Dataset Information

Identification of three new autoantibodies associated with systemic lupus erythematosus using two proteomic approaches.

ABSTRACT: Our objective was to identify new serum autoantibodies associated with systemic lupus erythematosus (SLE), focusing on those found in patients with central nervous system (CNS) syndromes. Autoantigens in human brain proteins were screened by multiple proteomic analyses: two-dimensional polyacrylamide gel electrophoresis/Western blots followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis and immunoprecipitation followed by liquid chromatography-tandem mass spectrometry shotgun analysis. The presence of serum IgG autoantibodies against 11 selected recombinant antigens was assessed by Western blot and enzyme-linked immunosorbent assay (ELISA) in the sera of 106 SLE patients and 100 normal healthy controls. The O.D. values in sera from SLE patients were significantly higher than those of controls for the antigens crystallin ?B (p = 0.0002), esterase D (p = 0.0002), APEX nuclease 1 (p < 0.0001), ribosomal protein P0 (p < 0.0001), and PA28? (p = 0.0005); the first three are newly reported. The anti-esterase D antibody levels were significantly higher in the CNS group than in the non-CNS group (p = 0.016). Moreover, when the SLE patients were categorized using CNS manifestations indicating neurologic or psychiatric disorders, the anti-APEX nuclease 1 antibody levels were significantly elevated in SLE patients with psychiatric disorders (p = 0.037). In conclusion, the association of SLE with several new and previously reported autoantibodies has been demonstrated. Statistically significant associations between anti-esterase D antibodies and CNS syndromes as well as between anti-APEX nuclease 1 antibodies and psychiatric disorders in SLE were also demonstrated. The combined immunoproteomic approaches used in this study are reliable and effective methods for identifying SLE autoantigens.

SUBMITTER: Katsumata Y

PROVIDER: S-EPMC3108835 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of three new autoantibodies associated with systemic lupus erythematosus using two proteomic approaches.

Katsumata Yasuhiro Y Kawaguchi Yasushi Y Baba Sayumi S Hattori Seisuke S Tahara Koji K Ito Kaori K Iwasaki Tadao T Yamaguchi Nozomi N Oyama Masaaki M Kozuka-Hata Hiroko H Hattori Hiroaki H Nagata Kinya K Yamanaka Hisashi H Hara Masako M

Molecular & cellular proteomics : MCP 20110407 6

Our objective was to identify new serum autoantibodies associated with systemic lupus erythematosus (SLE), focusing on those found in patients with central nervous system (CNS) syndromes. Autoantigens in human brain proteins were screened by multiple proteomic analyses: two-dimensional polyacrylamide gel electrophoresis/Western blots followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis and immunoprecipitation followed by liquid chromatography-tandem m ...[more]

PMID: 21474795

Similar Datasets

Project description:The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients (n = 86) compared to healthy controls (n = 30) (p < 0.0001 and p = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers (r s = 0.54, p < 0.0001) as well as with both IgG and IgM against β-2-glycoprotein I (anti-β2GPI; r s = 0.22, p = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA (p < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation (p = 0.04) and lupus nephritis (p = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-β2GPI-IgM (r s = 0.48, p < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: p = 0.01; aCL-IgM: p = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.

Project description:Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed.

Project description:Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption the GAPAID consortium examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n=211), with other systemic autoimmune diseases (n=65) and non-autoimmune control subjects (n=149) in two rheumatology tertiary care centers. Standard clinical and laboratory data were collected from all subjects and serum complement levels were determined in SLE patients. The genotype of SNP rs1143679 in the ITGAM gene was also determined. On-chip formation of immune complexes was examined using a functional immunoassay on autoantigen microarray. The amount of antigen-bound IgM, IgG and complement C4 and C3 was quantified on autoantigens comprising nucleic acids, proteins and lipids. Our results show that the relatively high complement consumption of nucleic acids is further increased upon binding of IgM and IgG. This is true even when serum complement levels are decreased due to complement consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, most protein and lipid autoantigens show positive correlation with C4 and C3 levels. Genetic analysis reveals that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) have lower levels of dsDNA specific IgM among SLE patients. Regarding organ involvement we find that besides anti-C1q IgG, low levels of dsDNA specific IgM and low complement C4 binding to C1q are also associated with renal injury. In summary, nucleic acids maintain a skewed complement deposition balance when bound by IgG and IgM, depleting the early classical complement pathway from other physiological processes. Dysfunction of the receptor responsible for complement-mediated apoptotic debris removal promotes the development of autoantibodies targeting nucleic acids. These observations provide serological and genetic evidence for complement-mediated clearance deficiency of apoptotic debris in lupus.

Dataset Information

Identification of three new autoantibodies associated with systemic lupus erythematosus using two proteomic approaches.

Publications

Identification of three new autoantibodies associated with systemic lupus erythematosus using two proteomic approaches.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure