in vitro and ex vivo, and peptides found to interact were functionally tested. The shortest effective peptide was T 256-P 271 complexed by avidin exhibited functional activity; they induced Fc + RIIb-mediated inhibition of the BCR-triggered Ca 2+ response of human Burkitt lymphoma cells, and inflammatory cytokine production (TNF- § and IL-6) by the human monocyte cell line MonoMac. In conclusion, our results suggest that the selected peptides functionally represent the Fc + RII-binding part of IgG1.
The pathogenesis of VWD Vicenza has remained elusive. VWD Vicenza is characterized by low plasma but normal platelet VWF concentration, the presence of ultra-large plasma multimers, and a heterozygous R1205H mutation. VWF Vicenza is reported to have a decreased half-life in the circulation. When we expressed rVWF Vicenza R1205H in 293T cells, it was secreted with wild type efficiency and multimer distribution, suggesting that the primary defect is accelerated clearance. To evaluate this hypothesis, we developed a pharmacokinetic model of VWF multimer catabolism. The initial assumptions are: 1. Secretion occurs at a fixed rate with the initial “ultra-large” multimer distribution seen in platelet alpha granules. 2. Cleavage of multimers occurs with a probability p that increases with increasing multimer size. 3. Clearance occurs with a time constant determined by the plasma half life and is independent of multimer size. Modeled multimer distributions were compared to those determined experimentally for patient plasma samples. The effects of DDAVP infusion also were modeled and compared to published data (Casonato et al, Blood2002; 99:180). For p = 7.5 x 10−4 min−1 and a half life of 12 h, the modeled multimer patterns were comparable to the observed steady-state distribution of normal VWF. Decreasing the half life to 2 hours produces a low plasma concentration of “ultra-large” multimers typical of VWD Vicenza without a change in any other parameter. Conversely, increasing the probability of cleavage by only thirty percent produces typical VWD 2A multimer distributions. The model also reproduces the triplet patterns of normal and type 2A VWF. Finally, the DDAVP simulations reproduced the time course of VWF plasma concentrations and multimer distributions of DDAVP-treated patients. We conclude that increased clearance alone can explain the ultra-large multimer distribution of VWD Vicenza. Similar modeling should allow the estimation of VWF cleavage and clearance rates in other variants of VWD and in other clinical situations including thrombotic thrombocytopenic purpura. Figure Figure Figure Figure
Background: Type 3 is the most severe form of von Willebrand disease (VWD) caused by the virtual absence of von Willebrand factor (VWF) in affected patients. The prevalence of type 3 VWD in Hungary is 2.6 per million. Capitalizing on a nationwide National Bleeding Disorder Registry, we designed a study to characterize the genetic background of the entire Hungarian type 3 VWD population. The current report focuses on the molecular characterization of a novel large deletion. Methods: 24 patients from 23 unrelated families were studied by direct sequencing of the 52 exons of the VWF gene. The breakpoints of a large deletion were characterized by standard gene mapping. Breakpoint-specific PCR was used to confirm the presence of the deletion, and to screen for identical deletions in other populations from Germany, Russia, and Poland. Results: A large partial deletion (delExon1-3) of the 5′-region of the VWF gene was detected in 10 alleles (19 percent of all type 3 mutations). Five patients from 4 unrelated families were homozygous, and 2 patients were heterozygous for the deletion. Consanguinity was known in one of the families. In comparison, 2435 delC in exon 18, a common cause of type 3 VWD in some European populations, was found on 6 alleles (12 percent; one patient homozygous). The large deletion resulted in the loss of a 35 kb fragment, incorporating exons 1, 2 and 3. The 5′ breakpoint is located in the 5′ untranslated region, while the 3′ breakpoint is in intron 3 of VWF. No other known gene is lost with the deletion. Clinically, all homozygous patients had serious bleeding episodes from infancy requiring frequent VWF substitutions. However, bleeding became much milder in all patients with no significant spontaneous bleeding after the age of 3-5 years. No inhibitor to VWF was detected. delExon1-3 was not detected in any of the other screened populations. Conclusion: We report a large novel deletion including exons 1, 2 and 3 of VWF commonly causing type 3 VWD in the Hungarian population. This mutation, which is most probably due to a founder effect, seems to be unique to Hungarian patients with a high allele frequency. Together, delExon1-3 and 2435delC make up 31 % of genetic defects in Hungarian patients with VWD type 3. This offers a rational approach to molecular testing of respective families in Hungary.
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