Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block

Salomonsson, Stina; Ottosson, Lars; Säfsten, Pär; Hof, Daniëlle; Brauner, Hanna; Sunnerhagen, Maria; Raats, Jos; Wahren‐Herlenius, Marie

doi:10.1016/j.jaut.2003.11.004

Cited by 21 publications

(19 citation statements)

References 40 publications

(49 reference statements)

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“…An even more compelling situation in SLE (and Sjögren's syndrome) is one where antibodies towards the immunodominant epitope (p200) of Ro52 are associated with neonatal heart block21 and where antibodies to this epitope can cause neonatal heart block in rodents in vivo22 and cause functional deficits in cardiac heart muscle cells in vitro 23…”

Section: Autoimmunity and Autoimmune Rheumatic Diseasesmentioning

confidence: 99%

Prevention of autoimmune rheumatic disease: state of the art and future perspectives

2010

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Prevention of disease can in principle be accomplished by identification of environmental and/or lifestyle risk and protective factors followed by public health measures (such as for smoking and lung cancer), or by modification of the individual's reactions to disease-inducing factors (such as in vaccinations against microbes). This review discusses both options based on emerging understanding of aetiologies in inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The major current opportunity for public health-based prevention lies in avoiding smoking. In RA, recent studies have calculated that, in Sweden (a country characterised by a low frequency of smoking), 20% of all RA cases and 33% of all cases of ACPA-positive RA would not have occurred in a smoke-free society. Smoking is also a major risk factor for SLE but no population attribution is yet available. New avenues for individualised and biology-based prevention are provided by the demonstration that several autoimmune rheumatic diseases are preceded by emergence of subclinical autoimmunity followed by laboratory-based signs of inflammation and finally overt disease. Examples of this process are provided from studies of autoimmunity to citrullinated proteins (in RA), to dsDNA (in SLE in general) and to Ro52 epitopes (in the case of neonatal heart block). The recognition of this sequence of events provides opportunities to intervene specifically and potentially curatively before onset of full-blown disease. Such prevention can be accomplished by modification of inciting antigens (environment), by modification of immunity (more or less specific immunomodulation) or by modification of specific gene functions. In all cases, prevention will be different in different subsets of disease and differ at different time points of disease development. Thus, the road map towards prevention of autoimmune rheumatic diseases includes increased understanding of how genes, environment and immunity interact.

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Section: Autoimmunity and Autoimmune Rheumatic Diseasesmentioning

confidence: 99%

Prevention of autoimmune rheumatic disease: state of the art and future perspectives

2010

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“…15 Autoantibodies to Ro52 are related to the development of congenital heart block, and patient-derived monoclonal antibodies against Ro52 have been shown to induce accumulating intracellular calcium levels in neonatal cardiomyocytes. [16][17][18] Interferon regulatory factor-8, a transcription factor that is important for the development and function of macrophages, was suggested as a substrate for Ro52 E3 ligase activity, 19 which functionally appears to regulate proliferation and cell death. 14 In view of these observations and since Ro52 comprises the common RBCC-SPRY domain arrangement, Ro52 provides an attractive molecular target for gaining insight into structure-function relationships in TRIM proteins.…”

Section: Introductionmentioning

confidence: 99%

The Fellowship of the RING: The RING–B-Box Linker Region Interacts with the RING in TRIM21/Ro52, Contains a Native Autoantigenic Epitope in Sjögren Syndrome, and is an Integral and Conserved Region in TRIM Proteins

Hennig

Bresell

Sandberg

et al. 2008

Journal of Molecular Biology

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“…The Ro52 coiled-coil contains a putative leucine-zipper between residues 211 and 232. Patient-derived monoclonal antibodies that bind to a peptide representing residues 200 -239 (p200) of the Ro52 protein cause accumulating intracellular calcium levels in neonatal cardiomyocytes and relate to the development of congenital heart block (3)(4)(5). Another antigenic epitope has been mapped to the N-terminal Zn 2ϩ -binding region of Ro52 (6) and was also suggested to relate to development of congenital heart block (7).…”

