Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis

Knevel, Rachel; Klein, Kerstin; Somers, Klaartje; Ospelt, Caroline; Houwing-Duistermaat, Jeanine J.; Nies, Jessica A B van; Rooy, D. P. C. de; Bock, Laura de; Kurreeman, Fina; Schonkeren, Joris; Stoeken-Rijsbergen, Gerrie; Helmer, Quinta; Linden, M. P. M. van der; Kern, Marlena; Manjarrez‐Orduño, Nataly; Rodriguez-Rodriquez, Luis; Stinissen, Piet; Huizinga, Tom W J; Toes, René E. M.; Gregersen, Peter K.; Somers, Veerle; Mil, Annette H M van der Helm-van

doi:10.1136/annrheumdis-2013-204050

Cited by 44 publications

(40 citation statements)

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“…Recent data reveal its presence in many tissues, including disease-relevant fibroblast-like synoviocytes in rheumatoid arthritis (15). In addition, the presence of multiple, not yet validated, SPAG16 isoforms increases the complexity.…”

Section: Discussionmentioning

confidence: 99%

“…Most research regarding SPAG16 has focused on its role in male fertility, but SPAG16 expression (either isoform) is not restricted to sperm cells. Recent data reveal its presence in many tissues, including other tissues with motile cilia such as the lungs and brain ventricles but also in hematopoietic cells in the bone marrow, fibroblast-like synoviocytes in rheumatoid arthritis, and in certain cancers (12)(13)(14)(15).…”

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confidence: 99%

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Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Bock

Somers

Fraussen

et al. 2014

The Journal of Immunology

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We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16—a protein with unknown function in the CNS—and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Bock

Somers

Fraussen

et al. 2014

The Journal of Immunology

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“…Three SNPs in the BRD2 locus were found to be associated with a subset of RA patients positive for citrullinated a-enolase peptide 1 and cyclic citrullinated peptides, independently of the HLA-DRB1 shared epitope alleles [40]. In addition, a SNP in the locus of another epigenetic reader protein, namely BRD1 (BRPF2) was shown to be protective in joint damage progression in stage I of a GWAS in ACPA þ RA patients [41]. Recently, therapeutic dosing of the BET inhibitor JQ1 was proven to be efficacious in two mouse models of autoimmunity, the models for CIA and for experimental autoimmune encephalomyelitis (EAE); BET inhibition suppressed the differentiation and activation of Th17 cells [42 && ].…”

Section: Targeting Epigenetic Reader Proteinsmentioning

confidence: 98%

Epigenetics in rheumatoid arthritis

Klein

2015

Current Opinion in Rheumatology

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PURPOSE OF REVIEW To give an overview of recently published articles addressing the role of epigenetic modifications in rheumatoid arthritis (RA). Here we focused on DNA methylation and posttranslational histone modifications. RECENT FINDINGS Recent studies attempted to link epigenetic modifications with genetic or environmental risk factors for RA. There is evidence that histone deacetylases confer effects of environmental triggers such as smoking, diet or therapy on expression levels of target genes. Additionally, disturbed methylation patterns and cell-type specific histone methylation marks were identified as potential mediators of genetic risk in RA. Altered methylome signatures were found in several cell types in RA, first of all RA synovial fibroblasts, and contribute to the intrinsic fibroblast activation. The reversal of DNA hypomethylation by inhibiting the polyamine recycling pathway was suggested as new epigenetic therapy in RA. Moreover, targeting epigenetic reader proteins, such as bromodomain proteins, emerged as a new field in drug development and the first studies underscored the potential of these drugs not only in malignant and inflammatory conditions but also in autoimmune diseases. SUMMARY Epigenetic factors represent a promising area to link genetics, regulation of gene expression and environmental risk factors. C URRENT OPINION Epigenetics in rheumatoid arthritis Kerstin Klein and Steffen GayPurpose of review To give an overview of recently published articles addressing the role of epigenetic modifications in rheumatoid arthritis (RA). Here we focused on DNA methylation and posttranslational histone modifications. Recent findingsRecent studies attempted to link epigenetic modifications with genetic or environmental risk factors for RA. There is evidence that histone deacetylases confer effects of environmental triggers such as smoking, diet or therapy on expression levels of target genes. Additionally, disturbed methylation patterns and cell-type specific histone methylation marks were identified as potential mediators of genetic risk in RA. Altered methylome signatures were found in several cell types in RA, first of all RA synovial fibroblasts, and contribute to the intrinsic fibroblast activation. The reversal of DNA hypomethylation by inhibiting the polyamine recycling pathway was suggested as new epigenetic therapy in RA. Moreover, targeting epigenetic reader proteins, such as bromodomain proteins, emerged as a new field in drug development and the first studies underscored the potential of these drugs not only in malignant and inflammatory conditions but also in autoimmune diseases. SummaryEpigenetic factors represent a promising area to link genetics, regulation of gene expression and environmental risk factors.

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“…For instance, key regulator FBN1 responsible for fibrosis and autoimmunity in mouse models of scleroderma is found as the homolog of fbl-1 in C. elegans, the putative target of DAF-12/VDR [10]. Another GWAS identified genetic variants for joint damage progression in autoantibody-positive rheumatoid arthritis (RA) and three key genes (sperm-associated antigen 16 (SPAG16), and Matrix Metallopeptidase1 and 3 (MMP1 and MMP3) [11]. They are among human homologue candidates of DAF-12/vitamin D receptor (VDR) target genes [2,7,8,12].…”

Section: One Of Our Recent Experiences Is As Followmentioning

confidence: 99%

Emerging Vitamin D Receptor-Centered Patterns of Genetic Overlap across Some Autoimmune Diseases and Associated Cancers

Zhang¹

2013

J Genet Syndr Gene Ther

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Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis

Abstract: Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.

Cited by 44 publications

References 31 publications

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Epigenetics in rheumatoid arthritis

Emerging Vitamin D Receptor-Centered Patterns of Genetic Overlap across Some Autoimmune Diseases and Associated Cancers

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