scholarly journals The DNA sensors AIM2 and IFI16 are NET-binding SLE autoantigens

2021 ◽  
Author(s):  
Brendan Antiochos ◽  
Paride Fenaroli ◽  
Avi Rosenberg ◽  
Alan Baer ◽  
Jungsan Sohn ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Nucleic Acid Binding ◽  
Extracellular Traps ◽  
Double Stranded Dna ◽  
Nucleic Acid Binding Proteins ◽  
Dna Antibodies ◽  
Inducible Protein ◽  
Clinical Measures ◽  
Interferon Inducible Protein

Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFNinducible innate sensors that form supramolecular assemblies along double-stranded DNA of various origins. Here, we identify the ALR Absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16 and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a proimmune context, finding that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE.

Inhibition of Adenovirus DNA Synthesis In Vitro by Sera from Patients with Systemic Lupus Erythematosus

1982 ◽  
Vol 2 (12) ◽  
pp. 1492-1500
Author(s):  
Marshall S. Horwitz ◽  
Beth R. Friefeld ◽  
Harold D. Keiser
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dna Synthesis ◽  
Lupus Erythematosus ◽  
Inhibitory Activity ◽  
Antinuclear Antibodies ◽  
Dna Binding Protein ◽  
Systemic Lupus ◽  
Double Stranded Dna ◽  
The Individual

Sera containing antinuclear antibodies from patients with systemic lupus erythematosus (SLE) and related disorders were tested for their effect on the synthesis of adenovirus (Ad) DNA in an in vitro replication system. After being heated at 60°C for 1 h, some sera from patients with SLE inhibited Ad DNA synthesis by 60 to 100%. Antibodies to double-stranded DNA were present in 15 of the 16 inhibitory sera, and inhibitory activity copurified with anti-double-stranded DNA in the immunoglobulin G fraction. These SLE sera did not inhibit the DNA polymerases α, β, γ and had no antibody to the 72,000-dalton DNA-binding protein necessary for Ad DNA synthesis. The presence of antibodies to single-stranded DNA and a variety of saline-extractable antigens (Sm, Ha, nRNP, and rRNP) did not correlate with SLE serum inhibitory activity. Methods previously developed for studying the individual steps in Ad DNA replication were used to determine the site of inhibition by the SLE sera that contained antibody to double-stranded DNA. Concentrations of the SLE inhibitor that decreased the elongation of Ad DNA by greater than 85% had no effect on either the initiation of Ad DNA synthesis or the polymerization of the first 26 deoxyribonucleotides.

scholarly journals Neutrophil Extracellular Traps-DNase Balance and Autoimmunity

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2667
Author(s):  
Andrea Angeletti ◽  
Stefano Volpi ◽  
Maurizio Bruschi ◽  
Francesca Lugani ◽  
Augusto Vaglio ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Causative Factor ◽  
Neutrophil Extracellular Traps ◽  
Limiting Factor ◽  
Systemic Lupus ◽  
Extracellular Traps ◽  
Number Of Patients ◽  
Selective Depletion ◽  
Dna Antibodies ◽  
Rate Limiting

Neutrophil extracellular traps (NETs) are macromolecular structures programmed to trap circulating bacteria and viruses. The accumulation of NETs in the circulation correlates with the formation of anti-double-stranded (ds) DNA antibodies and is considered a causative factor for systemic lupus erythematosus (SLE). The digestion of DNA by DNase1 and DNases1L3 is the rate- limiting factor for NET accumulation. Mutations occurring in one of these two DNASE genes determine anti-DNA formation and are associated with severe Lupus-like syndromes and lupus nephritis (LN). A second mechanism that may lead to DNase functional impairment is the presence of circulating DNase inhibitors in patients with low DNase activity, or the generation of anti-DNase antibodies. This phenomenon has been described in a relevant number of patients with SLE and may represent an important mechanism determining autoimmunity flares. On the basis of the reviewed studies, it is tempting to suppose that the blockade or selective depletion of anti-DNase autoantibodies could represent a potential novel therapeutic approach to prevent or halt SLE and LN. In general, strategies aimed at reducing NET formation might have a similar impact on the progression of SLE and LN.

scholarly journals The Sac10b homolog from Sulfolobus islandicus is an RNA chaperone