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confidence: 99%

Structural Organization and Zn2+-dependent Subdomain Interactions Involving Autoantigenic Epitopes in the Ring-B-box-Coiled-coil (RBCC) Region of Ro52

Hennig

Ottosson

Andrésen

et al. 2005

Journal of Biological Chemistry

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Ro52 is one of the major autoantigens targeted in the autoimmune disease Sjögren syndrome. By sequence similarity, Ro52 belongs to the RING-B-box-coiled-coil (RBCC) protein family. Disease-related antibodies bind Ro52 in a conformation-dependent way both in the coiled-coil region and in the Zn 2؉ -binding Ring-Bbox region. Primarily associated with Sjögren syndrome, Ro52 autoantibodies directed to a specific, partially structured epitope in the coiled-coil region may also induce a congenital heart block in the fetus of pregnant Ro52-positive mothers. To improve our understanding of the pathogenic effects of autoantibody binding to the Zn 2؉ -binding region, a multianalytical mapping of its structural, biophysical, and antigenic properties is presented. Structure content and ligand binding of subregions, dissected by peptide synthesis and subcloning, were analyzed by fluorescence and circular dichroism spectroscopy. A novel matrix-assisted laser desorption ionization time-of-flight mass spectrometry strategy for time-resolved proteolysis experiments of large protein domains was developed to facilitate analysis and to help resolve the tertiary arrangement of the entire RBCC subregion. The linker region between the RING and B-box motifs is crucial for full folding, and Zn 2؉ affinity of the RING-B-box region is further protected in the entire RBCC region and appears to interact with the coiled-coil region. Murine monoclonal antibodies raised toward the RING-B-box region were primarily directed toward the linker, further supporting a highly functional role for the linker in a cellular environment. Taken together with our previous analysis of autoantigenic epitopes in the coiled-coil region, localization of autoantigenic epitopes in Ro52 appears closely related to molecular functionalities.Ro52 is one of the main autoantigens in Sjögren syndrome, but autoantibodies to this intracellular protein occur also in systemic lupus erythematosus and rheumatoid arthritis (1). The immunodominant epitopes in Ro52 are predominantly localized in the structurally stable regions (2). The Ro52 coiled-coil contains a putative leucine-zipper between residues 211 and 232. Patient-derived monoclonal antibodies that bind to a peptide representing residues 200 -239 (p200) of the Ro52 protein cause accumulating intracellular calcium levels in neonatal cardiomyocytes and relate to the development of congenital heart block (3-5). Another antigenic epitope has been mapped to the N-terminal Zn 2ϩ -binding region of Ro52 (6) and was also suggested to relate to development of congenital heart block (7). However, the detailed location of the epitope in this 15-kDa region is yet unknown. The epitope is presumably conformation-dependent, because antigenicity is only observed in the reduced state (6), and because cysteines are conserved in the suggested Zn 2ϩ -binding sites. The reason why Ro52 is targeted in autoimmune disease is not known to date. Ro52 belongs to the rapidly growing RING/B-box/coiled-coil (RBCC) 2 family, also denoted as TRIM (trip...

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Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block

Cited by 21 publications

References 40 publications

Prevention of autoimmune rheumatic disease: state of the art and future perspectives

Prevention of autoimmune rheumatic disease: state of the art and future perspectives

The Fellowship of the RING: The RING–B-Box Linker Region Interacts with the RING in TRIM21/Ro52, Contains a Native Autoantigenic Epitope in Sjögren Syndrome, and is an Integral and Conserved Region in TRIM Proteins

Structural Organization and Zn2+-dependent Subdomain Interactions Involving Autoantigenic Epitopes in the Ring-B-box-Coiled-coil (RBCC) Region of Ro52

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