Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit

Satoh, Minoru; Ak, Ajmani; Stojanov, Lovorka; Jj, Langdon; Ogasawara, Takashi; Wang, J; Ma, Dooley; Hb, Richards; Jb, Winfield; Th, Carter; Wh, Reeves

doi:10.1046/j.1365-2249.1996.d01-775.x

Cited by 27 publications

(25 citation statements)

References 32 publications

(31 reference statements)

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“…* may reflect the presence of a subset of anti-DNA/chromatin Abs (15). These data strongly suggest that pristane enhances/accelerates autoantibody production in a manner different from lpr or gld.…”

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

confidence: 79%

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

Satoh

Weintraub

Yoshida

et al. 2000

The Journal of Immunology

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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.

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

confidence: 79%

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

Satoh

Weintraub

Yoshida

et al. 2000

The Journal of Immunology

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“…The occurrence of autoantibodies in linked sets together with the observation that some autoantibodies tend to stabilize assembled nucleoprotein complexes (5)(6)(7)(8) suggests that the complexes themselves may play an important role in the maintenance and propagation of the autoimmunity. It may be that novel epitopes are formed at protein-nucleic acid interfaces or as the result of conformational changes that accompany complex assembly (9).…”

Section: Identification Of Human Autoantibodies To the Dna Ligase Iv/mentioning

confidence: 99%

“…Subsequent studies using more sensitive techniques revealed the presence of anti-Ku Abs in 5-15% of SLE patients in U.S. populations (16 -18). Abs to another enzyme in the NHEJ pathway, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), have also been detected in SLE patients, and their incidence was shown to be significantly correlated with the presence of anti-Ku autoantibodies (5,19). This suggests that the autoimmune response may be directed in part against an assembled Ku/DNA-PKcs/DNA particle.…”

Section: Identification Of Human Autoantibodies To the Dna Ligase Iv/mentioning

confidence: 99%

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

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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.

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“…In the most recent issue of Clinical and Experimental Immunology, Satoh, Reeves and colleagues have provided experimental data that extend the concept of linked autoantibody sets in systemic humoral autoimmunity [15]. They showed that autoantibodies against different protein components of the DNAdependent protein kinase complex (DNA-PK), autoantigenic targets in SLE and other systemic autoimmune diseases, arose in a linked set.…”

Section: Autoimmunogens In Lupus Are Intact Particlesmentioning

confidence: 99%

Intrastructural help in diversification of humoral autoimmune responses

Fatenejad

Craft

1996

Clinical and Experimental Immunology

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Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit

Cited by 27 publications

References 32 publications

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

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

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

Intrastructural help in diversification of humoral autoimmune responses

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