2020 ◽  
Vol 48 (16) ◽  
pp. 9273-9284
Author(s):  
Ningning Zhang ◽  
Li Guo ◽  
Li Huang
Keyword(s):  
Elevated Temperatures ◽  
Normal Growth ◽  
Strand Exchange ◽  
Nucleic Acid Binding ◽  
Basic Residue ◽  
Rna Chaperone ◽  
Sulfolobus Islandicus ◽  
Nucleic Acid Binding Proteins ◽  
Rna Unwinding

Abstract Nucleic acid-binding proteins of the Sac10b family, also known as Alba, are widely distributed in Archaea. However, the physiological roles of these proteins have yet to be clarified. Here, we show that Sis10b, a member of the Sac10b family from the hyperthermophilic archaeon Sulfolobus islandicus, was active in RNA strand exchange, duplex RNA unwinding in vitro and RNA unfolding in a heterologous host cell. This protein exhibited temperature-dependent binding preference for ssRNA over dsRNA and was more efficient in RNA unwinding and RNA unfolding at elevated temperatures. Notably, alanine substitution of a highly conserved basic residue (K) at position 17 in Sis10b drastically reduced the ability of this protein to catalyse RNA strand exchange and RNA unwinding. Additionally, the preferential binding of Sis10b to ssRNA also depended on the presence of K17 or R17. Furthermore, normal growth was restored to a slow-growing Sis10b knockdown mutant by overproducing wild-type Sis10b but not by overproducing K17A in this mutant strain. Our results indicate that Sis10b is an RNA chaperone that likely functions most efficiently at temperatures optimal for the growth of S. islandicus, and K17 is essential for the chaperone activity of the protein.

scholarly journals Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus

2005 ◽  
Vol 52 (4) ◽  
pp. 1129-1137 ◽  
Author(s):  
Matthew D. Linnik ◽  
Jay Z. Hu ◽  
Kenneth R. Heilbrunn ◽  
Vibeke Strand ◽  
Frank L. Hurley ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Double Stranded Dna ◽  
Dna Antibodies

scholarly journals Transplanted Human Umbilical Cord Mesenchymal Stem Cells Facilitate Lesion Repair in B6.Fas Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Guang-ping Ruan ◽  
Xiang Yao ◽  
Shuang-juan Yang ◽  
Jin-xiang Wang ◽  
Fan Shu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Stem Cells ◽  
Umbilical Cord ◽  
Lupus Erythematosus ◽  
Human Umbilical Cord ◽  
Systemic Lupus ◽  
Multisystem Disease ◽  
Double Stranded Dna ◽  
Dna Antibodies ◽  
Disease Indicators

Background. Systemic lupus erythematosus (SLE) is a multisystem disease that is characterized by the appearance of serum autoantibodies. No effective treatment for SLE currently exists.Methods. We used human umbilical cord mesenchymal stem cell (H-UC-MSC) transplantation to treat B6.Fas mice.Results. After four rounds of cell transplantation, we observed a statistically significant decrease in the levels of mouse anti-nuclear, anti-histone, and anti-double-stranded DNA antibodies in transplanted mice compared with controls. The percentage of CD4+CD25+Foxp3+T cells in mouse peripheral blood significantly increased after H-UC-MSC transplantation.Conclusions. The results showed that H-UC-MSCs could repair lesions in B6.Fas mice such that all of the relevant disease indicators in B6.Fas mice were restored to the levels observed in normal C57BL/6 mice.

scholarly journals MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti–double-stranded DNA B Cells

1999 ◽  
Vol 189 (11) ◽  
pp. 1799-1814 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Su-jean Seo ◽  
Caroline Sokol ◽  
Kathryn M. Potts ◽  
Anh Bui ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Genetic Background ◽  
Systemic Lupus ◽  
Autoreactive B Cells ◽  
Developmental Arrest ◽  
Double Stranded Dna ◽  
Dna Antibodies ◽  
Cell Defect

A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is the presence of anti–double-stranded (ds)DNA antibodies (Abs). To identify the steps leading to the production of these Abs in autoimmune mice, we have compared the phenotype and localization of anti-dsDNA B cells in autoimmune (MRL+/+ and lpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNA B cells are actively regulated in BALB/c mice as indicated by their developmental arrest and accumulation at the T–B interface of the splenic follicle. In the MRL genetic background, anti-dsDNA B cells are no longer developmentally arrested, suggesting an intrinsic B cell defect conferred by MRL background genes. With intact Fas, they continue to exhibit follicular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident with the altered localization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells. Together, these data suggest that MRL mice are defective in maintaining the developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.

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