Objective. To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE).Methods. Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients.Results. Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 ؋ 10 ؊9 ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis.Conclusion. Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor  signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.The autoimmune disease systemic lupus erythematosus (SLE) is characterized by multiple immunologic abnormalities including the presence of circulating antinuclear antibodies and a sustained type I interferon (IFN) response (1), with up-regulation of type I IFN-
Anti-GBM disease is now a preferred term for what was earlier called Goodpasture's syndrome or Goodpasture's disease Anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation The diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease Therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases 20-35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease.
Proteinase 3 (PR3) is found in granules of all neutrophils but also on the plasma membrane of a subset of neutrophils (mPR3). CD177, another neutrophil protein, also displays a bimodal surface expression. In this study, we have investigated the coexpression of these two molecules, as well as the effect of cell activation on their surface expression. We can show that CD177 is expressed on the same subset of neutrophils as mPR3. Experiments show that the expression of mPR3 and CD177 on the plasma membrane is increased or decreased in parallel during cell stimulation or spontaneous apoptosis. Furthermore, we observed a rapid internalization and recirculation of mPR3 and plasma membrane CD177, where all mPR3 is replaced within 30 min. Our findings suggest that the PR3 found on the plasma membrane has its origin in the same intracellular storage as CD177, i.e., secondary granules and secretory vesicles and not primary granules. PR3- and CD177-expressing neutrophils constitute a subpopulation of neutrophils with an unknown role in the innate immune system, which may play an important role in diseases such as Wegener's granulomatosis and polycythemia vera.
SUMMARYInteractions between plasma proteins and MPO were studied. The protein fraction of normal plasma and serum was shown to exhibit an inhibitory effect on the peroxidase activity of MPO. Most of the inhibitory effect could be retained on an MPO-coupled affinity chromatography column. In particular, a protein with apparent mol. wt of 130 kD showed affinity for MPO. The protein was identified as ceruloplasmin by N-terminal amino acid sequencing and immunochemistry. During separation procedures the peroxidase inhibitory effect was limited to ceruloplasmin-containing fractions of plasma. Purified ceruloplasmin inhibited the peroxidase activity of MPO in a concentration-dependent manner, and exhibited selective binding to MPO-coated microtitre plates. This binding could be inhibited by MPO dissolved in buffer. Correspondingly the binding of MPO to ceruloplasmin-coated plates could be blocked by ceruloplasmin in solution, showing a physical interaction to occur between the two proteins under physiological conditions. We also found affinity to exist between MPO and C3 (and its C3d-containing fragments). However, C3 and C3 fragments did not inhibit the peroxidase reaction in vitro. We propose that ceruloplasmin takes part in the clearance and inactivation of MPO, in vivo. We also speculate that impaired inactivation of MPO may have a pathophysiological role in inflammatory diseases characterized by autoantibodies to MPO, such as rapidly progressive glomerulonephritis with P-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies).
Background: The nephrotoxic potential of anti-glomerular-basement-membrane (GBM) antibodies has been demonstrated in numerous animal experiments. However, it is not known to what extent the properties of circulating anti-GBM antibodies in human disease reflect the severity of the disease and predict the outcome. Methods: Clinical data were collected for 79 Swedish patients for whom a positive result had previously been obtained with anti-GBM ELISA. In stored sera from the patients, we measured antibody concentration, specificity and affinity together with antineutrophil cytoplasmic antibodies and α1-antitrypsin phenotype. Results: Six months after diagnosis, 27 (34%) were dead, 32 (41%) were on dialysis treatment and only 20 (25%) were alive with a functioning native kidney. The best predictor for renal survival was renal function at diagnosis. In patients who were not dialysis dependent at diagnosis however, renal survival was associated with a lower concentration of anti-GBM antibodies, a lower proportion of antibodies specific for the immunodominant epitope and the histological severity of the renal lesion. The only factor that correlated with patient survival was age. Conclusions: Immunochemical properties of autoantibodies do not affect patient survival in anti-GBM disease but seem to be a factor in renal survival in patients detected before renal damage is too advanced.
Anti-neutrophil cytoplasmic antibodies (ANCAs) have a pathogenic role in ANCA-associated vasculitis. The origin of ANCAs and anti-glomerular basement membrane (GBM) antibodies, however, is unknown. In this study, we determined whether natural autoantibodies against myeloperoxidase (MPO), proteinase 3 (PR3), and GBM were present in each of 10 healthy Chinese and Swedish individuals, negative for all three antigens by routine ELISA. Antibodies were purified from isolated IgG by antigen-specific affinity columns. Natural anti-GBM autoantibodies gave a linear staining pattern along the GBM of human renal sections. On ethanol-fixed granulocytes, both natural anti-MPO and anti-PR3 autoantibodies gave cytoplasmic staining. The titers of natural anti-MPO/PR3 autoantibodies were significantly lower than those from patients with vasculitis. In competition ELISA, the binding of natural anti-MPO autoantibodies could be inhibited by MPO, but not by PR3 or noncollagenous domains from type IV collagen. The same specificity results were found for natural anti-PR3 and anti-GBM autoantibodies. Overall, individuals of the Chinese origin had more natural autoantibodies than did those of the Swedish origin, but no other differences were found. Hence, our study shows that healthy individuals have masked circulating, noncross-reactive, antigen-specific natural autoantibodies against MPO, PR3, and GBM in their serum and IgG fractions. Further studies are needed to determine their role if any in the etiology of ANCA-associated vasculitis and anti-GBM disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.