Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein.

Satoh, Minoru; Langdon, J J; Hamilton, Kimberly J.; Richards, Hanno B.; Panka, David J.; Eisenberg, Robert A.; Reeves, Westley H.

doi:10.1172/jci118711

Cited by 45 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remaining 16 were very weak or negative (data not shown), presumably because they contained Abs at levels below the threshold for detection by immunoblotting or that were directed against conformational epitopes, which were lost when the Ag was subjected to SDS-PAGE. The presence of Abs directed against conformational epitopes is common in other autoantigen systems (40,41). ELISA-negative sera were very weak or negative when rescreened by immunoblotting (Fig.…”

Section: Rescreening and Determination Of Subunit Specificity By Immumentioning

confidence: 93%

Identification of Human Autoantibodies to the DNA Ligase IV/XRCC4 Complex and Mapping of an Autoimmune Epitope to a Potential Regulatory Region

Lee

Dong

Wang

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

The nonhomologous end-joining pathway is the principal mechanism for repair of ionizing radiation-induced, double-strand breaks in mammalian cells. Three polypeptides in this pathway, including the two subunits of Ku protein and the catalytic subunit of the DNA-dependent protein kinase, are known targets of autoantibodies in systemic rheumatic diseases. Here we show that two additional polypeptides in the pathway, DNA ligase IV and XRCC4, are also targets of autoantibodies. These Abs were present in 20% of patients with systemic lupus erythematosus and overlap syndrome. Previous work has shown that XRCC4 is subject to radiation-induced post-translational modification, including phosphorylation by DNA-dependent protein kinase and cleavage by caspase 3. We mapped a major autoimmune epitope in XRCC4 and found that it encompassed a DNA-dependent protein kinase phosphorylation site, which is located at serine 260; that it was adjacent to a site for caspase 3, which cleaves after residue 265; and that it also spanned a site for the inflammatory protease, granzyme B, which cleaves after residue 254. The finding that five different polypeptides in the nonhomologous end-joining pathway are potential targets of autoantibodies together with the observation that one of the autoimmune epitopes in XRCC4 coincides with a sequence that is a nexus for radiation-induced regulatory events suggest that exposure to agents that introduce DNA double-strand breaks may be one of the factors that influences the development of an autoimmune response in susceptible individuals.

show abstract

Section: Rescreening and Determination Of Subunit Specificity By Immumentioning

confidence: 93%

Identification of Human Autoantibodies to the DNA Ligase IV/XRCC4 Complex and Mapping of an Autoimmune Epitope to a Potential Regulatory Region

Lee

Dong

Wang

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…2C), and B6/lpr-gld double mutant mice (not shown). MRL/lpr mice also produce these autoantibodies (14), but this pattern was not seen in pristane-treated B6 mice, despite the induction of a variety of other lupus autoantibodies (Table I). mAbs specific for histones and dsDNA, but not ssDNA, also immunoprecipitate these proteins, arguing that this pattern a Abs to RNP (nRNP or Sm), Su, ribosomal P, NF90/NF45, and core histones were detected by immunoprecipitation using sera obtained 6 mo after treatment with pristane or PBS (0.5 ml i.p.).…”

Section: Autoantibodies Induced In B6 Mice By Pristane Vs Lpr or Gldmentioning

confidence: 99%

Fas and Fas Ligand Mutations Inhibit Autoantibody Production in Pristane-Induced Lupus

Satoh

Weintraub

Yoshida

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Mutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.

show abstract

“…The proteins recognized by human sera were evaluated by IP of radiolabeled K562 cell extracts and SDS-PAGE as described [12]. In brief, cells were labeled with [ 35 S]methionine and cysteine, lysed in 0.5 M NaCl, 2 mM EDTA, 50 mM Tris pH 7.5, 0.3% Nonidet P40 (0.5 M NaCl NET/Nonidet P40) buffer containing 1 mM phenylmethyl sulfonyl fluoride and 0.3 TIU (trypsin inhibitor units)/ml aprotinin, and immunoprecipitated with Protein A–Sepharose beads coated with 8 μl of human serum.…”

Section: Methodsmentioning

confidence: 99%

“…The reactivity with native RPA has not been evaluated. Autoimmune B-cell epitopes are often discontinuous [9,10], recognize native conformational epitopes, and in some cases are poorly reactive in western blot [11,12]. There are also antibodies that recognize quaternary structure consisting of several protein components in snRNPs [13] and DNA-dependent protein kinase (DNA-PK) [14].…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases

et al. 2006

View full text Add to dashboard Cite

Replication protein A (RPA), a heterotrimer with subunits of molecular masses 70, 32, and 14 kDa, is a single-stranded-DNA-binding factor involved in DNA replication, repair, and recombination. There have been only three reported cases of anti-RPA in systemic lupus erythematosus (SLE) and Sjögren syndrome (SjS). This study sought to clarify the clinical significance of autoantibodies against RPA. Sera from 1,119 patients enrolled during the period 2000 to 2005 were screened by immunoprecipitation (IP) of 35 S-labeled K562 cell extract. Antigen-capture ELISA with anti-RPA32 mAb, immunofluorescent antinuclear antibodies (ANA) and western blot analysis with purified RPA were also performed. Our results show that nine sera immunoprecipitated the RPA70-RPA32-RPA14 complex and all were strongly positive by ELISA (titers 1:62,500 to 1:312,500). No additional sera were positive by ELISA and subsequently confirmed by IP or western blotting. All sera showed fine speckled/homogeneous nuclear staining. Anti-RPA was found in 1.4% (4/276) of SLE and 2.5% (1/40) of SjS sera, but not in rheumatoid arthritis (0/35), systemic sclerosis (0/47), or polymyositis/dermatomyositis (0/43). Eight of nine patients were female and there was no racial predilection. Other positive patients had interstitial lung disease, autoimmune thyroiditis/hepatitis C virus/pernicious anemia, or an unknown diagnosis. Autoantibody specificities found in up to 40% of SLE and other diseases, such as anti-nRNP, anti-Sm, anti-Ro, and anti-La, were unusual in anti-RPA-positive sera. Only one of nine had anti-Ro, and zero of nine had anti-nRNP, anti-Sm, anti-La, or anti-ribosomal P antibodies. In summary, high titers of anti-RPA antibodies were found in nine patients (1.4% of SLE and other diseases). Other autoantibodies found in SLE were rare in this subset, suggesting that patients with anti-RPA may form a unique clinical and immunological subset.

show abstract

Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein.

Cited by 45 publications

References 43 publications

Identification of Human Autoantibodies to the DNA Ligase IV/XRCC4 Complex and Mapping of an Autoimmune Epitope to a Potential Regulatory Region

Identification of Human Autoantibodies to the DNA Ligase IV/XRCC4 Complex and Mapping of an Autoimmune Epitope to a Potential Regulatory Region

Fas and Fas Ligand Mutations Inhibit Autoantibody Production in Pristane-Induced Lupus

Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases

Contact Info

Product

Resources

About