Unknown,Transcriptomics,Genomics,Proteomics

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Illumina Humanmethylation450k array analysis of human lymph node stromal cells during the earliest phases of rheumatoid arthritis

ABSTRACT: Lymph node stromal cells (LNSCs) are an important lymphoid tissue cellular type that regulates the immune response and maintain peripheral tolerance. In rheumatoid arthritis, break of tolerance and formation of autoantibodies occurs years before arthritis. Studies in mice have shown lymph nodes activation before the onset of arthritis. We hypothesize that malfunctioning of LNSCs leads to a microenvironment where immune responses are not properly controlled leading to activation of (autoreactive) lymphocytes and the production of autoantibodies. Here we studied human LNSCs and search for differentially methylated genes between RA versus healthy using Illumina human methylation arrays in order to identify new epigenetic targets.

ORGANISM(S): Homo sapiens

SUBMITTER: Emmanuel Karouzakis

PROVIDER: E-MTAB-8085 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Rheumatoid arthritis is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis. A total of 559 human sera were profiled using a custom made panel of putative rheumatoid arthritis associated autoantigens. The cohort was comprised of 79 patients with clinical RA for whom stored serum was available from 1-10 years prior to disease onset and 80 control subjects without RA that were matched to cases based on age, gender, race, region of assignment, and time of serum sampling.

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Illumina Humanmethylation450k array analysis of human lymph node stromal cells during the earliest phases of rheumatoid arthritis

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